Pharmaceutics

21 pages, 3750 KiB

Open AccessEditor’s ChoiceReview

An Insight on the Possible Association between Inflammatory Bowel Disease and Biologic Therapy with IL-17 Inhibitors in Psoriasis Patients

by Olguța Anca Orzan, Cristian George Țieranu, Andrei Ovidiu Olteanu, Alexandra Maria Dorobanțu, Anca Cojocaru, Mara Mădălina Mihai, Liliana Gabriela Popa, Ana Maria Gheorghiu, Călin Giurcăneanu and Ana Ion

Pharmaceutics 2023, 15(8), 2171; https://doi.org/10.3390/pharmaceutics15082171 - 21 Aug 2023

Cited by 3 | Viewed by 1894

Abstract

Psoriasis is a chronic, inflammatory, multisystemic disease which affects approximately 2–3% of the population globally, whose onset is triggered by genetic and environmental factors which activate both dendritic cells and keratinocytes, resulting in the production of proinflammatory cytokines such as tumor necrosis factor [...] Read more.

Psoriasis is a chronic, inflammatory, multisystemic disease which affects approximately 2–3% of the population globally, whose onset is triggered by genetic and environmental factors which activate both dendritic cells and keratinocytes, resulting in the production of proinflammatory cytokines such as tumor necrosis factor alpha, interleukin 17, interleukin 23, interleukin 22, and interleukin 1β. An in-depth understanding of the pathophysiology of psoriasis led to significant advances in the development of safe and efficient novel therapeutic options, with four classes of biologic therapy being approved for the management of moderate to severe psoriasis: tumor necrosis factor alpha inhibitors, interleukin 23 inhibitors, anti-interleukin 12/23 agents, anti-interleukin 17 agents, as well as small-molecule inhibitors, such as apremilast. Psoriasis is associated with comorbid conditions, namely psoriatic arthritis, cardiovascular disease, metabolic syndrome, psychiatric disorders, malignancy, as well as inflammatory bowel disease. For patients affected by both psoriasis and inflammatory bowel disease, there is a strong recommendation to avoid IL-17 inhibitors since they may play a part in the exacerbation of the gastrointestinal disease. Our aim was to perform a thorough literature review regarding the development of inflammatory bowel disease lesions in psoriasis patients treated with IL-17 inhibitors, along with a case presentation to emphasize the need for close follow-up of these patients. Full article

(This article belongs to the Special Issue Targeted Therapies for Skin Diseases)

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36 pages, 2575 KiB

Open AccessEditor’s ChoiceReview

Drug Repurposing to Circumvent Immune Checkpoint Inhibitor Resistance in Cancer Immunotherapy

by Kenneth K. W. To and William C. Cho

Pharmaceutics 2023, 15(8), 2166; https://doi.org/10.3390/pharmaceutics15082166 - 21 Aug 2023

Cited by 2 | Viewed by 2300

Abstract

Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of [...] Read more.

Immune checkpoint inhibitors (ICI) have achieved unprecedented clinical success in cancer treatment. However, drug resistance to ICI therapy is a major hurdle that prevents cancer patients from responding to the treatment or having durable disease control. Drug repurposing refers to the application of clinically approved drugs, with characterized pharmacological properties and known adverse effect profiles, to new indications. It has also emerged as a promising strategy to overcome drug resistance. In this review, we summarized the latest research about drug repurposing to overcome ICI resistance. Repurposed drugs work by either exerting immunostimulatory activities or abolishing the immunosuppressive tumor microenvironment (TME). Compared to the de novo drug design strategy, they provide novel and affordable treatment options to enhance cancer immunotherapy that can be readily evaluated in the clinic. Biomarkers are exploited to identify the right patient population to benefit from the repurposed drugs and drug combinations. Phenotypic screening of chemical libraries has been conducted to search for T-cell-modifying drugs. Genomics and integrated bioinformatics analysis, artificial intelligence, machine and deep learning approaches are employed to identify novel modulators of the immunosuppressive TME. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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27 pages, 6312 KiB

Open AccessEditor’s ChoiceReview

Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday with a Targeted Payload

by Aleksei Kondrashov, Surendra Sapkota, Aditya Sharma, Ivy Riano, Razelle Kurzrock and Jacob J. Adashek

Pharmaceutics 2023, 15(8), 2160; https://doi.org/10.3390/pharmaceutics15082160 - 19 Aug 2023

Cited by 1 | Viewed by 3085

Abstract

Antibody–drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components—an antibody, a linker molecule, and a cytotoxic agent (“payload”), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific [...] Read more.

Antibody–drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components—an antibody, a linker molecule, and a cytotoxic agent (“payload”), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs’ effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies. Full article

(This article belongs to the Section Drug Targeting and Design)

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22 pages, 2692 KiB

Open AccessEditor’s ChoiceReview

Exploring the Antioxidant Potential of Gellan and Guar Gums in Wound Healing

by Gianina Dodi, Rosina E. Sabau, Bianca E.-B. Crețu and Ioannis Gardikiotis

Pharmaceutics 2023, 15(8), 2152; https://doi.org/10.3390/pharmaceutics15082152 - 17 Aug 2023

Cited by 3 | Viewed by 1716

Abstract

It is acknowledged that the presence of antioxidants boosts the wound-healing process. Many biopolymers have been explored over the years for their antioxidant potential in wound healing, but limited research has been performed on gum structures and their derivatives. This review aims to [...] Read more.

It is acknowledged that the presence of antioxidants boosts the wound-healing process. Many biopolymers have been explored over the years for their antioxidant potential in wound healing, but limited research has been performed on gum structures and their derivatives. This review aims to evaluate whether the antioxidant properties of gellan and guar gums and wound healing co-exist. PubMed was the primary platform used to explore published reports on the antioxidant wound-healing interconnection, wound dressings based on gellan and guar gum, as well as the latest review papers on guar gum. The literature search disclosed that some wound-healing supports based on gellan gum hold considerable antioxidant properties, as evident from the results obtained using different antioxidant assays. It has emerged that the antioxidant properties of guar gum are overlooked in the wound-healing field, in most cases, even if this feature improves the healing outcome. This review paper is the first that examines guar gum vehicles throughout the wound-healing process. Further research is needed to design and evaluate customized wound dressings that can scavenge excess reactive oxygen species, especially in clinical practice. Full article

(This article belongs to the Special Issue The Study of Plant Compounds in Antioxidant Activity and Anticancer Activity)

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20 pages, 4967 KiB

Open AccessEditor’s ChoiceArticle

Antibiofilm Effect of Lavandula multifida Essential Oil: A New Approach for Chronic Infections

by Jorge Alves-Silva, Mónica Zuzarte, Carlos Cavaleiro and Lígia Salgueiro

Pharmaceutics 2023, 15(8), 2142; https://doi.org/10.3390/pharmaceutics15082142 - 15 Aug 2023

Cited by 3 | Viewed by 1329

Abstract

Fungal infections are associated with high morbidity and mortality rates, being highly prevalent in patients with underlying health complications such as chronic lung disease, HIV, cancer, and diabetes mellitus. To mitigate these infections, the development of effective antifungals is imperative, with plants standing [...] Read more.

Fungal infections are associated with high morbidity and mortality rates, being highly prevalent in patients with underlying health complications such as chronic lung disease, HIV, cancer, and diabetes mellitus. To mitigate these infections, the development of effective antifungals is imperative, with plants standing out as promising sources of bioactive compounds. In the present study, we focus on the antibiofilm potential of Lavandula multifida essential oil (EO) against dermatophyte strains and Candida albicans. The EO was characterized using GC and GC–MS, and its antifungal effect was assessed on both biofilm formation and disruption. Biofilm mass, extracellular matrix, and viability were quantified using crystal violet, safranin, and XTT assays, respectively, and morphological alterations were confirmed using optical and scanning electron microscopy. L. multifida EO showed very high amounts of carvacrol and was very effective in inhibiting and disrupting fungal biofilms. The EO significantly decreased biofilm mass and viability in all tested fungi. In addition, a reduction in dermatophytes’ extracellular matrix was observed, particularly during biofilm formation. Morphological alterations were evident in mature biofilms, with a clear decrease in hypha diameter. These promising results support the use of L. multifida EO in the development of effective plant-based antifungal products. Full article

(This article belongs to the Special Issue Essential Oil in Pharmaceutical Products for the Management of Chronic Diseases)

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17 pages, 2749 KiB

Open AccessEditor’s ChoiceArticle

Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab

by Blaise Pasquiers, Salih Benamara, Mathieu Felices, David Ternant, Xavier Declèves and Alicja Puszkiel

Pharmaceutics 2023, 15(8), 2129; https://doi.org/10.3390/pharmaceutics15082129 - 14 Aug 2023

Viewed by 1708

Abstract

Interspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide better prediction of TMDD regarding [...] Read more.

Interspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide better prediction of TMDD regarding inter-species translation during preclinical and clinical development steps of mAbs. The objective of this study was to develop a generic PBPK translational approach for mAbs using the open-source software (PK-Sim^® and Mobi^®). The translation of bevacizumab based on data in non-human primates (NHP), healthy volunteers (HV), and cancer patients was used as a case example for model demonstration purpose. A PBPK model for bevacizumab concentration-time data was developed using data from literature and the Open Systems Pharmacology (OSP) Suite version 10. PK-sim^® was used to build the linear part of bevacizumab PK (mainly FcRn-mediated), whereas MoBi^® was used to develop the target-mediated part. The model was first developed for NHP and used for a priori PK prediction in HV. Then, the refined model obtained in HV was used for a priori prediction in cancer patients. A priori predictions were within 2-fold prediction error (predicted/observed) for both area under the concentration-time curve (AUC) and maximum concentration (C_max) and all the predicted concentrations were within 2-fold average fold error (AFE) and average absolute fold error (AAFE). Sensitivity analysis showed that FcRn-mediated distribution and elimination processes must be accounted for at all mAb concentration levels, whereas the lower the mAb concentration, the more significant the target-mediated elimination. This project is the first step to generalize the full PBPK translational approach in Model-Informed Drug Development (MIDD) of mAbs using OSP Suite. Full article

(This article belongs to the Special Issue Applications of Physiologically-Based Pharmacokinetic (PBPK) Modeling, 2nd Edition)

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20 pages, 2401 KiB

Open AccessEditor’s ChoiceReview

The Value of Microbes in Cancer Neoantigen Immunotherapy

by Junrui Tian and Jian Ma

Pharmaceutics 2023, 15(8), 2138; https://doi.org/10.3390/pharmaceutics15082138 - 14 Aug 2023

Viewed by 1533

Abstract

Tumor neoantigens are widely used in cancer immunotherapy, and a growing body of research suggests that microbes play an important role in these neoantigen-based immunotherapeutic processes. The human body and its surrounding environment are filled with a large number of microbes that are [...] Read more.

Tumor neoantigens are widely used in cancer immunotherapy, and a growing body of research suggests that microbes play an important role in these neoantigen-based immunotherapeutic processes. The human body and its surrounding environment are filled with a large number of microbes that are in long-term interaction with the organism. The microbiota can modulate our immune system, help activate neoantigen-reactive T cells, and play a great role in the process of targeting tumor neoantigens for therapy. Recent studies have revealed the interconnection between microbes and neoantigens, which can cross-react with each other through molecular mimicry, providing theoretical guidance for more relevant studies. The current applications of microbes in immunotherapy against tumor neoantigens are mainly focused on cancer vaccine development and immunotherapy with immune checkpoint inhibitors. This article summarizes the related fields and suggests the importance of microbes in immunotherapy against neoantigens. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

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17 pages, 796 KiB

Open AccessEditor’s ChoiceReview

Targeting EGFR/PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma

by Jieun Bang, Mihyeon Jun, Soyun Lee, Hyuk Moon and Simon Weonsang Ro

Pharmaceutics 2023, 15(8), 2130; https://doi.org/10.3390/pharmaceutics15082130 - 14 Aug 2023

Cited by 9 | Viewed by 2399

Abstract

Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways [...] Read more.

Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways that play central roles in hepatocarcinogenesis. In particular, the EGFR/PI3K/AKT/mTOR signaling pathway in HCC has garnered renewed attention from both basic and clinical researchers. Preclinical studies in vitro and in vivo have shown the effectiveness of targeting the key components of this signaling pathway in human HCC cells. Thus, targeting these signaling pathways with small molecule inhibitors holds promise as a potential therapeutic option for patients with HCC. In this review, we explore recent advancements in understanding the role of the EGFR/PI3K/AKT/mTOR signaling pathway in HCC and assess the effectiveness of targeting this signaling cascade as a potential strategy for HCC therapy based on preclinical studies. Full article

(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy)

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27 pages, 6464 KiB

Open AccessEditor’s ChoiceArticle

New Imidazolium Alkaloids with Broad Spectrum of Action from the Marine Bacterium Shewanella aquimarina

by Rosa Giugliano, Gerardo Della Sala, Carmine Buonocore, Carla Zannella, Pietro Tedesco, Fortunato Palma Esposito, Costanza Ragozzino, Annalisa Chianese, Maria Vittoria Morone, Valerio Mazzella, Laura Núñez-Pons, Veronica Folliero, Gianluigi Franci, Anna De Filippis, Massimiliano Galdiero and Donatella de Pascale

Pharmaceutics 2023, 15(8), 2139; https://doi.org/10.3390/pharmaceutics15082139 - 14 Aug 2023

Viewed by 1405

Abstract

The continuous outbreak of drug-resistant bacterial and viral infections imposes the need to search for new drug candidates. Natural products from marine bacteria still inspire the design of pharmaceuticals. Indeed, marine bacteria have unique metabolic flexibility to inhabit each ecological niche, thus expanding [...] Read more.

The continuous outbreak of drug-resistant bacterial and viral infections imposes the need to search for new drug candidates. Natural products from marine bacteria still inspire the design of pharmaceuticals. Indeed, marine bacteria have unique metabolic flexibility to inhabit each ecological niche, thus expanding their biosynthetic ability to assemble unprecedented molecules. The One-Strain-Many-Compounds approach and tandem mass spectrometry allowed the discovery of a Shewanella aquimarina strain as a source of novel imidazolium alkaloids via molecular networking. The alkaloid mixture was shown to exert bioactivities such as: (a) antibacterial activity against antibiotic-resistant Staphylococcus aureus clinical isolates at 100 µg/mL, (b) synergistic effects with tigecycline and linezolid, (c) restoration of MRSA sensitivity to fosfomycin, and (d) interference with the biofilm formation of S. aureus 6538 and MRSA. Moreover, the mixture showed antiviral activity against viruses with and without envelopes. Indeed, it inhibited the entry of coronavirus HcoV-229E and herpes simplex viruses into human cells and inactivated poliovirus PV-1 in post-infection assay at 200 µg/mL. Finally, at the same concentration, the fraction showed anthelminthic activity against Caenorhabditis elegans, causing 99% mortality after 48 h. The broad-spectrum activities of these compounds are partially due to their biosurfactant behavior and make them promising candidates for breaking down drug-resistant infectious diseases. Full article

(This article belongs to the Special Issue Recent Advances in Biotechnological Applications of Microbial Surfactants)

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22 pages, 4061 KiB

Open AccessEditor’s ChoiceArticle

Cinnamyl-Modified Polyglycidol/Poly(ε-Caprolactone) Block Copolymer Nanocarriers for Enhanced Encapsulation and Prolonged Release of Cannabidiol

by Natalia Toncheva-Moncheva, Erik Dimitrov, Georgi Grancharov, Denitsa Momekova, Petar Petrov and Stanislav Rangelov

Pharmaceutics 2023, 15(8), 2128; https://doi.org/10.3390/pharmaceutics15082128 - 13 Aug 2023

Cited by 2 | Viewed by 1341

Abstract

The present study describes the development of novel block copolymer nanocarriers of the phytocannabinoid cannabidiol (CBD), designed to enhance the solubility of the drug in water while achieving high encapsulation efficiency and prolonged drug release. Firstly, a well-defined amphiphilic block copolymer consisting of [...] Read more.

The present study describes the development of novel block copolymer nanocarriers of the phytocannabinoid cannabidiol (CBD), designed to enhance the solubility of the drug in water while achieving high encapsulation efficiency and prolonged drug release. Firstly, a well-defined amphiphilic block copolymer consisting of two outer hydrophilic polyglycidol (PG) blocks and a middle hydrophobic block of poly(ε-caprolactone) bearing pendant cinnamyl moieties (P(CyCL-co-CL)) were synthesized by the click coupling reaction of PG-monoalkyne and P(CyCL-co-CL)-diazide functional macroreagents. A non-modified polyglycidol/poly(ε-caprolactone) amphiphilic block copolymer was obtained as a referent system. Micellar carriers based on the two block copolymers were formed via the solvent evaporation method and loaded with CBD following two different protocols—loading during micelle formation and loading into preformed micelles. The key parameters/characteristics of blank and CBD-loaded micelles such as size, size distribution, zeta potential, molar mass, critical micelle concentration, morphology, and encapsulation efficiency were determined by using dynamic and static multiangle and electrophoretic light scattering, transmission electron microscopy, and atomic force microscopy. Embedding CBD into the micellar carriers affected their hydrodynamic radii to some extent, while the spherical morphology of particles was not changed. The nanoformulation based on the copolymer bearing cinnamyl moieties possessed significantly higher encapsulation efficiency and a slower rate of drug release than the non-modified copolymer. The comparative assessment of the antiproliferative effect of micellar CBD vs. the free drug against the acute myeloid leukemia-derived HL-60 cell line and Sezary Syndrome HUT-78 demonstrated that the newly developed systems have pronounced antitumor activity. Full article

(This article belongs to the Special Issue Application of Polymeric Micelles for Drug and Gene Delivery)

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16 pages, 8999 KiB

Open AccessEditor’s ChoiceArticle

Protopanaxadiol-Enriched Rice Exerted Antiadipogenic Activity during 3T3-L1 Differentiation and Anti-Inflammatory Activity in 3T3-L1 Adipocytes

by Chaiwat Monmai, Jin-Suk Kim, Hyun Bo Sim, Doh-Won Yun, Sung-Dug Oh, Eui-Shik Rha, Jong-Jin Kim and So-Hyeon Baek

Pharmaceutics 2023, 15(8), 2123; https://doi.org/10.3390/pharmaceutics15082123 - 11 Aug 2023

Viewed by 1066

Abstract

Ginseng is a traditional medicine with health benefits for humans. Protopanaxadiol (PPD) is an important bioactive compound found in ginseng. Transgenic rice containing PPD has been generated previously. In the present study, extracts of this transgenic rice were evaluated to assess their antiadipogenic [...] Read more.

Ginseng is a traditional medicine with health benefits for humans. Protopanaxadiol (PPD) is an important bioactive compound found in ginseng. Transgenic rice containing PPD has been generated previously. In the present study, extracts of this transgenic rice were evaluated to assess their antiadipogenic and anti-inflammatory activities. During adipogenesis, cells were treated with transgenic rice seed extracts. The results revealed that the concentrations of the rice seed extracts tested in this study did not affect cell viability at 3 days post-treatment. However, the rice seed extracts significantly reduced the accumulation of lipids in cells and suppressed the activation of CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ), which in turn inhibited the expression of adipogenesis-related mRNAs, such as adiponectin, PPARγ, C/EBPα, sterol regulatory element-binding protein 1, glucose transport member 4, and fatty acid synthase. In adipocytes, the extracts significantly reduced the mRNA expression of inflammation-related factors following LPS treatment. The activation of NF-κB p65 and ERK 1/2 was inhibited in extract-treated adipocytes. Moreover, treatment with extract #8 markedly reduced the cell population of the G2/M phase. Collectively, these results indicate that transgenic rice containing PPD may act as an obesity-reducing and/or -preventing agent. Full article

(This article belongs to the Special Issue Anti-inflammatory Effects from Natural Bioactive Compounds—from Bench to Bedside, 2nd Edition)

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42 pages, 5191 KiB

Open AccessEditor’s ChoiceReview

Photosensitizers-Loaded Nanocarriers for Enhancement of Photodynamic Therapy in Melanoma Treatment

by Ana Maria Udrea, Adriana Smarandache, Andra Dinache, Catalina Mares, Simona Nistorescu, Speranta Avram and Angela Staicu

Pharmaceutics 2023, 15(8), 2124; https://doi.org/10.3390/pharmaceutics15082124 - 11 Aug 2023

Cited by 11 | Viewed by 2508

Abstract

Malignant melanoma poses a significant global health burden. It is the most aggressive and lethal form of skin cancer, attributed to various risk factors such as UV radiation exposure, genetic modifications, chemical carcinogens, immunosuppression, and fair complexion. Photodynamic therapy is a promising minimally [...] Read more.

Malignant melanoma poses a significant global health burden. It is the most aggressive and lethal form of skin cancer, attributed to various risk factors such as UV radiation exposure, genetic modifications, chemical carcinogens, immunosuppression, and fair complexion. Photodynamic therapy is a promising minimally invasive treatment that uses light to activate a photosensitizer, resulting in the formation of reactive oxygen species, which ultimately promote cell death. When selecting photosensitizers for melanoma photodynamic therapy, the presence of melanin should be considered. Melanin absorbs visible radiation similar to most photosensitizers and has antioxidant properties, which undermines the reactive species generated in photodynamic therapy processes. These characteristics have led to further research for new photosensitizing platforms to ensure better treatment results. The development of photosensitizers has advanced with the use of nanotechnology, which plays a crucial role in enhancing solubility, optical absorption, and tumour targeting. This paper reviews the current approaches (that use the synergistic effect of different photosensitizers, nanocarriers, chemotherapeutic agents) in the photodynamic therapy of melanoma. Full article

(This article belongs to the Special Issue Applications of Nanotechnology for Melanoma Treatment and Diagnosis)

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30 pages, 2546 KiB

Open AccessEditor’s ChoiceReview

Contemporary Aspects of Designing Marine Polysaccharide Microparticles as Drug Carriers for Biomedical Application

by Paolina Lukova and Plamen Katsarov

Pharmaceutics 2023, 15(8), 2126; https://doi.org/10.3390/pharmaceutics15082126 - 11 Aug 2023

Cited by 3 | Viewed by 1383

Abstract

The main goal of modern pharmaceutical technology is to create new drug formulations that are safer and more effective. These formulations should allow targeted drug delivery, improved drug stability and bioavailability, fewer side effects, and reduced drug toxicity. One successful approach for achieving [...] Read more.

The main goal of modern pharmaceutical technology is to create new drug formulations that are safer and more effective. These formulations should allow targeted drug delivery, improved drug stability and bioavailability, fewer side effects, and reduced drug toxicity. One successful approach for achieving these objectives is using polymer microcarriers for drug delivery. They are effective for treating various diseases through different administration routes. When creating pharmaceutical systems, choosing the right drug carrier is crucial. Biomaterials have become increasingly popular over the past few decades due to their lack of toxicity, renewable sources, and affordability. Marine polysaccharides, in particular, have been widely used as substitutes for synthetic polymers in drug carrier applications. Their inherent properties, such as biodegradability and biocompatibility, make marine polysaccharide-based microcarriers a prospective platform for developing drug delivery systems. This review paper explores the principles of microparticle design using marine polysaccharides as drug carriers. By reviewing the current literature, the paper highlights the challenges of formulating polymer microparticles, and proposes various technological solutions. It also outlines future perspectives for developing marine polysaccharides as drug microcarriers. Full article

(This article belongs to the Special Issue Carbohydrate-Based Carriers for Drug Delivery)

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23 pages, 6453 KiB

Open AccessEditor’s ChoiceReview

Biopolymers and Their Application in Bioprinting Processes for Dental Tissue Engineering

by Suhon Kim, Hanjun Hwangbo, SooJung Chae and Hyeongjin Lee

Pharmaceutics 2023, 15(8), 2118; https://doi.org/10.3390/pharmaceutics15082118 - 10 Aug 2023

Cited by 7 | Viewed by 1713

Abstract

Dental tissues are composed of multiple tissues with complex organization, such as dentin, gingiva, periodontal ligament, and alveolar bone. These tissues have different mechanical and biological properties that are essential for their functions. Therefore, dental diseases and injuries pose significant challenges for restorative [...] Read more.

