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Pharmaceutics, Volume 14, Issue 2 (February 2022) – 251 articles

Cover Story (view full-size image): Delivery of therapeutics to the brain continues to be a challenge for researchers, and new modes of drug-delivery methodologies continue to be researched. This article presents a comprehensive review of the various nano-based drug delivery systems that help with drug delivery across the blood–brain barrier. Inorganic nanodelivery systems including gold and magnetic nanoparticles, as well as organic systems such as dendrimers, liposomes, niosomes, micelles, and polymeric nanoparticles, are discussed. Various techniques commonly used to functionalize nanoparticles for brain delivery are also discussed, including surface modification through physical adsorption using electrostatic forces, chemical crosslinkage, covalent end-group modifications, and layer-by-layer assembly techniques. View this paper.
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19 pages, 5741 KiB  
Article
Carboxyl-Functionalized Carbon Nanotubes Loaded with Cisplatin Promote the Inhibition of PI3K/Akt Pathway and Suppress the Migration of Breast Cancer Cells
by Madalina Andreea Badea, Mihaela Balas, Mariana Prodana, Florentina Gina Cojocaru, Daniela Ionita and Anca Dinischiotu
Pharmaceutics 2022, 14(2), 469; https://doi.org/10.3390/pharmaceutics14020469 - 21 Feb 2022
Cited by 12 | Viewed by 2496
Abstract
PI3K/Akt signaling is one of the most frequently dysregulated pathways in cancer, including triple-negative breast cancer. With considerable roles in tumor growth and proliferation, this pathway is studied as one of the main targets in controlling the therapies’ efficiency. Nowadays, the development of [...] Read more.
PI3K/Akt signaling is one of the most frequently dysregulated pathways in cancer, including triple-negative breast cancer. With considerable roles in tumor growth and proliferation, this pathway is studied as one of the main targets in controlling the therapies’ efficiency. Nowadays, the development of nanoparticle–drug conjugates attracts a great deal of attention due to the advantages they provide in cancer treatment. Hence, the main purpose of this study was to design a nanoconjugate based on single-walled carbon nanotubes functionalized with carboxyl groups (SWCNT-COOH) and cisplatin (CDDP) and to explore the potential of inhibiting the PI3K/Akt signaling pathway. MDA-MB-231 cells were exposed to various doses (0.01–2 µg/mL SWCNT-COOH and 0.00632–1.26 µg/mL CDDP) of SWCNT-COOH-CDDP and free components for 24 and 48 h. In vitro biological tests revealed that SWCNT-COOH-CDDP had a high cytotoxic effect, as shown by a time-dependent decrease in cell viability and the presence of a significant number of dead cells in MDA-MB-231 cultures at higher doses. Moreover, the nanoconjugates induced the downregulation of PI3K/Akt signaling, as revealed by the decreased expression of PI3K and p-Akt in parallel with PTEN activation, the promotion of Akt protein degradation, and inhibition of tumor cell migration. Full article
(This article belongs to the Special Issue Novel Strategies for Cancer Targeted Delivery)
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18 pages, 14895 KiB  
Article
An On-Demand Drug Delivery System for Control of Epileptiform Seizures
by Takashi Nakano, Shakila B. Rizwan, David M. A. Myint, Jason Gray, Sean M. Mackay, Paul Harris, Christopher G. Perk, Brian I. Hyland, Ruth Empson, Eng Wui Tan, Keshav M. Dani, John NJ Reynolds and Jeffery R. Wickens
Pharmaceutics 2022, 14(2), 468; https://doi.org/10.3390/pharmaceutics14020468 - 21 Feb 2022
Cited by 8 | Viewed by 4505
Abstract
Drug delivery systems have the potential to deliver high concentrations of drug to target areas on demand, while elsewhere and at other times encapsulating the drug, to limit unwanted actions. Here we show proof of concept in vivo and ex vivo tests of [...] Read more.
Drug delivery systems have the potential to deliver high concentrations of drug to target areas on demand, while elsewhere and at other times encapsulating the drug, to limit unwanted actions. Here we show proof of concept in vivo and ex vivo tests of a novel drug delivery system based on hollow-gold nanoparticles tethered to liposomes (HGN-liposomes), which become transiently permeable when activated by optical or acoustic stimulation. We show that laser or ultrasound simulation of HGN-liposomes loaded with the GABAA receptor agonist, muscimol, triggers rapid and repeatable release in a sufficient concentration to inhibit neurons and suppress seizure activity. In particular, laser-stimulated release of muscimol from previously injected HGN-liposomes caused subsecond hyperpolarizations of the membrane potential of hippocampal pyramidal neurons, measured by whole cell intracellular recordings with patch electrodes. In hippocampal slices and hippocampal–entorhinal cortical wedges, seizure activity was immediately suppressed by muscimol release from HGN-liposomes triggered by laser or ultrasound pulses. After intravenous injection of HGN-liposomes in whole anesthetized rats, ultrasound stimulation applied to the brain through the dura attenuated the seizure activity induced by pentylenetetrazol. Ultrasound alone, or HGN-liposomes without ultrasound stimulation, had no effect. Intracerebrally-injected HGN-liposomes containing kainic acid retained their contents for at least one week, without damage to surrounding tissue. Thus, we demonstrate the feasibility of precise temporal control over exposure of neurons to the drug, potentially enabling therapeutic effects without continuous exposure. For future application, studies on the pharmacokinetics, pharmacodynamics, and toxicity of HGN-liposomes and their constituents, together with improved methods of targeting, are needed, to determine the utility and safety of the technology in humans. Full article
(This article belongs to the Special Issue Brain-Targeted Drug Delivery)
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11 pages, 859 KiB  
Article
Drug Properties Prediction Based on Deep Learning
by Soyoung Yoo, Junghyun Kim and Guang J. Choi
Pharmaceutics 2022, 14(2), 467; https://doi.org/10.3390/pharmaceutics14020467 - 21 Feb 2022
Cited by 9 | Viewed by 2535
Abstract
In recent research on the formulation prediction of oral dissolving drugs, deep learning models with significantly improved performance compared to machine learning models were proposed. However, the performance degradation due to limitations of an imbalanced dataset with a small size and inefficient neural [...] Read more.
In recent research on the formulation prediction of oral dissolving drugs, deep learning models with significantly improved performance compared to machine learning models were proposed. However, the performance degradation due to limitations of an imbalanced dataset with a small size and inefficient neural network structure has still not been resolved. Therefore, we propose new deep learning-based prediction models that maximize the prediction performance for disintegration time of oral fast disintegrating films (OFDF) and cumulative dissolution profiles of sustained-release matrix tablets (SRMT). In the case of OFDF, we use principal component analysis (PCA) to reduce the dimensionality of the dataset, thereby improving the prediction performance and reducing the training time. In the case of SRMT, the Wasserstein generative adversarial network (WGAN), a neural network-based generative model, is used to overcome the limitation of performance improvement due to the lack of experimental data. To the best of our knowledge, this is the first work that utilizes WGAN for pharmaceutical formulation prediction. Experimental results show that the proposed methods have superior performance than the existing methods for all the performance metrics considered. Full article
(This article belongs to the Special Issue Computational Intelligence (CI) Tools in Drug Discovery and Design)
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20 pages, 7656 KiB  
Article
Hyaluronic Acid Nanoparticles for Immunogenic Chemotherapy of Leukemia and T-Cell Lymphoma
by Vinu Krishnan, Vimisha Dharamdasani, Shirin Bakre, Ved Dhole, Debra Wu, Bogdan Budnik and Samir Mitragotri
Pharmaceutics 2022, 14(2), 466; https://doi.org/10.3390/pharmaceutics14020466 - 21 Feb 2022
Cited by 7 | Viewed by 3738
Abstract
Ratiometric delivery of combination chemotherapy can achieve therapeutic efficacy based on synergistic interactions between drugs. It is critical to design such combinations with drugs that complement each other and reduce cancer growth through multiple mechanisms. Using hyaluronic acid (HA) as a carrier, two [...] Read more.
Ratiometric delivery of combination chemotherapy can achieve therapeutic efficacy based on synergistic interactions between drugs. It is critical to design such combinations with drugs that complement each other and reduce cancer growth through multiple mechanisms. Using hyaluronic acid (HA) as a carrier, two chemotherapeutic agents—doxorubicin (DOX) and camptothecin (CPT)—were incorporated and tested for their synergistic potency against a broad panel of blood-cancer cell lines. The pair also demonstrated the ability to achieve immunogenic cell death by increasing the surface exposure levels of Calreticulin, thereby highlighting its ability to induce apoptosis via an alternate pathway. Global proteomic profiling of cancer cells treated with HA–DOX–CPT identified pathways that could potentially predict patient sensitivity to HA–DOX–CPT. This lays the foundation for further exploration of integrating drug delivery and proteomics in personalized immunogenic chemotherapy. Full article
(This article belongs to the Special Issue Pharmaceutical and Bioengineering Advances in Medicine)
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13 pages, 22569 KiB  
Article
A Non-thermal Biocompatible Plasma-Modified Chitosan Scaffold Enhances Osteogenic Differentiation in Bone Marrow Stem Cells
by Ihn Han, Juie Nahushkumar Rana, Ji-Hye Kim, Eun Ha Choi and Youngsun Kim
Pharmaceutics 2022, 14(2), 465; https://doi.org/10.3390/pharmaceutics14020465 - 21 Feb 2022
Cited by 13 | Viewed by 2347
Abstract
Non-thermal biocompatible plasma (NBP) was considered as an efficient tool in tissue engineering to modify the surface of biomaterials. Three-dimensional chitosan scaffolds have been extensively used in different ways because it holds some remarkable properties, including biodegradability and biocompatibility. In this study, we [...] Read more.