Dental tissues are composed of multiple tissues with complex organization, such as dentin, gingiva, periodontal ligament, and alveolar bone. These tissues have different mechanical and biological properties that are essential for their functions. Therefore, dental diseases and injuries pose significant challenges for restorative dentistry, as they require innovative strategies to regenerate damaged or missing dental tissues. Biomimetic bioconstructs that can effectively integrate with native tissues and restore their functionalities are desirable for dental tissue regeneration. However, fabricating such bioconstructs is challenging due to the diversity and complexity of dental tissues. This review provides a comprehensive overview of the recent developments in polymer-based tissue engineering and three-dimensional (3D) printing technologies for dental tissue regeneration. It also discusses the current state-of-the-art, focusing on key techniques, such as polymeric biomaterials and 3D printing with or without cells, used in tissue engineering for dental tissues. Moreover, the final section of this paper identifies the challenges and future directions of this promising research field. Full article

(This article belongs to the Special Issue Recent Advances in Hydrogels for Biomedical Applications)

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39 pages, 2743 KiB

Open AccessEditor’s ChoiceReview

Non-Invasive Vaccines: Challenges in Formulation and Vaccine Adjuvants

by Sumin Han, Panjae Lee and Hyo-Jick Choi

Pharmaceutics 2023, 15(8), 2114; https://doi.org/10.3390/pharmaceutics15082114 - 9 Aug 2023

Cited by 2 | Viewed by 1584

Abstract

Given the limitations of conventional invasive vaccines, such as the requirement for a cold chain system and trained personnel, needle-based injuries, and limited immunogenicity, non-invasive vaccines have gained significant attention. Although numerous approaches for formulating and administrating non-invasive vaccines have emerged, each of [...] Read more.

Given the limitations of conventional invasive vaccines, such as the requirement for a cold chain system and trained personnel, needle-based injuries, and limited immunogenicity, non-invasive vaccines have gained significant attention. Although numerous approaches for formulating and administrating non-invasive vaccines have emerged, each of them faces its own challenges associated with vaccine bioavailability, toxicity, and other issues. To overcome such limitations, researchers have created novel supplementary materials and delivery systems. The goal of this review article is to provide vaccine formulation researchers with the most up-to-date information on vaccine formulation and the immunological mechanisms available, to identify the technical challenges associated with the commercialization of non-invasive vaccines, and to guide future research and development efforts. Full article

(This article belongs to the Special Issue Non-invasive Biopharmaceutical/Vaccine Delivery Systems and Formulation Strategies)

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25 pages, 3855 KiB

Open AccessEditor’s ChoiceReview

Pluronic F-68 and F-127 Based Nanomedicines for Advancing Combination Cancer Therapy

by Nisar Ul Khaliq, Juyeon Lee, Sangwoo Kim, Daekyung Sung and Hyungjun Kim

Pharmaceutics 2023, 15(8), 2102; https://doi.org/10.3390/pharmaceutics15082102 - 9 Aug 2023

Cited by 16 | Viewed by 4953

Abstract

Pluronics are amphiphilic triblock copolymers composed of two hydrophilic poly (ethylene oxide) (PEO) chains linked via a central hydrophobic polypropylene oxide (PPO). Owing to their low molecular weight polymer and greater number of PEO segments, Pluronics induce micelle formation and gelation at critical [...] Read more.

Pluronics are amphiphilic triblock copolymers composed of two hydrophilic poly (ethylene oxide) (PEO) chains linked via a central hydrophobic polypropylene oxide (PPO). Owing to their low molecular weight polymer and greater number of PEO segments, Pluronics induce micelle formation and gelation at critical micelle concentrations and temperatures. Pluronics F-68 and F-127 are the only United States (U.S.) FDA-approved classes of Pluronics and have been extensively used as materials for living bodies. Owing to the fascinating characteristics of Pluronics, many studies have suggested their role in biomedical applications, such as drug delivery systems, tissue regeneration scaffolders, and biosurfactants. As a result, various studies have been performed using Pluronics as a tool in nanomedicine and targeted delivery systems. This review sought to describe the delivery of therapeutic cargos using Pluronic F-68 and F-127-based cancer nanomedicines and their composites for combination therapy. Full article

(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)

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19 pages, 1146 KiB

Open AccessEditor’s ChoiceReview

Cavitation-Mediated Immunomodulation and Its Use with Checkpoint Inhibitors

by Matilde Maardalen, Robert Carlisle and Constantin Coussios

Pharmaceutics 2023, 15(8), 2110; https://doi.org/10.3390/pharmaceutics15082110 - 9 Aug 2023

Cited by 3 | Viewed by 1682

Abstract

The promotion of anti-tumour immune responses can be an effective route to the complete remission of primary and metastatic tumours in a small proportion of patients. Hence, researchers are currently investigating various methods to further characterise and enhance such responses to achieve a [...] Read more.

The promotion of anti-tumour immune responses can be an effective route to the complete remission of primary and metastatic tumours in a small proportion of patients. Hence, researchers are currently investigating various methods to further characterise and enhance such responses to achieve a beneficial impact across a wider range of patients. Due to its non-invasive, non-ionising, and targetable nature, the application of ultrasound-mediated cavitation has proven to be a popular method to enhance the delivery and activity of immune checkpoint inhibitors. However, to optimise this approach, it is important to understand the biological and physical mechanisms by which cavitation may promote anti-tumour immune responses. Here, the published literature relating to the role that cavitation may play in modulating anti-tumour immunity is therefore assessed. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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38 pages, 3331 KiB

Open AccessEditor’s ChoiceReview

Light-Based Anti-Biofilm and Antibacterial Strategies

by Ambreen Kauser, Emilio Parisini, Giulia Suarato and Rossella Castagna

Pharmaceutics 2023, 15(8), 2106; https://doi.org/10.3390/pharmaceutics15082106 - 9 Aug 2023

Cited by 4 | Viewed by 2749

Abstract

Biofilm formation and antimicrobial resistance pose significant challenges not only in clinical settings (i.e., implant-associated infections, endocarditis, and urinary tract infections) but also in industrial settings and in the environment, where the spreading of antibiotic-resistant bacteria is on the rise. Indeed, developing effective [...] Read more.

Biofilm formation and antimicrobial resistance pose significant challenges not only in clinical settings (i.e., implant-associated infections, endocarditis, and urinary tract infections) but also in industrial settings and in the environment, where the spreading of antibiotic-resistant bacteria is on the rise. Indeed, developing effective strategies to prevent biofilm formation and treat infections will be one of the major global challenges in the next few years. As traditional pharmacological treatments are becoming inadequate to curb this problem, a constant commitment to the exploration of novel therapeutic strategies is necessary. Light-triggered therapies have emerged as promising alternatives to traditional approaches due to their non-invasive nature, precise spatial and temporal control, and potential multifunctional properties. Here, we provide a comprehensive overview of the different biofilm formation stages and the molecular mechanism of biofilm disruption, with a major focus on the quorum sensing machinery. Moreover, we highlight the principal guidelines for the development of light-responsive materials and photosensitive compounds. The synergistic effects of combining light-triggered therapies with conventional treatments are also discussed. Through elegant molecular and material design solutions, remarkable results have been achieved in the fight against biofilm formation and antibacterial resistance. However, further research and development in this field are essential to optimize therapeutic strategies and translate them into clinical and industrial applications, ultimately addressing the global challenges posed by biofilm and antimicrobial resistance. Full article

(This article belongs to the Special Issue Design and Characterization of Functional, Light-Responsive Materials for Drug Delivery and Tissue Engineering)

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26 pages, 65668 KiB

Open AccessEditor’s ChoiceReview

An Overview of Stimuli-Responsive Intelligent Antibacterial Nanomaterials

by Jinqiao Zhang, Wantao Tang, Xinyi Zhang, Zhiyong Song and Ting Tong

Pharmaceutics 2023, 15(8), 2113; https://doi.org/10.3390/pharmaceutics15082113 - 9 Aug 2023

Cited by 5 | Viewed by 1957

Abstract

Drug-resistant bacteria and infectious diseases associated with biofilms pose a significant global health threat. The integration and advancement of nanotechnology in antibacterial research offer a promising avenue to combat bacterial resistance. Nanomaterials possess numerous advantages, such as customizable designs, adjustable shapes and sizes, [...] Read more.

Drug-resistant bacteria and infectious diseases associated with biofilms pose a significant global health threat. The integration and advancement of nanotechnology in antibacterial research offer a promising avenue to combat bacterial resistance. Nanomaterials possess numerous advantages, such as customizable designs, adjustable shapes and sizes, and the ability to synergistically utilize multiple active components, allowing for precise targeting based on specific microenvironmental variations. They serve as a promising alternative to antibiotics with diverse medical applications. Here, we discuss the formation of bacterial resistance and antibacterial strategies, and focuses on utilizing the distinctive physicochemical properties of nanomaterials to achieve inherent antibacterial effects by investigating the mechanisms of bacterial resistance. Additionally, we discuss the advancements in developing intelligent nanoscale antibacterial agents that exhibit responsiveness to both endogenous and exogenous responsive stimuli. These nanomaterials hold potential for enhanced antibacterial efficacy by utilizing stimuli such as pH, temperature, light, or ultrasound. Finally, we provide a comprehensive outlook on the existing challenges and future clinical prospects, offering valuable insights for the development of safer and more effective antibacterial nanomaterials. Full article

(This article belongs to the Special Issue Antimicrobial Agents Based on Nanomaterials)

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14 pages, 1519 KiB

Open AccessEditor’s ChoiceArticle

Ampicillin Stability in a Portable Elastomeric Infusion Pump: A Step Forward in Outpatient Parenteral Antimicrobial Therapy

by Lorena Rodríguez-Martínez, Ana Castro-Balado, Gonzalo Hermelo-Vidal, Enrique Bandín-Vilar, Iria Varela-Rey, Francisco José Toja-Camba, Teresa Rodríguez-Jato, Ignacio Novo-Veleiro, Pablo Manuel Varela-García, Irene Zarra-Ferro, Miguel González-Barcia, Cristina Mondelo-García, Jesús Mateos and Anxo Fernández-Ferreiro

Pharmaceutics 2023, 15(8), 2099; https://doi.org/10.3390/pharmaceutics15082099 - 8 Aug 2023

Viewed by 2147

Abstract

Outpatient parenteral antimicrobial therapy (OPAT) with continuous infusion pumps is postulated as a very promising solution to treat complicated infections, such as endocarditis or osteomyelitis, that require patients to stay in hospital during extended periods of time, thus reducing their quality of life [...] Read more.

Outpatient parenteral antimicrobial therapy (OPAT) with continuous infusion pumps is postulated as a very promising solution to treat complicated infections, such as endocarditis or osteomyelitis, that require patients to stay in hospital during extended periods of time, thus reducing their quality of life and increasing the risk of complications. However, stability studies of drugs in elastomeric devices are scarce, which limits their use in OPAT. Therefore, we evaluated the stability of ampicillin in sodium chloride 0.9% at two different concentrations, 50 and 15 mg/mL, in an elastomeric infusion pump when stored in the refrigerator and subsequently in real-life conditions at two different temperatures, 25 and 32 °C, with and without the use of a cooling device. The 15 mg/mL ampicillin is stable for up to 72 h under refrigeration, allowing subsequent dosing at 25 °C for 24 h with and without a cooling device, but at 32 °C its concentration drops below 90% after 8 h. In contrast, 50 mg/mL ampicillin only remains stable for the first 24 h under refrigeration, and subsequent administration at room temperature is not possible, even with the use of a cooling system. Our data support that 15 mg/mL AMP is suitable for use in OPAT if the volume and rate of infusion are tailored to the dosage needs of antimicrobial treatments. Full article

(This article belongs to the Special Issue Novel Drugs, Targets and Therapies against Infectious Diseases)

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28 pages, 3592 KiB

Open AccessEditor’s ChoiceReview

Development of Organs-on-Chips and Their Impact on Precision Medicine and Advanced System Simulation

by Ying Luo, Xiaoxiao Li, Yawei Zhao, Wen Zhong, Malcolm Xing and Guozhong Lyu

Pharmaceutics 2023, 15(8), 2094; https://doi.org/10.3390/pharmaceutics15082094 - 7 Aug 2023

Cited by 1 | Viewed by 1809

Abstract

Drugs may undergo costly preclinical studies but still fail to demonstrate their efficacy in clinical trials, which makes it challenging to discover new drugs. Both in vitro and in vivo models are essential for disease research and therapeutic development. However, these models cannot [...] Read more.