Non-thermal biocompatible plasma (NBP) was considered as an efficient tool in tissue engineering to modify the surface of biomaterials. Three-dimensional chitosan scaffolds have been extensively used in different ways because it holds some remarkable properties, including biodegradability and biocompatibility. In this study, we evaluated the osteogenic potential of NBP-treated chitosan scaffolds using two different plasma sources: a dielectric barrier discharge (NBP-DBD) and a soft jet (NBP-J). The surface modification of the scaffold was evaluated using scanning electron microscopy. For osteogenic differentiation of cells, proliferation and differentiation were tested by using bone marrow-derived stem cells (BMSCs). We observed that cell viability using NBP-DBD and NBP-J treated chitosan scaffolds yielded significant improvements in cell viability and differentiation. The results obtained with MTT and live/dead assays showed that NBP-modified scaffold increases cell metabolic by MTT assay and live/dead assay. It also observed that the NBP treatment is more effective at 5 min with DBD and was selected for further investigations. Enhanced osteogenic differentiation was observed using NBP-treated scaffolds, as reflected by increased alkaline phosphatase activity. Our findings showed that NBP is an innovative and beneficial tool for modifying chitosan scaffolds to increase their activity, making them suitable as biocompatible materials and for bone tissue engineering. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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46 pages, 8281 KiB  
Review
The 3D Bioprinted Scaffolds for Wound Healing
by Pablo Edmundo Antezana, Sofia Municoy, María Inés Álvarez-Echazú, Pablo Luis Santo-Orihuela, Paolo Nicolás Catalano, Taleb H. Al-Tel, Firoz Babu Kadumudi, Alireza Dolatshahi-Pirouz, Gorka Orive and Martin Federico Desimone
Pharmaceutics 2022, 14(2), 464; https://doi.org/10.3390/pharmaceutics14020464 - 21 Feb 2022
Cited by 58 | Viewed by 6647
Abstract
Skin tissue engineering and regeneration aim at repairing defective skin injuries and progress in wound healing. Until now, even though several developments are made in this field, it is still challenging to face the complexity of the tissue with current methods of fabrication. [...] Read more.
Skin tissue engineering and regeneration aim at repairing defective skin injuries and progress in wound healing. Until now, even though several developments are made in this field, it is still challenging to face the complexity of the tissue with current methods of fabrication. In this review, short, state-of-the-art on developments made in skin tissue engineering using 3D bioprinting as a new tool are described. The current bioprinting methods and a summary of bioink formulations, parameters, and properties are discussed. Finally, a representative number of examples and advances made in the field together with limitations and future needs are provided. Full article
(This article belongs to the Special Issue Biopolymer Materials for Wound Healing)
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18 pages, 6024 KiB  
Article
NanoSIMS Imaging Reveals the Impact of Ligand-ASO Conjugate Stability on ASO Subcellular Distribution
by Emma Kay, Rouven Stulz, Cécile Becquart, Jelena Lovric, Carolina Tängemo, Aurélien Thomen, Dženita Baždarević, Neda Najafinobar, Anders Dahlén, Anna Pielach, Julia Fernandez-Rodriguez, Roger Strömberg, Carina Ämmälä, Shalini Andersson and Michael Kurczy
Pharmaceutics 2022, 14(2), 463; https://doi.org/10.3390/pharmaceutics14020463 - 21 Feb 2022
Cited by 5 | Viewed by 4765
Abstract
The delivery of antisense oligonucleotides (ASOs) to specific cell types via targeted endocytosis is challenging due to the low cell surface expression of target receptors and inefficient escape of ASOs from the endosomal pathway. Conjugating ASOs to glucagon-like peptide 1 (GLP1) leads to [...] Read more.
The delivery of antisense oligonucleotides (ASOs) to specific cell types via targeted endocytosis is challenging due to the low cell surface expression of target receptors and inefficient escape of ASOs from the endosomal pathway. Conjugating ASOs to glucagon-like peptide 1 (GLP1) leads to efficient target knockdown, specifically in pancreatic β-cells. It is presumed that ASOs dissociate from GLP1 intracellularly to enable an ASO interaction with its target RNA. It is unknown where or when this happens following GLP1-ASO binding to GLP1R and endocytosis. Here, we use correlative nanoscale secondary ion mass spectroscopy (NanoSIMS) and transmission electron microscopy to explore GLP1-ASO subcellular trafficking in GLP1R overexpressing HEK293 cells. We isotopically label both eGLP1 and ASO, which do not affect the eGLP1-ASO conjugate function. We found that the eGLP1 peptide and ASO are not detected at the same level in the same endosomes, within 30 min of GLP1R-HEK293 cell exposure to eGLP1-ASO. When we utilized different linker chemistry to stabilize the GLP1-ASO conjugate, we observed more ASO located with GLP1 compared to cell incubation with the less stable conjugate. Overall, our work suggests that the ASO separates from GLP1 relatively early in the endocytic pathway, and that linker chemistry might impact the GLP1-ASO function. Full article
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18 pages, 17120 KiB  
Article
Silver Nimesulide Complex in Bacterial Cellulose Membranes as an Innovative Therapeutic Method for Topical Treatment of Skin Squamous Cell Carcinoma
by Tuany Zambroti Candido, Raphael Enoque Ferraz de Paiva, Mariana Cecchetto Figueiredo, Lilian de Oliveira Coser, Silmara Cristina Lazarini Frajácomo, Camilla Abbehausen, Izilda Aparecida Cardinalli, Wilton Rogerio Lustri, João Ernesto Carvalho, Ana Lucia Tasca Gois Ruiz, Pedro Paulo Corbi and Carmen Silvia Passos Lima
Pharmaceutics 2022, 14(2), 462; https://doi.org/10.3390/pharmaceutics14020462 - 21 Feb 2022
Cited by 15 | Viewed by 2843
Abstract
Oxidative stress and inflammation act on skin squamous cell carcinoma (SSCC) development and progression. Curative therapy for SSCC patients is mainly based on surgical resection, which can cause various sequelae. Silver ions have in vitro activities over tumor cells, while nimesulide has antioxidant [...] Read more.
Oxidative stress and inflammation act on skin squamous cell carcinoma (SSCC) development and progression. Curative therapy for SSCC patients is mainly based on surgical resection, which can cause various sequelae. Silver ions have in vitro activities over tumor cells, while nimesulide has antioxidant and anti-inflammatory activities. This study aimed to evaluate the effects of a silver(I) complex with nimesulide (AgNMS) incorporated in a sustained release device based on bacterial cellulose membrane, named AgNMS@BCM, on topic SSCC treatment. The antiproliferative effect of AgNMS complex was evaluated in the SCC4, SCC15 and FaDu SCC lines. AgNMS complex activity on exposure of phosphatidylserine (PS) residues and multicaspase activation were evaluated on FaDu cells by flow cytometry. The AgNMS@BCM effects were evaluated in a SSCC model induced by 7,12-dimethylbenzanthracene/12-o-tetradecanoyl-phorbol-13-acetate (DMBA/TPA) in mice. Toxicity and tumor size were evaluated throughout the study. AgNMS complex showed antiproliferative activity in SCC15 and FaDu lines in low to moderate concentrations (67.3 µM and 107.3 µM, respectively), and induced multicaspase activation on FaDu cells. The AgNMS@BCM did not induce toxicity and reduced tumor size up to 100%. Thus, the application of AgNMS@BCM was effective and safe in SSCC treatment in mice, and can be seen as a potential and safe agent for topic treatment of SSCC in humans. Full article
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23 pages, 2394 KiB  
Article
Multicenter Observational/Exploratory Study Addressed to the Evaluation of the Effectiveness and Safety of Pharmacological Therapy in Opioid-Dependent Patients in Maintenance Therapy in Southern Italy
by Fatima Maqoud, Giada Fabio, Nunzio Ciliero, Marina Antonacci, Francesca Mastrangelo, Giorgio Sammarruco, Roberto Cataldini, Gabriella Schirosi, Salvatore De Fazio and Domenico Tricarico
Pharmaceutics 2022, 14(2), 461; https://doi.org/10.3390/pharmaceutics14020461 - 21 Feb 2022
Cited by 3 | Viewed by 2584
Abstract
A multicenter-observational study was performed to assess the effectiveness of rac-methadone, levomethadone, and buprenorphine in opioid-dependent patients in polytherapy in Southern Italy. The primary endpoint was the reduction of urinary positivity to the substances and the maintaining doses. Patients (N = 266, age [...] Read more.
A multicenter-observational study was performed to assess the effectiveness of rac-methadone, levomethadone, and buprenorphine in opioid-dependent patients in polytherapy in Southern Italy. The primary endpoint was the reduction of urinary positivity to the substances and the maintaining doses. Patients (N = 266, age = 44.80 ± 5.65, male = 79.70%, female = 20.30%) have been recruited. At recruitment, 75% of them were on treatment with rac-methadone, levomethadone, and buprenorphine/naloxone. The patients were grouped into three clusters. The levomethadone patients of Cluster A (N patients = 211), after 180 days, showed stability in urinary methadone positivity, with a marked decrease in heroin −53 ± 4%, cannabinol’s −48 ± 2%, and cocaine −37 ± 6% positivity, with no differences between treatments. A lower QTcF value of 426 ± 8.4 ms was recorded in the levomethadone patients (delta = −19 ms) vs. rac-methadone, at significantly lower doses of levomethadone (−34%, −50.2% in males) (p < 0.05). The Cluster B data were collected from 37 patients, with a high prevalence of comorbidity infections (HIV/HCV/HPV), monitored for 21 months during COVID-19. High doses of levomethadone (58.33 ± 31.58 mg/day) were needed to stabilize those that were negative for opioids and cannabinoids, in contrast to the rac-methadone and buprenorphine/naloxone patients that showed positive toxicology. Eighteen patients of the Cluster C in double diagnosis (major depressive 38.90%, bipolar 27.78%, and schizophrenia 16.67%) were stabilized with high doses of racemate 97.5 ± 8 mg/day, 51.8 ± 5 mg/day of levomethadone (−46.8% vs. rac-methadone; −71% in men), and 2.5 ± 1 mg/day of buprenorphine/naloxone. Three patients in remission were treated with tapering doses of levomethadone. Significantly reduced QTcF values were recorded with levomethadone (delta −32 ms vs. rac-methadone) in the bipolar patients, as well as the schizophrenia patients in remission (delta −45.19 ms vs. rac-methadone). Our patients were safely stabilized. Levomethadone, compared to the racemate, contributes to reducing the illicit use, especially of opioids and cannabinoids at significantly lower doses with cardiovascular safety, which, in bipolar patients, is clinically significant. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring as a Useful Tool in Therapy Improvement)
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33 pages, 23040 KiB  
Review
The Potential of Nanomedicine to Unlock the Limitless Applications of mRNA
by Laura Taina-González and María de la Fuente
Pharmaceutics 2022, 14(2), 460; https://doi.org/10.3390/pharmaceutics14020460 - 21 Feb 2022
Cited by 11 | Viewed by 6921
Abstract
The year 2020 was a turning point in the way society perceives science. Messenger RNA (mRNA) technology finally showed and shared its potential, starting a new era in medicine. However, there is no doubt that commercialization of these vaccines would not have been [...] Read more.