Drugs may undergo costly preclinical studies but still fail to demonstrate their efficacy in clinical trials, which makes it challenging to discover new drugs. Both in vitro and in vivo models are essential for disease research and therapeutic development. However, these models cannot simulate the physiological and pathological environment in the human body, resulting in limited drug detection and inaccurate disease modelling, failing to provide valid guidance for clinical application. Organs-on-chips (OCs) are devices that serve as a micro-physiological system or a tissue-on-a-chip; they provide accurate insights into certain functions and the pathophysiology of organs to precisely predict the safety and efficiency of drugs in the body. OCs are faster, more economical, and more precise. Thus, they are projected to become a crucial addition to, and a long-term replacement for, traditional preclinical cell cultures, animal studies, and even human clinical trials. This paper first outlines the nature of OCs and their significance, and then details their manufacturing-related materials and methodology. It also discusses applications of OCs in drug screening and disease modelling and treatment, and presents the future perspective of OCs. Full article

(This article belongs to the Special Issue Emerging Trends and Translational Challenges in Drug and Vaccine Delivery)

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31 pages, 1142 KiB

Open AccessEditor’s ChoiceReview

Membrane-Active Peptides and Their Potential Biomedical Application

by Andreea Gostaviceanu, Simona Gavrilaş, Lucian Copolovici and Dana Maria Copolovici

Pharmaceutics 2023, 15(8), 2091; https://doi.org/10.3390/pharmaceutics15082091 - 6 Aug 2023

Cited by 3 | Viewed by 2370

Abstract

Membrane-active peptides (MAPs) possess unique properties that make them valuable tools for studying membrane structure and function and promising candidates for therapeutic applications. This review paper provides an overview of the fundamental aspects of MAPs, focusing on their membrane interaction mechanisms and potential [...] Read more.

Membrane-active peptides (MAPs) possess unique properties that make them valuable tools for studying membrane structure and function and promising candidates for therapeutic applications. This review paper provides an overview of the fundamental aspects of MAPs, focusing on their membrane interaction mechanisms and potential applications. MAPs exhibit various structural features, including amphipathic structures and specific amino acid residues, enabling selective interaction with multiple membranes. Their mechanisms of action involve disrupting lipid bilayers through different pathways, depending on peptide properties and membrane composition. The therapeutic potential of MAPs is significant. They have demonstrated antimicrobial activity against bacteria and fungi, making them promising alternatives to conventional antibiotics. MAPs can selectively target cancer cells and induce apoptosis, opening new avenues in cancer therapeutics. Additionally, MAPs serve as drug delivery vectors, facilitating the transport of therapeutic cargoes across cell membranes. They represent a fascinating class of biomolecules with significant potential in basic research and clinical applications. Understanding their mechanisms of action and designing peptides with enhanced selectivity and efficacy will further expand their utility in diverse fields. Exploring MAPs holds promise for developing novel therapeutic strategies against infections, cancer, and drug delivery challenges. Full article

(This article belongs to the Special Issue State of the Art of Membrane Active Peptides)

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26 pages, 2040 KiB

Open AccessEditor’s ChoiceReview

Pharmacological Treatments and Therapeutic Drug Monitoring in Patients with Chronic Pain

by Federica De Rosa, Bruno Giannatiempo, Bruno Charlier, Albino Coglianese, Francesca Mensitieri, Giulia Gaudino, Armando Cozzolino, Amelia Filippelli, Ornella Piazza, Fabrizio Dal Piaz and Viviana Izzo

Pharmaceutics 2023, 15(8), 2088; https://doi.org/10.3390/pharmaceutics15082088 - 5 Aug 2023

Cited by 3 | Viewed by 1585

Abstract

Pain is an unpleasant sensory and emotional experience that affects every aspect of a patient’s life and which may be treated through different pharmacological and non-pharmacological approaches. Analgesics are the drugs most commonly used to treat pain, and in specific situations, the use [...] Read more.

Pain is an unpleasant sensory and emotional experience that affects every aspect of a patient’s life and which may be treated through different pharmacological and non-pharmacological approaches. Analgesics are the drugs most commonly used to treat pain, and in specific situations, the use of opioids may be considered with caution. These drugs, in fact, do not always induce optimal analgesia in patients, and several problems are associated with their use. The purpose of this narrative review is to describe the pharmacological approaches currently used for the management of chronic pain. We review several aspects, from the pain-scale-based methods currently available to assess the type and intensity of pain, to the most frequently administered drugs (non-narcotic analgesics and narcotic analgesics), whose pharmacological characteristics are briefly reported. Overall, we attempt to provide an overview of different pharmacological treatments while also illustrating the relevant guidelines and indications. We then report the strategies that may be used to reduce problems related to opioid use. Specifically, we focus our attention on therapeutic drug monitoring (TDM), a tool that could help clinicians select the most suitable drug and dose to be used for each patient. The actual potential of using TDM to optimize and personalize opioid-based pain treatments is finally discussed based on recent scientific reports. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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21 pages, 5479 KiB

Open AccessEditor’s ChoiceArticle

Effect of Gut Microbiota on the Pharmacokinetics of Nifedipine in Spontaneously Hypertensive Rats

by Rong Zhou, Haijun Yang, Peng Zhu, Yujie Liu, Yanjuan Zhang, Wei Zhang, Honghao Zhou, Xiong Li and Qing Li

Pharmaceutics 2023, 15(8), 2085; https://doi.org/10.3390/pharmaceutics15082085 - 3 Aug 2023

Viewed by 1548

Abstract

The pharmacokinetic variability of nifedipine widely observed in the clinic cannot be fully explained by pharmacogenomics. As a new factor affecting drug metabolism, how the gut microbiota affects the pharmacokinetics of nifedipine needs to be explored. Spontaneously hypertensive rats (SHRs) have been commonly [...] Read more.

The pharmacokinetic variability of nifedipine widely observed in the clinic cannot be fully explained by pharmacogenomics. As a new factor affecting drug metabolism, how the gut microbiota affects the pharmacokinetics of nifedipine needs to be explored. Spontaneously hypertensive rats (SHRs) have been commonly used in hypertension-related research and served as the experimental groups; Wistar rats were used as control groups. In this study, the bioavailability of nifedipine decreased by 18.62% (p < 0.05) in the SHRs compared with the Wistar rats. Changes in microbiota were associated with the difference in pharmacokinetics. The relative abundance of Bacteroides dorei was negatively correlated with AUC_0–t (r = −0.881, p = 0.004) and C_max (r = −0.714, p = 0.047). Analysis of serum bile acid (BA) profiles indicated that glycoursodeoxycholic acid (GUDCA) and glycochenodeoxycholic acid (GCDCA) were significantly increased in the SHRs. Compared with the Wistar rats, the expressions of CYP3A1 and PXR were upregulated and the enzyme activity of CYP3A1 increased in the SHRs. Spearman’s rank correlation revealed that Bacteroides stercoris was negatively correlated with GUDCA (r = −0.7126, p = 0.0264) and GCDCA (r = −0.6878, p = 0.0339). Moreover, GUDCA was negatively correlated with C_max (r = −0.556, p = 0.025). In primary rat hepatocytes, GUDCA could induce the expressions of PXR target genes CYP3A1 and Mdr1a. Furthermore, antibiotic treatments in SHRs verified the impact of microbiota on the pharmacokinetics of nifedipine. Generally, gut microbiota affects the pharmacokinetics of nifedipine through microbial biotransformation or by regulating the enzyme activity of CYP3A1. Full article

(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics, Volume II)

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13 pages, 19968 KiB

Open AccessEditor’s ChoiceArticle

The Use of an Inspiration-Synchronized Vibrating Mesh Nebulizer for Prolonged Inhalative Iloprost Administration in Mechanically Ventilated Patients—An In Vitro Model

by Matthias Otto, Yannik Kropp, Evelyn Jäger, Michael Neumaier, Manfred Thiel, Michael Quintel and Charalambos Tsagogiorgas

Pharmaceutics 2023, 15(8), 2080; https://doi.org/10.3390/pharmaceutics15082080 - 3 Aug 2023

Viewed by 1222

Abstract

Mechanically ventilated patients suffering from acute respiratory distress syndrome (ARDS) frequently receive aerosolized iloprost. Because of prostacyclin’s short half-life, prolonged inhalative administration might improve its clinical efficacy. But, this is technically challenging. A solution might be the use of inspiration-synchronized vibrating mesh nebulizers [...] Read more.

Mechanically ventilated patients suffering from acute respiratory distress syndrome (ARDS) frequently receive aerosolized iloprost. Because of prostacyclin’s short half-life, prolonged inhalative administration might improve its clinical efficacy. But, this is technically challenging. A solution might be the use of inspiration-synchronized vibrating mesh nebulizers (VMN_syn), which achieve high drug deposition rates while showing prolonged nebulization times. However, there are no data comparing prolonged to bolus iloprost nebulization using a continuous vibrating mesh nebulizer (VMN_cont) and investigating the effects of different ventilation modes on inspiration-synchronized nebulization. Therefore, in an in vitro model of mechanically ventilated adults, a VMN_syn and a VMN_cont were compared in volume-controlled (VC-CMV) and pressure-controlled continuous mandatory ventilation (PC-CMV) regarding iloprost deposition rate and nebulization time. During VC-CMV, the deposition rate of the VMN_syn was comparable to the rate obtained with the VMN_cont, but 10.9% lower during PC-CMV. The aerosol output of the VMN_syn during both ventilation modes was significantly lower compared to the VMN_cont, leading to a 7.5 times longer nebulization time during VC-CMV and only to a 4.2 times longer nebulization time during PC-CMV. Inspiration-synchronized nebulization during VC-CMV mode therefore seems to be the most suitable for prolonged inhalative iloprost administration in mechanically ventilated patients. Full article

(This article belongs to the Special Issue Drug Delivery Systems for Respiratory Diseases)

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25 pages, 37359 KiB

Open AccessEditor’s ChoiceArticle

Comparative Studies of the Uptake and Internalization Pathways of Different Lipid Nano-Systems Intended for Brain Delivery

by Ljubica Mihailova, Dushko Shalabalija, Andreas Zimmer, Nikola Geskovski, Petre Makreski, Marija Petrushevska, Maja Simonoska Crcarevska and Marija Glavas Dodov

Pharmaceutics 2023, 15(8), 2082; https://doi.org/10.3390/pharmaceutics15082082 - 3 Aug 2023

Cited by 1 | Viewed by 1663

Abstract

Lipid nano-systems were prepared and characterized in a series of well-established in vitro tests that could assess their interactions with the hCMEC/D3 and SH-SY5Y cell lines as a model for the blood–brain barrier and neuronal function, accordingly. The prepared formulations of nanoliposomes and [...] Read more.