The year 2020 was a turning point in the way society perceives science. Messenger RNA (mRNA) technology finally showed and shared its potential, starting a new era in medicine. However, there is no doubt that commercialization of these vaccines would not have been possible without nanotechnology, which has finally answered the long-term question of how to deliver mRNA in vivo. The aim of this review is to showcase the importance of this scientific milestone for the development of additional mRNA therapeutics. Firstly, we provide a full description of the marketed vaccine formulations and disclose LNPs’ pharmaceutical properties, including composition, structure, and manufacturing considerations Additionally, we review different types of lipid-based delivery technologies currently in preclinical and clinical development, namely lipoplexes and cationic nanoemulsions. Finally, we highlight the most promising clinical applications of mRNA in different fields such as vaccinology, immuno-oncology, gene therapy for rare genetic diseases and gene editing using CRISPR Cas9. Full article
(This article belongs to the Special Issue Messenger RNA Therapeutics)
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17 pages, 3179 KiB  
Article
Multiple Light-Activated Photodynamic Therapy of Tetraphenylethylene Derivative with AIE Characteristics for Hepatocellular Carcinoma via Dual-Organelles Targeting
by Chuxing Chai, Tao Zhou, Jianfang Zhu, Yong Tang, Jun Xiong, Xiaobo Min, Qi Qin, Min Li, Na Zhao and Chidan Wan
Pharmaceutics 2022, 14(2), 459; https://doi.org/10.3390/pharmaceutics14020459 - 21 Feb 2022
Cited by 14 | Viewed by 3175
Abstract
Photodynamic therapy (PDT) has emerged as a promising locoregional therapy of hepatocellular carcinoma (HCC). The utilization of luminogens with aggregation-induced emission (AIE) characteristics provides a new opportunity to design functional photosensitizers (PS). PSs targeting the critical organelles that are susceptible to reactive oxygen [...] Read more.
Photodynamic therapy (PDT) has emerged as a promising locoregional therapy of hepatocellular carcinoma (HCC). The utilization of luminogens with aggregation-induced emission (AIE) characteristics provides a new opportunity to design functional photosensitizers (PS). PSs targeting the critical organelles that are susceptible to reactive oxygen species damage is a promising strategy to enhance the effectiveness of PDT. In this paper, a new PS, 1-[2-hydroxyethyl]-4-[4-(1,2,2-triphenylvinyl)styryl]pyridinium bromide (TPE-Py-OH) of tetraphenylethylene derivative with AIE feature was designed and synthesized for PDT. The TPE-Py-OH can not only simultaneously target lipid droplets and mitochondria, but also stay in cells for a long period (more than 7 days). Taking advantage of the long retention ability of TPE-Py-OH in tumor, the PDT effect of TPE-Py-OH can be activated through multiple irradiations after one injection, which provides a specific multiple light-activated PDT effect. We believe that this AIE-active PS will be promising for the tracking and photodynamic ablation of HCC with sustained effectiveness. Full article
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24 pages, 4716 KiB  
Article
Increased Targeting Area in Tumors by Dual-Ligand Modification of Liposomes with RGD and TAT Peptides
by Mohamadreza Amin, Mercedeh Mansourian, Peter C. Burgers, Bahareh Amin, Mahmoud Reza Jaafari and Timo L. M. ten Hagen
Pharmaceutics 2022, 14(2), 458; https://doi.org/10.3390/pharmaceutics14020458 - 21 Feb 2022
Cited by 13 | Viewed by 3259
Abstract
Modification with polyethylene glycol (PEGylation) and the use of rigid phospholipids drastically improve the pharmacokinetics of chemotherapeutics and result in more manageable or reduced side-effects. A major drawback is retarded cellular delivery of content, which, along with tumor heterogeneity, are the two main [...] Read more.
Modification with polyethylene glycol (PEGylation) and the use of rigid phospholipids drastically improve the pharmacokinetics of chemotherapeutics and result in more manageable or reduced side-effects. A major drawback is retarded cellular delivery of content, which, along with tumor heterogeneity, are the two main obstacles against tumor targeting. To enhance cellular delivery and reach a bigger area of a tumor, we designed liposomes decorated with two ligands: one for targeting tumor vasculature via a cyclic-pentapeptide containing arginine-glycine-aspartic acid (RGD), which impacts tumor independent of passive accumulation inside tumors, and one for extravascular targeting of tumor cells via a cell-penetrating peptide derived from human immunodeficiency virus type 1 transactivator of transcription (TAT). Liposomes with different ligand combinations were prepared and compared with respect to performance in targeting. Intravital imaging illustrates the heterogeneous behavior of RGD-liposomes in both intravascular and extravascular distribution, whereas TAT-liposomes exhibit a predictable extravascular localization but no intravascular targeting. Dual-ligand modification results in enhanced vascular targeting and a predictable extravascular behavior that improves the therapeutic efficacy of doxorubicin-loaded liposomes but also an augmented clearance rate of liposomes. However, the dual-modified liposome could be a great candidate for targeted delivery of non-toxic payloads or contrast agents for therapeutic or diagnostic purposes. Here we show that the combination of vascular-specific and tumor cell-specific ligands in a liposomal system is beneficial in bypassing the heterogeneous expression of tumor-specific markers. Full article
(This article belongs to the Special Issue Development of Novel Tumor-Targeting Nanoparticles)
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13 pages, 2011 KiB  
Article
Stability of Plant Leaf-Derived Extracellular Vesicles According to Preservative and Storage Temperature
by Kimin Kim, Jungjae Park, Yehjoo Sohn, Chan-Eui Oh, Ji-Ho Park, Jong-Min Yuk and Ju-Hun Yeon
Pharmaceutics 2022, 14(2), 457; https://doi.org/10.3390/pharmaceutics14020457 - 21 Feb 2022
Cited by 31 | Viewed by 4333
Abstract
Plant-derived extracellular vesicles (EVs) are capable of efficiency delivering mRNAs, miRNAs, bioactive lipids, and proteins to mammalian cells. Plant-derived EVs critically contribute to the ability of plants to defend against pathogen attacks at the plant cell surface. They also represent a novel candidate [...] Read more.