Lipid nano-systems were prepared and characterized in a series of well-established in vitro tests that could assess their interactions with the hCMEC/D3 and SH-SY5Y cell lines as a model for the blood–brain barrier and neuronal function, accordingly. The prepared formulations of nanoliposomes and nanostructured lipid carriers were characterized by z-average diameters of ~120 nm and ~105 nm, respectively, following a unimodal particle size distribution (PDI < 0.3) and negative Z-potential (−24.30 mV to −31.20 mV). Stability studies implied that the nano-systems were stable in a physiologically relevant medium as well as human plasma, except nanoliposomes containing poloxamer on their surface, where there was an increase in particle size of ~26%. The presence of stealth polymer tends to decrease the amount of adsorbed proteins onto a particle’s surface, according to protein adsorption studies. Both formulations of nanoliposomes were characterized by a low cytotoxicity, while their cell viability was reduced when incubated with the highest concentration (100 μg/mL) of nanostructured lipid formulations, which could have been associated with the consumption of cellular energy, thus resulting in a reduction in metabolic active cells. The uptake of all the nano-systems in the hCMEC/D3 and SH-SY5Y cell lines was successful, most likely following ATP-dependent internalization, as well as transport via passive diffusion. Full article

(This article belongs to the Topic Smart Materials: New Tools for the Treatment of Brain Diseases)

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18 pages, 4164 KiB

Open AccessEditor’s ChoiceArticle

Locally Administered Photodynamic Therapy for Cancer Using Nano-Adhesive Photosensitizer

by Yoshiki Komatsu, Toru Yoshitomi, Van Thi Hong Doan, Hiromi Kurokawa, Saori Fujiwara, Naoki Kawazoe, Guoping Chen and Hirofumi Matsui

Pharmaceutics 2023, 15(8), 2076; https://doi.org/10.3390/pharmaceutics15082076 - 3 Aug 2023

Viewed by 1328

Abstract

Photodynamic therapy (PDT) is a great potential anti-tumor therapy owing to its non-invasiveness and high spatiotemporal selectivity. However, systemically administered photosensitizers diffuse in the skin and the eyes for a long duration, which cause phototoxicity to bright light and sunlight. Therefore, following PDT, [...] Read more.

Photodynamic therapy (PDT) is a great potential anti-tumor therapy owing to its non-invasiveness and high spatiotemporal selectivity. However, systemically administered photosensitizers diffuse in the skin and the eyes for a long duration, which cause phototoxicity to bright light and sunlight. Therefore, following PDT, patients must avoid exposure of to light and sunlight to avoid this phototoxicity. In this study, we have developed a locally administered PDT using nano-adhesive porphyrin with polycations consisting of quaternary ammonium salt groups (aHP) as a photosensitizer. The aHP, approximately 3.0 nm in diameter, adhered the negatively charged cell membrane via electrostatic interaction. The aHP localized to the endosome via cell adhesion and induced apoptosis upon 635 nm light irradiation. On being administered subcutaneously on the tumor, 30% of the injected aHP remained in the administered sites. However, low-molecular-weight hematoporphyrin dihydrochloride (HP) disappeared due to rapid diffusion. PDT with locally administered aHP showed a higher anti-tumor effect after light irradiation at 635 nm for three days compared to low-molecular-weight HP. Intraperitoneal administration of HP caused severe phototoxicity upon irradiation with ultraviolet A at 10 J cm⁻², whereas aHP did not cause phototoxicity because its diffusion into the skin could be suppressed, probably due to the high-molecular weight of aHP. Therefore, locally administered PDT with aHP is a potential PDT having high therapeutic efficacy without phototoxicity. Full article

(This article belongs to the Special Issue Advances in Cancer Nanotechnology for Photodynamic and Photothermal Therapy)

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32 pages, 18644 KiB

Open AccessEditor’s ChoiceReview

A Novel Platform of MOF for Sonodynamic Therapy Advanced Therapies

by Donghui Liao, Jiefeng Huang, Chenyi Jiang, Luyi Zhou, Mingbin Zheng, Alireza Nezamzadeh-Ejhieh, Na Qi, Chengyu Lu and Jianqiang Liu

Pharmaceutics 2023, 15(8), 2071; https://doi.org/10.3390/pharmaceutics15082071 - 1 Aug 2023

Cited by 7 | Viewed by 2239

Abstract

Metal–organic frameworks (MOFs) combined with sonodynamic therapy (SDT) have been introduced as a new and efficient treatment method. The critical advantage of SDT is its ability to penetrate deep tissues and concentrate energy on the tumor site to achieve a non-invasive or minimally [...] Read more.

Metal–organic frameworks (MOFs) combined with sonodynamic therapy (SDT) have been introduced as a new and efficient treatment method. The critical advantage of SDT is its ability to penetrate deep tissues and concentrate energy on the tumor site to achieve a non-invasive or minimally invasive effect. Using a sonosensitizer to generate reactive oxygen species (ROS) under ultrasound is the primary SDT-related method of killing tumor cells. In the presence of a sonosensitizer, SDT exhibits a more lethal effect on tumors. The fast development of micro/nanotechnology has effectively improved the efficiency of SDT, and MOFs have been broadly evaluated in SDT due to their easy synthesis, easy surface functionalization, high porosity, and high biocompatibility. This article reviews the main mechanism of action of sonodynamic therapy in cancer treatment, and also reviews the applications of MOFs in recent years. The application of MOFs in sonodynamic therapy can effectively improve the targeting ability of SDT and the conversion ability of reactive oxygen species, thus improving their killing ability on cancer cells. This provides new ideas for the application of micro/nano particles in SDT and cancer therapy. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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19 pages, 3786 KiB

Open AccessEditor’s ChoiceArticle

Biosynthetic Melanin/Ce6-Based Photothermal and Sonodynamic Therapies Significantly Improved the Anti-Tumor Efficacy

by Yuping Yang, Yaling He, Meijun Zhou, Meijun Fu, Xinxin Li, Hongmei Liu and Fei Yan

Pharmaceutics 2023, 15(8), 2058; https://doi.org/10.3390/pharmaceutics15082058 - 31 Jul 2023

Cited by 3 | Viewed by 1177

Abstract

Photothermal therapy (PTT) and sonodynamic therapy (SDT) are becoming promising therapeutic modalities against various tumors in recent years. However, the single therapeutic modality with SDT or PTT makes it difficult to achieve a satisfactory anti-tumor outcome due to their own inherent limitations, such [...] Read more.

Photothermal therapy (PTT) and sonodynamic therapy (SDT) are becoming promising therapeutic modalities against various tumors in recent years. However, the single therapeutic modality with SDT or PTT makes it difficult to achieve a satisfactory anti-tumor outcome due to their own inherent limitations, such as poor tissue penetration for the near-infrared (NIR) laser and the limited cytotoxic reactive oxygen species (ROS) generated from conventional sonosensitizers irradiated by ultrasound (US). Here, we successfully biosynthesized melanin with a controllable particle size with genetically engineered bacteria harboring a heat-inducible gene circuit. The biosynthetic melanin with 8 nm size and chlorin e6 (Ce6) was further encapsulated into liposomes and obtained SDT/PTT dual-functional liposomes (designated as MC@Lip). The resulting MC@Lip had an approximately 100 nm particle size, with 74.71% ± 0.54% of encapsulation efficiency for melanin and 94.52% ± 0.78% for Ce6. MC@Lip exhibited efficient ¹O₂ production and photothermal conversion capability upon receiving irradiation by US and NIR laser, producing significantly enhanced anti-tumor efficacy in vitro and in vivo. Especially, US and NIR laser irradiation of tumors received with MC@Lip lead to complete tumor regression in all tested tumor-bearing mice, indicating the great advantage of the combined use of SDT and PTT. More importantly, MC@Lip possessed good photoacoustic (PA) and fluorescence dual-modal imaging performance, making it possible to treat tumors under imaging guidance. Our study provides a novel approach to synthesize a melanin nanoparticle with controllable size and develops a promising combined SDT/PTT strategy to treat tumors. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

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14 pages, 850 KiB

Open AccessEditor’s ChoiceReview

Overview of Solid Lipid Nanoparticles in Breast Cancer Therapy

by Kyumin Mo, Ayoung Kim, Soohyun Choe, Miyoung Shin and Hyunho Yoon

Pharmaceutics 2023, 15(8), 2065; https://doi.org/10.3390/pharmaceutics15082065 - 31 Jul 2023

Cited by 5 | Viewed by 2164

Abstract

Lipid nanoparticles (LNPs), composed of ionized lipids, helper lipids, and cholesterol, provide general therapeutic effects by facilitating intracellular transport and avoiding endosomal compartments. LNP-based drug delivery has great potential for the development of novel gene therapies and effective vaccines. Solid lipid nanoparticles (SLNs) [...] Read more.

Lipid nanoparticles (LNPs), composed of ionized lipids, helper lipids, and cholesterol, provide general therapeutic effects by facilitating intracellular transport and avoiding endosomal compartments. LNP-based drug delivery has great potential for the development of novel gene therapies and effective vaccines. Solid lipid nanoparticles (SLNs) are derived from physiologically acceptable lipid components and remain robust at body temperature, thereby providing high structural stability and biocompatibility. By enhancing drug delivery through blood vessels, SLNs have been used to improve the efficacy of cancer treatments. Breast cancer, the most common malignancy in women, has a declining mortality rate but remains incurable. Recently, as an anticancer drug delivery system, SLNs have been widely used in breast cancer, improving the therapeutic efficacy of drugs. In this review, we discuss the latest advances of SLNs for breast cancer treatment and their potential in clinical use. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy of Solid Tumors with Polymeric Nanoparticles)

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17 pages, 7566 KiB

Open AccessEditor’s ChoiceArticle

Polymeric Patches Based on Chitosan/Green Clay Composites and Hazelnut Shell Extract as Bio-Sustainable Medication for Wounds

by Carmen Laura Pérez Gutíerrez, Alessandro Di Michele, Cinzia Pagano, Debora Puglia, Francesca Luzi, Tommaso Beccari, Maria Rachele Ceccarini, Sara Primavilla, Andrea Valiani, Camilla Vicino, Maurizio Ricci, César Antonio Viseras Iborra and Luana Perioli

Pharmaceutics 2023, 15(8), 2057; https://doi.org/10.3390/pharmaceutics15082057 - 31 Jul 2023

Cited by 1 | Viewed by 1048

Abstract

Hazelnut shells, the main waste deriving from hazelnut processing, represent an interesting source of active molecules useful in pharmaceutics, although they have not yet been examined in depth. A hydrosoluble extract (hazelnut shell extract, HSE) was prepared by the maceration method using a [...] Read more.

Hazelnut shells, the main waste deriving from hazelnut processing, represent an interesting source of active molecules useful in pharmaceutics, although they have not yet been examined in depth. A hydrosoluble extract (hazelnut shell extract, HSE) was prepared by the maceration method using a hydroalcoholic solution and used as the active ingredient of patches (prepared by casting method) consisting of composites of highly deacetylated chitosan and green clay. In vitro studies showed that the formulation containing HSE is able to stimulate keratinocyte growth, which is useful for healing purposes, and to inhibit the growth of S. aureus (Log CFU/mL 0.95 vs. 8.85 of the control after 48 h); this bacterium is often responsible for wound infections and is difficult to treat by conventional antibiotics due to its antibiotic resistance. The produced patches showed suitable tensile properties that are necessary to withstand mechanical stress during both the removal from the packaging and application. The obtained results suggest that the developed patch could be a suitable product to treat wounds. Full article

(This article belongs to the Special Issue Application of Clay Minerals for Drug Delivery)

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30 pages, 2535 KiB

Open AccessEditor’s ChoiceReview

Neurodegenerative Proteinopathies Induced by Environmental Pollutants: Heat Shock Proteins and Proteasome as Promising Therapeutic Tools

by Paula Moyano, Emma Sola, María Victoria Naval, Lucia Guerra-Menéndez, Maria De la Cabeza Fernández and Javier del Pino

Pharmaceutics 2023, 15(8), 2048; https://doi.org/10.3390/pharmaceutics15082048 - 30 Jul 2023

Cited by 1 | Viewed by 1339

Abstract

Environmental pollutants’ (EPs) amount and diversity have increased in recent years due to anthropogenic activity. Several neurodegenerative diseases (NDs) are theorized to be related to EPs, as their incidence has increased in a similar way to human EPs exposure and they reproduce the [...] Read more.

Environmental pollutants’ (EPs) amount and diversity have increased in recent years due to anthropogenic activity. Several neurodegenerative diseases (NDs) are theorized to be related to EPs, as their incidence has increased in a similar way to human EPs exposure and they reproduce the main ND hallmarks. EPs induce several neurotoxic effects, including accumulation and gradual deposition of misfolded toxic proteins, producing neuronal malfunction and cell death. Cells possess different mechanisms to eliminate these toxic proteins, including heat shock proteins (HSPs) and the proteasome system. The accumulation and deleterious effects of toxic proteins are induced through HSPs and disruption of proteasome proteins’ homeostatic function by exposure to EPs. A therapeutic approach has been proposed to reduce accumulation of toxic proteins through treatment with recombinant HSPs/proteasome or the use of compounds that increase their expression or activity. Our aim is to review the current literature on NDs related to EP exposure and their relationship with the disruption of the proteasome system and HSPs, as well as to discuss the toxic effects of dysfunction of HSPs and proteasome and the contradictory effects described in the literature. Lastly, we cover the therapeutic use of developed drugs and recombinant proteasome/HSPs to eliminate toxic proteins and prevent/treat EP-induced neurodegeneration. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Neurodegenerative Diseases Treatment, 2nd Edition)

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45 pages, 1441 KiB

Open AccessEditor’s ChoiceReview

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

by Natalia Siwecka, Kamil Saramowicz, Grzegorz Galita, Wioletta Rozpędek-Kamińska and Ireneusz Majsterek

Pharmaceutics 2023, 15(8), 2051; https://doi.org/10.3390/pharmaceutics15082051 - 30 Jul 2023

Cited by 2 | Viewed by 2205

Abstract

α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a [...] Read more.

α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson’s disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies. Full article

(This article belongs to the Special Issue Advances in Drug Targeting for Central Nervous System Disease)

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17 pages, 3431 KiB

Open AccessEditor’s ChoiceArticle

Stability of Monoclonal Antibodies as Solid Formulation for Auto-Injectors: A Pilot Study

by Fatima Garcia-Villen, Idoia Gallego, Myriam Sainz-Ramos, Jorge Ordoyo-Pascual, Sandra Ruiz-Alonso, Laura Saenz-del-Burgo, Conor O’Mahony and Jose Luis Pedraz

Pharmaceutics 2023, 15(8), 2049; https://doi.org/10.3390/pharmaceutics15082049 - 30 Jul 2023

Cited by 1 | Viewed by 1238

Abstract

Drug adherence is a significant medical issue, often responsible for sub-optimal outcomes during the treatment of chronic diseases such as rheumatoid or psoriatic arthritis. Monoclonal antibodies (which are exclusively given parenterally) have been proven to be an effective treatment in these cases. The [...] Read more.

Drug adherence is a significant medical issue, often responsible for sub-optimal outcomes during the treatment of chronic diseases such as rheumatoid or psoriatic arthritis. Monoclonal antibodies (which are exclusively given parenterally) have been proven to be an effective treatment in these cases. The use of auto-injectors is an effective strategy to improve drug adherence in parenteral treatments since these pen-like devices offer less discomfort and increased user-friendliness over conventional syringe-based delivery. This study aims to investigate the feasibility of including a monoclonal antibody as a solid formulation inside an auto-injector pen. Specifically, the objective was to evaluate the drug stability after a concentration (to reduce the amount of solvent and space needed) and freeze-drying procedure. A preliminary screening of excipients to improve stability was also performed. The nano-DSC results showed that mannitol improved the stability of the concentrated, freeze-dried antibody in comparison to its counterpart without it. However, a small instability of the C_H2 domain was still found for mannitol samples, which will warrant further investigation. The present results serve as a stepping stone towards advancing future drug delivery systems that will ultimately improve the patient experience and associated drug adherence. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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40 pages, 8503 KiB

Open AccessEditor’s ChoiceReview

Ferrocene-Based Drugs, Delivery Nanomaterials and Fenton Mechanism: State of the Art, Recent Developments and Prospects

by Catia Ornelas and Didier Astruc

Pharmaceutics 2023, 15(8), 2044; https://doi.org/10.3390/pharmaceutics15082044 - 29 Jul 2023

Cited by 14 | Viewed by 3491

Abstract

Ferrocene has been the most used organometallic moiety introduced in organic and bioinorganic drugs to cure cancers and various other diseases. Following several pioneering studies, two real breakthroughs occurred in 1996 and 1997. In 1996, Jaouen et al. reported ferrocifens, ferrocene analogs of [...] Read more.

Ferrocene has been the most used organometallic moiety introduced in organic and bioinorganic drugs to cure cancers and various other diseases. Following several pioneering studies, two real breakthroughs occurred in 1996 and 1997. In 1996, Jaouen et al. reported ferrocifens, ferrocene analogs of tamoxifen, the chemotherapeutic for hormone-dependent breast cancer. Several ferrocifens are now in preclinical evaluation. Independently, in 1997, ferroquine, an analog of the antimalarial drug chloroquine upon the introduction of a ferrocenyl substituent in the carbon chain, was reported by the Biot-Brocard group and found to be active against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Ferroquine, in combination with artefenomel, completed phase IIb clinical evaluation in 2019. More than 1000 studies have been published on ferrocenyl-containing pharmacophores against infectious diseases, including parasitic, bacterial, fungal, and viral infections, but the relationship between structure and biological activity has been scarcely demonstrated, unlike for ferrocifens and ferroquines. In a majority of ferrocene-containing drugs, however, the production of reactive oxygen species (ROS), in particular the OH. radical, produced by Fenton catalysis, plays a key role and is scrutinized in this mini-review, together with the supramolecular approach utilizing drug delivery nanosystems, such as micelles, metal–organic frameworks (MOFs), polymers, and dendrimers. Full article

(This article belongs to the Special Issue Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 85th Birthday for His Outstanding Achievements in Advancing the Field of Dendrimers)

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29 pages, 2545 KiB

Open AccessEditor’s ChoiceReview

Exosome-Based Drug Delivery: Translation from Bench to Clinic

by Hee Byung Koh, Hyo Jeong Kim, Shin-Wook Kang and Tae-Hyun Yoo

Pharmaceutics 2023, 15(8), 2042; https://doi.org/10.3390/pharmaceutics15082042 - 29 Jul 2023

Cited by 18 | Viewed by 2400

Abstract

Exosome-based drug delivery is emerging as a promising field with the potential to revolutionize therapeutic interventions. Exosomes, which are small extracellular vesicles released by various cell types, have attracted significant attention due to their unique properties and natural ability to transport bioactive molecules. [...] Read more.

Exosome-based drug delivery is emerging as a promising field with the potential to revolutionize therapeutic interventions. Exosomes, which are small extracellular vesicles released by various cell types, have attracted significant attention due to their unique properties and natural ability to transport bioactive molecules. These nano-sized vesicles, ranging in size from 30 to 150 nm, can effectively transport a variety of cargoes, including proteins, nucleic acids, and lipids. Compared to traditional drug delivery systems, exosomes exhibit unique biocompatibility, low immunogenicity, and reduced toxicity. In addition, exosomes can be designed and tailored to improve targeting efficiency, cargo loading capacity, and stability, paving the way for personalized medicine and precision therapy. However, despite the promising potential of exosome-based drug delivery, its clinical application remains challenging due to limitations in exosome isolation and purification, low loading efficiency of therapeutic cargoes, insufficient targeted delivery, and rapid elimination in circulation. This comprehensive review focuses on the transition of exosome-based drug delivery from the bench to clinic, highlighting key aspects, such as exosome structure and biogenesis, cargo loading methods, surface engineering techniques, and clinical applications. It also discusses challenges and prospects in this emerging field. Full article

(This article belongs to the Special Issue Exosome-Based Drug Delivery: Translation from Bench to Clinic)

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14 pages, 5991 KiB

Open AccessEditor’s ChoiceArticle

Label-Free Optical Sensing and Medical Grade Resins: An Advanced Approach to Investigate Cell–Material Interaction and Biocompatibility

by Valentina Bergamini, Elisa Resca, Alberto Portone, Tiziana Petrachi, Francesco Ganzerli, Stefano Truzzi, Giorgio Mari, Luigi Rovati, Massimo Dominici and Elena Veronesi

Pharmaceutics 2023, 15(8), 2043; https://doi.org/10.3390/pharmaceutics15082043 - 29 Jul 2023

Viewed by 965

Abstract

The Corning Epic^® label-free (ELF) system is an innovative technology widely used in drug discovery, immunotherapy, G-protein-associated studies, and biocompatibility tests. Here, we challenge the use of ELF to further investigate the biocompatibility of resins used in manufacturing of blood filters, a [...] Read more.

The Corning Epic^® label-free (ELF) system is an innovative technology widely used in drug discovery, immunotherapy, G-protein-associated studies, and biocompatibility tests. Here, we challenge the use of ELF to further investigate the biocompatibility of resins used in manufacturing of blood filters, a category of medical devices representing life-saving therapies for the increasing number of patients with kidney failure. The biocompatibility assays were carried out by developing a cell model aimed at mimicking the clinical use of the blood filters and complementing the existing cytotoxicity assay requested by ISO10993-5. Experiments were performed by putting fibroblasts in both direct contact with two types of selected resins, and indirect contact by means of homemade customized well inserts that were precisely designed and developed for this technology. For both types of contact, fibroblasts were cultured in medium and human plasma. ELF tests confirmed the biocompatibility of both resins, highlighting a statistically significant different biological behavior of a polyaromatic resin compared to control and ion-exchanged resin, when materials were in indirect contact and soaking with plasma. Overall, the ELF test is able to mimic clinical scenarios and represents a promising approach to investigate biocompatibility, showing peculiar biological behaviors and suggesting the activation of specific intracellular pathways. Full article

(This article belongs to the Section Gene and Cell Therapy)

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13 pages, 3255 KiB

Open AccessEditor’s ChoiceArticle

Material Transport Characteristics in Planetary Roller Melt Granulation

by Tom Lang, Andreas Bramböck, Markus Thommes and Jens Bartsch

Pharmaceutics 2023, 15(8), 2039; https://doi.org/10.3390/pharmaceutics15082039 - 28 Jul 2023

Cited by 3 | Viewed by 911

Abstract

Melt granulation for improving material handling by modifying particle size distribution offers significant advantages compared to the standard methods of dry and wet granulation in dust reduction, obviating a subsequent drying step. Furthermore, current research in pharmaceutical technology aims for continuous methods, as [...] Read more.

Melt granulation for improving material handling by modifying particle size distribution offers significant advantages compared to the standard methods of dry and wet granulation in dust reduction, obviating a subsequent drying step. Furthermore, current research in pharmaceutical technology aims for continuous methods, as these have an enhanced potential to reduce product quality fluctuations. Concerning both aspects, the use of a planetary roller granulator is consequential. The process control with these machines benefits from the enhanced ratio of heated surface to processed volume, compared to the usually-applied twin-screw systems. This is related to the unique concept of planetary spindles flowing around a central spindle in a roller cylinder. Herein, the movement pattern defines the transport characteristics, which determine the energy input and overall processing conditions. The aim of this study is to investigate the residence time distribution in planetary roller melt granulation (PRMG) as an indicator for the material transport. By altering feed rate and rotation speed, the fill level in the granulator is adjusted, which directly affects the average transport velocity and mixing volume. The two-compartment model was utilized to reflect these coherences, as the model parameters symbolize the sub-processes of axial material transport and mixing. Full article

(This article belongs to the Special Issue Pharmaceutical Continuous Manufacturing: Then and Now)

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18 pages, 8462 KiB

Open AccessEditor’s ChoiceArticle

Effects of Adding Chitosan on Drug Entrapment Efficiency and Release Duration for Paclitaxel-Loaded Hydroxyapatite—Gelatin Composite Microspheres

by Meng-Ying Wu, I-Fang Kao, Chien-Yao Fu and Shiow-Kang Yen

Pharmaceutics 2023, 15(8), 2025; https://doi.org/10.3390/pharmaceutics15082025 - 26 Jul 2023

Cited by 6 | Viewed by 1602

Abstract

Hydroxyapatite—gelatin microspheres with cone-like pores were synthesized via the wet-chemical method using ammonium dihydrogen phosphate ((NH₄)H₂PO₄) and calcium nitrate (Ca(NO₃)₂·4H₂O) as a source of calcium and phosphate ions with the addition [...] Read more.