Plant-derived extracellular vesicles (EVs) are capable of efficiency delivering mRNAs, miRNAs, bioactive lipids, and proteins to mammalian cells. Plant-derived EVs critically contribute to the ability of plants to defend against pathogen attacks at the plant cell surface. They also represent a novel candidate natural substance that shows potential to be developed for food, cosmetic, and pharmaceutical products. However, although plant-derived EVs are acknowledged as having potential for various industrial applications, little is known about how their stability is affected by storage conditions. In this study, we evaluated the stability of Dendropanax morbifera leaf-derived extracellular vesicles (LEVs) alone or combined with the preservatives, 1,3-butylene glycol (to yield LEVs-1,3-BG) or TMO (LEVs-TMO). We stored these formulations at −20, 4, 25, and 45 °C for up to 4 weeks, and compared the stability of fresh and stored LEVs. We also assessed the effect of freeze-thawing cycles on the quantity and morphology of the LEVs. We found that different storage temperatures and number of freeze-thawing cycles altered the stability, size distribution, protein content, surface charge, and cellular uptake of LEVs compared to those of freshly isolated LEVs. LEVs-TMO showed higher stability when stored at 4 °C, compared to LEVs and LEVs-1,3-BG. Our study provides comprehensive information on how storage conditions affect LEVs and suggests that the potential industrial applications of plant-derived EVs may be broadened by the use of preservatives. Full article
(This article belongs to the Special Issue Phytopharmaceutical Technology)
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29 pages, 5866 KiB  
Review
Progress and Viewpoints of Multifunctional Composite Nanomaterials for Glioblastoma Theranostics
by Ming-Hsien Chan, Wen-Tse Huang, Aishwarya Satpathy, Ting-Yi Su, Michael Hsiao and Ru-Shi Liu
Pharmaceutics 2022, 14(2), 456; https://doi.org/10.3390/pharmaceutics14020456 - 21 Feb 2022
Cited by 7 | Viewed by 3149
Abstract
The most common malignant tumor of the brain is glioblastoma multiforme (GBM) in adults. Many patients die shortly after diagnosis, and only 6% of patients survive more than 5 years. Moreover, the current average survival of malignant brain tumors is only about 15 [...] Read more.
The most common malignant tumor of the brain is glioblastoma multiforme (GBM) in adults. Many patients die shortly after diagnosis, and only 6% of patients survive more than 5 years. Moreover, the current average survival of malignant brain tumors is only about 15 months, and the recurrence rate within 2 years is almost 100%. Brain diseases are complicated to treat. The reason for this is that drugs are challenging to deliver to the brain because there is a blood–brain barrier (BBB) protection mechanism in the brain, which only allows water, oxygen, and blood sugar to enter the brain through blood vessels. Other chemicals cannot enter the brain due to their large size or are considered harmful substances. As a result, the efficacy of drugs for treating brain diseases is only about 30%, which cannot satisfy treatment expectations. Therefore, researchers have designed many types of nanoparticles and nanocomposites to fight against the most common malignant tumors in the brain, and they have been successful in animal experiments. This review will discuss the application of various nanocomposites in diagnosing and treating GBM. The topics include (1) the efficient and long-term tracking of brain images (magnetic resonance imaging, MRI, and near-infrared light (NIR)); (2) breaking through BBB for drug delivery; and (3) natural and chemical drugs equipped with nanomaterials. These multifunctional nanoparticles can overcome current difficulties and achieve progressive GBM treatment and diagnosis results. Full article
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38 pages, 4503 KiB  
Review
Latest Trends in Surface Modification for Dental Implantology: Innovative Developments and Analytical Applications
by Francesca Accioni, Juan Vázquez, Manuel Merinero, Belén Begines and Ana Alcudia
Pharmaceutics 2022, 14(2), 455; https://doi.org/10.3390/pharmaceutics14020455 - 21 Feb 2022
Cited by 43 | Viewed by 8552
Abstract
An increase in the world population and its life expectancy, as well as the ongoing concern about our physical appearance, have elevated the relevance of dental implantology in recent decades. Engineering strategies to improve the survival rate of dental implants have been widely [...] Read more.