Hydroxyapatite—gelatin microspheres with cone-like pores were synthesized via the wet-chemical method using ammonium dihydrogen phosphate ((NH₄)H₂PO₄) and calcium nitrate (Ca(NO₃)₂·4H₂O) as a source of calcium and phosphate ions with the addition of gelatin, which proved to be more osteoconductive than commercial products, such as fibrin glue and Osteoset^® Bone Graft Substitute. Following the method of the previous study for loading paclitaxel (PTX), a drug entrapment efficiency of around 58% was achieved, which is much lower than that of the doxorubicin (DOX)-loaded one. Since PTX is hydrophobic while DOX is hydrophilic, the order of chitosan processing and addition of the solvent were tuned in this study, finally leading to an increase in drug entrapment efficiency of 94%. Additionally, the release duration of PTX exceeded six months. The MTT assay indicated that the effect of drug release on the suppression of cancer cells reached more than 40% after one week, thereby showcasing PTX’s capacity to carry out its medicinal functions without being affected by the loading procedures. Full article

(This article belongs to the Special Issue Development of Chitosan/Cyclodextrins in Drug Delivery Field)

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19 pages, 1031 KiB

Open AccessEditor’s ChoiceReview

Chronotherapeutics for Solid Tumors

by Claire O. Kisamore, Brittany D. Elliott, A. Courtney DeVries, Randy J. Nelson and William H. Walker II

Pharmaceutics 2023, 15(8), 2023; https://doi.org/10.3390/pharmaceutics15082023 - 26 Jul 2023

Cited by 1 | Viewed by 2355

Abstract

Circadian rhythms are internal manifestations of the 24-h solar day that allow for synchronization of biological and behavioral processes to the external solar day. This precise regulation of physiology and behavior improves adaptive function and survival. Chronotherapy takes advantage of circadian rhythms in [...] Read more.

Circadian rhythms are internal manifestations of the 24-h solar day that allow for synchronization of biological and behavioral processes to the external solar day. This precise regulation of physiology and behavior improves adaptive function and survival. Chronotherapy takes advantage of circadian rhythms in physiological processes to optimize the timing of drug administration to achieve maximal therapeutic efficacy and minimize negative side effects. Chronotherapy for cancer treatment was first demonstrated to be beneficial more than five decades ago and has favorable effects across diverse cancer types. However, implementation of chronotherapy in clinic remains limited. The present review examines the evidence for chronotherapeutic treatment for solid tumors. Specifically, studies examining chrono-chemotherapy, chrono-radiotherapy, and alternative chronotherapeutics (e.g., hormone therapy, TKIs, antiangiogenic therapy, immunotherapy) are discussed. In addition, we propose areas of needed research and identify challenges in the field that remain to be addressed. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy of Solid Tumors with Polymeric Nanoparticles)

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19 pages, 3151 KiB

Open AccessEditor’s ChoiceArticle

Stem Cell Bioengineering with Bioportides: Inhibition of Planarian Head Regeneration with Peptide Mimetics of Eyes Absent Proteins

by Sarah Jones, Bárbara Matos, Sarah Dennison, Margarida Fardilha and John Howl

Pharmaceutics 2023, 15(8), 2018; https://doi.org/10.3390/pharmaceutics15082018 - 26 Jul 2023

Viewed by 1148

Abstract

Djeya1 (RKLAFRYRRIKELYNSYR) is a very effective cell penetrating peptide (CPP) that mimics the α5 helix of the highly conserved Eya domain (ED) of eyes absent (Eya) proteins. The objective of this study was to bioengineer analogues of Djeya1 that, following effective translocation into [...] Read more.

Djeya1 (RKLAFRYRRIKELYNSYR) is a very effective cell penetrating peptide (CPP) that mimics the α5 helix of the highly conserved Eya domain (ED) of eyes absent (Eya) proteins. The objective of this study was to bioengineer analogues of Djeya1 that, following effective translocation into planarian tissues, would reduce the ability of neoblasts (totipotent stem cells) and their progeny to regenerate the anterior pole in decapitated S. mediterranea. As a strategy to increase the propensity for helix formation, molecular bioengineering of Djeya1 was achieved by the mono-substitution of the helicogenic aminoisobutyric acid (Aib) at three species-variable sites: 10, 13, and 16. CD analyses indicated that Djeya1 is highly helical, and that Aib-substitution had subtle influences upon the secondary structures of bioengineered analogues. Aib-substituted Djeya1 analogues are highly efficient CPPs, devoid of influence upon cell viability or proliferation. All three peptides increase the migration of PC-3 cells, a prostate cancer line that expresses high concentrations of Eya. Two peptides, [Aib¹³]Djeya1 and [Aib¹⁶]Djeya1, are bioportides which delay planarian head regeneration. As neoblasts are the only cell population capable of division in planaria, these data indicate that bioportide technologies could be utilised to directly manipulate other stem cells in situ, thus negating any requirement for genetic manipulation. Full article

(This article belongs to the Special Issue Current State of the Field of Cell-Penetrating Peptides as an Honorific Issue for Professor Ülo Langel)

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34 pages, 5182 KiB

Open AccessEditor’s ChoiceReview

The Spicy Science of Dendrimers in the Realm of Cancer Nanomedicine: A Report from the COST Action CA17140 Nano2Clinic

by Sabrina Pricl

Pharmaceutics 2023, 15(7), 2013; https://doi.org/10.3390/pharmaceutics15072013 - 24 Jul 2023

Cited by 4 | Viewed by 1456

Abstract

COST Action CA17140 Cancer Nanomedicine—from the bench to the bedside (Nano2Clinic,) is the first, pan-European interdisciplinary network of representatives from academic institutions and small and medium enterprises including clinical research organizations (CROs) devoted to the development of nanosystems carrying anticancer drugs from their [...] Read more.

COST Action CA17140 Cancer Nanomedicine—from the bench to the bedside (Nano2Clinic,) is the first, pan-European interdisciplinary network of representatives from academic institutions and small and medium enterprises including clinical research organizations (CROs) devoted to the development of nanosystems carrying anticancer drugs from their initial design, preclinical testing of efficacy, pharmacokinetics and toxicity to the preparation of detailed protocols needed for the first phase of their clinical studies. By promoting scientific exchanges, technological implementation, and innovative solutions, the action aims at providing a timely instrument to rationalize and focus research efforts at the European level in dealing with the grand challenge of nanomedicine translation in cancer, one of the major and societal-burdening human pathologies. Within CA17140, dendrimers in all their forms (from covalent to self-assembling dendrons) play a vital role as powerful nanotheranostic agents in oncology; therefore, the purpose of this review work is to gather and summarize the major results in the field stemming from collaborative efforts in the framework of the European Nano2Clinic COST Action. Full article

(This article belongs to the Special Issue Dendrimers for Drug Delivery)

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17 pages, 1790 KiB

Open AccessEditor’s ChoiceReview

From the Discovery of Targets to Delivery Systems: How to Decipher and Improve the Metallodrugs’ Actions at a Molecular Level

by Ilaria Iacobucci, Sara La Manna, Irene Cipollone, Vittoria Monaco, Luisa Canè and Flora Cozzolino

Pharmaceutics 2023, 15(7), 1997; https://doi.org/10.3390/pharmaceutics15071997 - 21 Jul 2023

Cited by 2 | Viewed by 1352

Abstract

Metals are indispensable for the life of all organisms, and their dysregulation leads to various disorders due to the disruption of their homeostasis. Nowadays, various transition metals are used in pharmaceutical products as diagnostic and therapeutic agents because their electronic structure allows them [...] Read more.

Metals are indispensable for the life of all organisms, and their dysregulation leads to various disorders due to the disruption of their homeostasis. Nowadays, various transition metals are used in pharmaceutical products as diagnostic and therapeutic agents because their electronic structure allows them to adjust the properties of molecules differently from organic molecules. Therefore, interest in the study of metal–drug complexes from different aspects has been aroused, and numerous approaches have been developed to characterize, activate, deliver, and clarify molecular mechanisms. The integration of these different approaches, ranging from chemoproteomics to nanoparticle systems and various activation strategies, enables the understanding of the cellular responses to metal drugs, which may form the basis for the development of new drugs and/or the modification of currently used drugs. The purpose of this review is to briefly summarize the recent advances in this field by describing the technological platforms and their potential applications for identifying protein targets for discovering the mechanisms of action of metallodrugs and improving their efficiency during delivery. Full article

(This article belongs to the Special Issue Metallodrugs: Investigation of the Mechanism of Action and Advanced Delivery Systems at Molecular Level)

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21 pages, 1249 KiB

Open AccessEditor’s ChoiceReview

Targeting Potential of Innate Lymphoid Cells in Melanoma and Other Cancers

by Hobin Seo, Amisha Verma, Megan Kinzel, Qiutong Huang, Douglas J. Mahoney and Nicolas Jacquelot

Pharmaceutics 2023, 15(7), 2001; https://doi.org/10.3390/pharmaceutics15072001 - 21 Jul 2023

Cited by 1 | Viewed by 1520

Abstract

Reinvigorating the killing function of tumor-infiltrating immune cells through the targeting of regulatory molecules expressed on lymphocytes has markedly improved the prognosis of cancer patients, particularly in melanoma. While initially thought to solely strengthen adaptive T lymphocyte anti-tumor activity, recent investigations suggest that [...] Read more.

Reinvigorating the killing function of tumor-infiltrating immune cells through the targeting of regulatory molecules expressed on lymphocytes has markedly improved the prognosis of cancer patients, particularly in melanoma. While initially thought to solely strengthen adaptive T lymphocyte anti-tumor activity, recent investigations suggest that other immune cell subsets, particularly tissue-resident innate lymphoid cells (ILCs), may benefit from immunotherapy treatment. Here, we describe the recent findings showing immune checkpoint expression on tissue-resident and tumor-infiltrating ILCs and how their effector function is modulated by checkpoint blockade-based therapies in cancer. We discuss the therapeutic potential of ILCs beyond the classical PD-1 and CTLA-4 regulatory molecules, exploring other possibilities to manipulate ILC effector function to further impede tumor growth and quench disease progression. Full article

(This article belongs to the Special Issue Immunotherapy of Melanoma)

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63 pages, 5895 KiB

Open AccessEditor’s ChoiceReview

Hacking the Immune Response to Solid Tumors: Harnessing the Anti-Cancer Capacities of Oncolytic Bacteria

by Jason M. Roe, Kevin Seely, Caleb J. Bussard, Emily Eischen Martin, Elizabeth G. Mouw, Kenneth W. Bayles, Michael A. Hollingsworth, Amanda E. Brooks and Kaitlin M. Dailey

Pharmaceutics 2023, 15(7), 2004; https://doi.org/10.3390/pharmaceutics15072004 - 21 Jul 2023

Cited by 1 | Viewed by 4036

Abstract

Oncolytic bacteria are a classification of bacteria with a natural ability to specifically target solid tumors and, in the process, stimulate a potent immune response. Currently, these include species of Klebsiella, Listeria, Mycobacteria, Streptococcus/Serratia (Coley’s Toxin), Proteus, [...] Read more.

Oncolytic bacteria are a classification of bacteria with a natural ability to specifically target solid tumors and, in the process, stimulate a potent immune response. Currently, these include species of Klebsiella, Listeria, Mycobacteria, Streptococcus/Serratia (Coley’s Toxin), Proteus, Salmonella, and Clostridium. Advancements in techniques and methodology, including genetic engineering, create opportunities to “hijack” typical host–pathogen interactions and subsequently harness oncolytic capacities. Engineering, sometimes termed “domestication”, of oncolytic bacterial species is especially beneficial when solid tumors are inaccessible or metastasize early in development. This review examines reported oncolytic bacteria–host immune interactions and details the known mechanisms of these interactions to the protein level. A synopsis of the presented membrane surface molecules that elicit particularly promising oncolytic capacities is paired with the stimulated localized and systemic immunogenic effects. In addition, oncolytic bacterial progression toward clinical translation through engineering efforts are discussed, with thorough attention given to strains that have accomplished Phase III clinical trial initiation. In addition to therapeutic mitigation after the tumor has formed, some bacterial species, referred to as “prophylactic”, may even be able to prevent or “derail” tumor formation through anti-inflammatory capabilities. These promising species and their particularly favorable characteristics are summarized as well. A complete understanding of the bacteria–host interaction will likely be necessary to assess anti-cancer capacities and unlock the full cancer therapeutic potential of oncolytic bacteria. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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19 pages, 1019 KiB

Open AccessEditor’s ChoiceReview

Colour of Medicines and Children’s Acceptability? A Systematic Literature Review of Children’s Perceptions about Colours of Oral Dosage Forms

by Elisa Alessandrini, Milena Gonakova, Hannah Batchelor, Sveinbjorn Gizurarson, Sonia Iurian, Sandra Klein, Daniel Schaufelberger, Roy Turner, Jennifer Walsh and Catherine Tuleu

Pharmaceutics 2023, 15(7), 1992; https://doi.org/10.3390/pharmaceutics15071992 - 20 Jul 2023

Cited by 2 | Viewed by 2049

Abstract

The colour of a product plays an important role in consumer experiences, and in the context of pharmaceutical products, this could potentially affect a patient’s expectations, behaviours, and adherence. Several studies have been conducted on adults, but little is known about children’s opinions [...] Read more.

The colour of a product plays an important role in consumer experiences, and in the context of pharmaceutical products, this could potentially affect a patient’s expectations, behaviours, and adherence. Several studies have been conducted on adults, but little is known about children’s opinions on colours of medicines and to what extent medicines’ colour affects their acceptability. To address this gap, a systematic search in PubMed, Scopus, MEDLINE, and Web of Science was conducted. Two authors independently screened the titles, abstracts, and references of all articles and selected studies conducted on children (0–18 years old), assessing children’s preferences or opinions about colour of oral dosage forms as either a primary or secondary objective or as an anecdotal record. A total of 989 publications were identified and, after screening, 18 publications were included in the review. Red and pink were the most liked colours and there appeared to be a relationship between the colour of a medicine and expected taste/flavour. The review also highlighted a scarcity of information, usually collected as an anecdotal record. Several gaps in the current knowledge were underlined, emphasizing the need of patient-centred studies to understand if the use of certain colours can improve or worsen the acceptability of a paediatric medicine. This will help inform pharmaceutical manufacturers and regulators on the role and need of colours in children’s medicines beyond quality purposes. Full article

(This article belongs to the Special Issue Advance in Development of Patient-Centric Dosage Form, 2nd Edition)

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13 pages, 2659 KiB

Open AccessEditor’s ChoiceArticle

Natural Antimicrobials Block the Host NF-κB Pathway and Reduce Enterocytozoon hepatopenaei Infection Both In Vitro and In Vivo

by Iulia Adelina Bunduruș, Igori Balta, Eugenia Butucel, Todd Callaway, Cosmin Alin Popescu, Tiberiu Iancu, Ioan Pet, Lavinia Stef and Nicolae Corcionivoschi

Pharmaceutics 2023, 15(7), 1994; https://doi.org/10.3390/pharmaceutics15071994 - 20 Jul 2023

Cited by 1 | Viewed by 1228

Abstract

The objective of this work was to investigate, for the first time, the antioxidant effect of a mixture of natural antimicrobials in an Enterocytozoon hepatopenaei (EHP) shrimp-gut model of infection and the biological mechanisms involved in their way of action. The study approach [...] Read more.

The objective of this work was to investigate, for the first time, the antioxidant effect of a mixture of natural antimicrobials in an Enterocytozoon hepatopenaei (EHP) shrimp-gut model of infection and the biological mechanisms involved in their way of action. The study approach included investigations, firstly, in vitro, on shrimp-gut primary (SGP) epithelial cells and in vivo by using EHP-challenged shrimp. Our results show that exposure of EHP spores to 0.1%, 0.5%, 1%, and 2% AuraAqua (Aq) significantly reduced spore activity at all concentrations but was more pronounced after exposure to 0.5% Aq. The Aq was able to reduce EHP infection of SGP cells regardless of cells being pretreated or cocultured during infection with Aq. The survivability of SGP cells infected with EHP spores was significantly increased in both scenarios; however, a more noticeable effect was observed when the infected cells were pre-exposed to Aq. Our data show that infection of SGP cells by EHP activates the host NADPH oxidases and the release of H₂O₂ produced. When Aq was used during infection, a significant reduction in H₂O₂ was observed concomitant with a significant increase in the levels of CAT and SOD enzymes. Moreover, in the presence of 0.5% Aq, the overproduction of CAT and SOD was correlated with the inactivation of the NF-κB pathway, which, otherwise, as we show, is activated upon EHP infection of SGP cells. In a challenge test, Aq was able to significantly reduce mortality in EHP-infected shrimp and increase the levels of CAT and SOD in the gut tissue. Conclusively, these results show, for the first time, that a mixture of natural antimicrobials (Aq) can reduce the EHP-spore activity, improve the survival rates of primary gut-shrimp epithelial cells and reduce the oxidative damage caused by EHP infection. Moreover, we show that Aq was able to stop the H₂O₂ activation of the NF-κB pathway of Crustins, Penaeidins, and the lysozyme, and the CAT and SOD activity both in vitro and in a shrimp challenge test. Full article

(This article belongs to the Special Issue Studies on the Cytotoxicity and Antimicrobial Effects of Synthetic and Natural Compounds)

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12 pages, 3226 KiB

Open AccessEditor’s ChoiceArticle

Inherently Fluorescent Peanut-Shaped Polymersomes for Active Cargo Transportation

by Jianhong Wang, Yingtong Luo, Hanglong Wu, Shoupeng Cao, Loai K. E. A. Abdelmohsen, Jingxin Shao and Jan C. M. van Hest

Pharmaceutics 2023, 15(7), 1986; https://doi.org/10.3390/pharmaceutics15071986 - 20 Jul 2023

Cited by 3 | Viewed by 1506

Abstract

Nanomotors have been extensively explored for various applications in nanomedicine, especially in cargo transportation. Motile properties enable them to deliver pharmaceutical ingredients more efficiently to the targeted site. However, it still remains a challenge to design motor systems that are therapeutically active and [...] Read more.

Nanomotors have been extensively explored for various applications in nanomedicine, especially in cargo transportation. Motile properties enable them to deliver pharmaceutical ingredients more efficiently to the targeted site. However, it still remains a challenge to design motor systems that are therapeutically active and can also be effectively traced when taken up by cells. Here, we designed a nanomotor with integrated fluorescence and therapeutic potential based on biodegradable polymersomes equipped with aggregation-induced emission (AIE) agents. The AIE segments provided the polymersomes with autofluorescence, facilitating the visualization of cell uptake. Furthermore, the membrane structure enabled the reshaping of the AIE polymersomes into asymmetric, peanut-shaped polymersomes. Upon laser irradiation, these peanut polymersomes not only displayed fluorescence, but also produced reactive oxygen species (ROS). Because of their specific shape, the ROS gradient induced motility in these particles. As ROS is also used for cancer cell treatment, the peanut polymersomes not only acted as delivery vehicles but also as therapeutic agents. As an integrated platform, these peanut polymersomes therefore represent an interesting delivery system with biomedical potential. Full article

(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)

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20 pages, 1926 KiB

Open AccessEditor’s ChoiceReview

SGLT2 Inhibitors in the Treatment of Diabetic Kidney Disease: More than Just Glucose Regulation

by Jasna Klen and Vita Dolžan

Pharmaceutics 2023, 15(7), 1995; https://doi.org/10.3390/pharmaceutics15071995 - 20 Jul 2023

Cited by 9 | Viewed by 5307

Abstract

Diabetic kidney disease (DKD) is a severe and common complication and affects a quarter of patients with type 2 diabetes mellitus (T2DM). Oxidative stress and inflammation related to hyperglycemia are interlinked and contribute to the occurrence of DKD. It was shown that sodium–glucose [...] Read more.

Diabetic kidney disease (DKD) is a severe and common complication and affects a quarter of patients with type 2 diabetes mellitus (T2DM). Oxidative stress and inflammation related to hyperglycemia are interlinked and contribute to the occurrence of DKD. It was shown that sodium–glucose cotransporter-2 (SGLT2) inhibitors, a novel yet already widely used therapy, may prevent the development of DKD and alter its natural progression. SGLT2 inhibitors induce systemic and glomerular hemodynamic changes, provide metabolic advantages, and reduce inflammatory and oxidative stress pathways. In T2DM patients, regardless of cardiovascular diseases, SGLT2 inhibitors may reduce albuminuria, progression of DKD, and doubling of serum creatinine levels, thus lowering the need for kidney replacement therapy by over 40%. The molecular mechanisms behind these beneficial effects of SGLT2 inhibitors extend beyond their glucose-lowering effects. The emerging studies are trying to explain these mechanisms at the genetic, epigenetic, transcriptomic, and proteomic levels. Full article

(This article belongs to the Special Issue Effective Therapies for Diabetes)

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17 pages, 3288 KiB

Open AccessEditor’s ChoiceArticle

Targeted Bioluminescent Imaging of Pancreatic Ductal Adenocarcinoma Using Nanocarrier-Complexed EGFR-Binding Affibody–Gaussia Luciferase Fusion Protein

by Jessica Hersh, Yu-Ping Yang, Evan Roberts, Daniel Bilbao, Wensi Tao, Alan Pollack, Sylvia Daunert and Sapna K. Deo

Pharmaceutics 2023, 15(7), 1976; https://doi.org/10.3390/pharmaceutics15071976 - 19 Jul 2023

Cited by 5 | Viewed by 1606

Abstract

In vivo imaging has enabled impressive advances in biological research, both preclinical and clinical, and researchers have an arsenal of imaging methods available. Bioluminescence imaging is an advantageous method for in vivo studies that allows for the simple acquisition of images with low [...] Read more.

In vivo imaging has enabled impressive advances in biological research, both preclinical and clinical, and researchers have an arsenal of imaging methods available. Bioluminescence imaging is an advantageous method for in vivo studies that allows for the simple acquisition of images with low background signals. Researchers have increasingly been looking for ways to improve bioluminescent imaging for in vivo applications, which we sought to achieve by developing a bioluminescent probe that could specifically target cells of interest. We chose pancreatic ductal adenocarcinoma (PDAC) as the disease model because it is the most common type of pancreatic cancer and has an extremely low survival rate. We targeted the epidermal growth factor receptor (EGFR), which is frequently overexpressed in pancreatic cancer cells, using an EGFR-specific affibody to selectively identify PDAC cells and delivered a Gaussia luciferase (GLuc) bioluminescent protein for imaging by engineering a fusion protein with both the affibody and the bioluminescent protein. This fusion protein was then complexed with a G5-PAMAM dendrimer nanocarrier. The dendrimer was used to improve the protein stability in vivo and increase signal strength. Our targeted bioluminescent complex had an enhanced uptake into PDAC cells in vitro and localized to PDAC tumors in vivo in pancreatic cancer xenograft mice. The bioluminescent complexes could delineate the tumor shape, identify multiple masses, and locate metastases. Through this work, an EGFR-targeted bioluminescent–dendrimer complex enabled the straightforward identification and imaging of pancreatic cancer cells in vivo in preclinical models. This argues for the targeted nanocarrier-mediated delivery of bioluminescent proteins as a way to improve in vivo bioluminescent imaging. Full article

(This article belongs to the Special Issue Dendrimers for Drug Delivery)

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