An increase in the world population and its life expectancy, as well as the ongoing concern about our physical appearance, have elevated the relevance of dental implantology in recent decades. Engineering strategies to improve the survival rate of dental implants have been widely investigated, focusing on implant material composition, geometry (usually guided to reduce stiffness), and interface surrounding tissues. Although efforts to develop different implant surface modifications are being applied in commercial dental prostheses today, the inclusion of surface coatings has gained special interest, as they can be tailored to efficiently enhance osseointegration, as well as to reduce bacterial-related infection, minimizing peri-implantitis appearance and its associated risks. The use of biomaterials to replace teeth has highlighted the need for the development of reliable analytical methods to assess the therapeutic benefits of implants. This literature review considers the state-of-the-art strategies for surface modification or coating and analytical methodologies for increasing the survival rate for teeth restoration. Full article
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25 pages, 5276 KiB  
Article
Antifungal and Antibiofilm Activity of Cyclic Temporin L Peptide Analogues against Albicans and Non-Albicans Candida Species
by Rosa Bellavita, Angela Maione, Francesco Merlino, Antonietta Siciliano, Principia Dardano, Luca De Stefano, Stefania Galdiero, Emilia Galdiero, Paolo Grieco and Annarita Falanga
Pharmaceutics 2022, 14(2), 454; https://doi.org/10.3390/pharmaceutics14020454 - 21 Feb 2022
Cited by 21 | Viewed by 3027
Abstract
Temporins are one of the largest families of antimicrobial peptides with both anti-inflammatory and antimicrobial activity. Herein, for a panel of cyclic temporin L isoform analogues, the antifungal and antibiofilm activities were determined against representative Candida strains, including C. albicans, C. glabrata [...] Read more.
Temporins are one of the largest families of antimicrobial peptides with both anti-inflammatory and antimicrobial activity. Herein, for a panel of cyclic temporin L isoform analogues, the antifungal and antibiofilm activities were determined against representative Candida strains, including C. albicans, C. glabrata, C. auris, C. parapsilosis and C. tropicalis. The outcomes indicated a significant anti-candida activity against planktonic and biofilm growth for four peptides (3, 7, 15 and 16). The absence of toxicity up to high concentrations and survival after infection were assessed in vivo by using Galleria mellonella larvae, and the correlation between conformation and cytotoxicity was investigated by fluorescence assays and circular dichroism (CD). By combining fluorescence spectroscopy, CD, dynamic light scattering, confocal and atomic force microscopy, the mode of action of four analogues was hypothesized. The results pinpointed that peptide 3 emerged as a non-toxic compound showing a potent antibiofilm activity and represents a promising compound for biomedical applications. Full article
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17 pages, 2581 KiB  
Article
New Preservative-Free Formulation for the Enhanced Ocular Bioavailability of Prostaglandin Analogues in Glaucoma
by Gabriel Alviset, Yohann Corvis, Karim Hammad, Josiane Lemut, Marc Maury, Nathalie Mignet and Vincent Boudy
Pharmaceutics 2022, 14(2), 453; https://doi.org/10.3390/pharmaceutics14020453 - 20 Feb 2022
Cited by 6 | Viewed by 4433
Abstract
Glaucoma is a wide-spread eye disease caused by elevated intraocular pressure. Uncontrolled, this pressure may lead to damages to the optic nerve. Prostaglandin analogues, such as latanoprost and travoprost (which are water-insoluble active substances), are the most used class of active pharmaceutical ingredient. [...] Read more.
Glaucoma is a wide-spread eye disease caused by elevated intraocular pressure. Uncontrolled, this pressure may lead to damages to the optic nerve. Prostaglandin analogues, such as latanoprost and travoprost (which are water-insoluble active substances), are the most used class of active pharmaceutical ingredient. To administer them as eye drops, preservatives, such as benzalkonium chloride, are used as solubilizers. The latter is known to cause a local inflammation when used chronically and is not recommended for patients with ocular surface disorders. In this work, we sought to use polysorbate 80 (PS80) as a solubilizing agent simultaneously with sodium hyaluronate (NaHA) as a thickener and cytoprotective agent for the corneal surface. The first part of this study assessed the compatibility of the excipients with the active substance, using physicochemical methods such as spectra fluorescence and differential scanning calorimetry (DSC), as well as the solubilization mechanism of PS80 regarding prostaglandin analogues using nuclear magnetic resonance (NMR). The second part evaluated the stability of a formula candidate, its viscosity upon instillation, and its pharmacokinetic profile in rabbits as compared to the commercially approved medicine Travatan®. The results show that sodium hyaluronate is inert with respect to travoprost, while PS80 successfully solubilizes it, meaning that benzalkonium chloride is no longer required. Moreover, the pharmacokinetic profiles of the rabbits showed that the original formula described in the present study enhanced the ocular bioavailability of the drug, making it a promising product to control intraocular pressure with a potential reduced dosage of travoprost, therefore minimizing its related side effects. Full article
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23 pages, 5416 KiB  
Article
Lyotropic Liquid Crystals: A Biocompatible and Safe Material for Local Cardiac Application
by Antonia Mancuso, Eleonora Cianflone, Maria Chiara Cristiano, Nadia Salerno, Martine Tarsitano, Fabiola Marino, Claudia Molinaro, Massimo Fresta, Daniele Torella and Donatella Paolino
Pharmaceutics 2022, 14(2), 452; https://doi.org/10.3390/pharmaceutics14020452 - 20 Feb 2022
Cited by 15 | Viewed by 2552
Abstract
The regeneration of cardiac tissue is a multidisciplinary research field aiming to improve the health condition of the post-heart attack patient. Indeed, myocardial tissue has a poor ability to self-regenerate after severe damage. The scientific efforts focused on the research of a biomaterial [...] Read more.
The regeneration of cardiac tissue is a multidisciplinary research field aiming to improve the health condition of the post-heart attack patient. Indeed, myocardial tissue has a poor ability to self-regenerate after severe damage. The scientific efforts focused on the research of a biomaterial able to adapt to heart tissue, thus guaranteeing the in situ release of active substances or growth promoters. Many types of hydrogels were proposed for this purpose, showing several limitations. The aim of this study was to suggest a new usage for glyceryl monooleate-based lyotropic liquid crystals (LLCs) as a biocompatible and inert material for a myocardial application. The main advantages of LLCs are mainly related to their easy in situ injection as lamellar phase and their instant in situ transition in the cubic phase. In vivo studies proved the biocompatibility and the inertia of LLCs after their application on the myocardial tissue of mice. In detail, the cardiac activity was monitored through 28 days, and no significant alterations were recorded in the heart anatomy and functionality. Moreover, gross anatomy showed the ability of LLCs to be bio-degraded in a suitable time frame. Overall, these results permitted us to suppose a potential use of LLCs as materials for cardiac drug delivery. Full article
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26 pages, 5235 KiB  
Review
Molecular Imaging of Brain Tumors and Drug Delivery Using CEST MRI: Promises and Challenges
by Jianpan Huang, Zilin Chen, Se-Weon Park, Joseph H. C. Lai and Kannie W. Y. Chan
Pharmaceutics 2022, 14(2), 451; https://doi.org/10.3390/pharmaceutics14020451 - 20 Feb 2022
Cited by 17 | Viewed by 4736
Abstract
Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) detects molecules in their natural forms in a sensitive and non-invasive manner. This makes it a robust approach to assess brain tumors and related molecular alterations using endogenous molecules, such as proteins/peptides, and drugs [...] Read more.
Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) detects molecules in their natural forms in a sensitive and non-invasive manner. This makes it a robust approach to assess brain tumors and related molecular alterations using endogenous molecules, such as proteins/peptides, and drugs approved for clinical use. In this review, we will discuss the promises of CEST MRI in the identification of tumors, tumor grading, detecting molecular alterations related to isocitrate dehydrogenase (IDH) and O-6-methylguanine-DNA methyltransferase (MGMT), assessment of treatment effects, and using multiple contrasts of CEST to develop theranostic approaches for cancer treatments. Promising applications include (i) using the CEST contrast of amide protons of proteins/peptides to detect brain tumors, such as glioblastoma multiforme (GBM) and low-grade gliomas; (ii) using multiple CEST contrasts for tumor stratification, and (iii) evaluation of the efficacy of drug delivery without the need of metallic or radioactive labels. These promising applications have raised enthusiasm, however, the use of CEST MRI is not trivial. CEST contrast depends on the pulse sequences, saturation parameters, methods used to analyze the CEST spectrum (i.e., Z-spectrum), and, importantly, how to interpret changes in CEST contrast and related molecular alterations in the brain. Emerging pulse sequence designs and data analysis approaches, including those assisted with deep learning, have enhanced the capability of CEST MRI in detecting molecules in brain tumors. CEST has become a specific marker for tumor grading and has the potential for prognosis and theranostics in brain tumors. With increasing understanding of the technical aspects and associated molecular alterations detected by CEST MRI, this young field is expected to have wide clinical applications in the near future. Full article
(This article belongs to the Special Issue Nanoparticle Delivery to Tumors: Challenges and Advances)
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19 pages, 5971 KiB  
Article
Cutaneous Delivery of Cosmeceutical Peptides Enhanced by Picosecond- and Nanosecond-Domain Nd:YAG Lasers with Quick Recovery of the Skin Barrier Function: Comparison with Microsecond-Domain Ablative Lasers
by Woan-Ruoh Lee, Chien-Yu Hsiao, Zi-Yu Chang, Pei-Wen Wang, Ibrahim A. Aljuffali, Jie-Yu Lin and Jia-You Fang
Pharmaceutics 2022, 14(2), 450; https://doi.org/10.3390/pharmaceutics14020450 - 19 Feb 2022
Cited by 5 | Viewed by 3466
Abstract
Picosecond or nanosecond-domain non-ablative lasers generate faster photothermal effects and cause less injury than microsecond lasers. In this study, we investigated the enhancing effect of 1064 nm picosecond- and nanosecond-domain neodymium (Nd):yttrium–aluminum–garnet (YAG) lasers on the cutaneous delivery of cosmeceutical peptides. Microsecond-domain fractional [...] Read more.
Picosecond or nanosecond-domain non-ablative lasers generate faster photothermal effects and cause less injury than microsecond lasers. In this study, we investigated the enhancing effect of 1064 nm picosecond- and nanosecond-domain neodymium (Nd):yttrium–aluminum–garnet (YAG) lasers on the cutaneous delivery of cosmeceutical peptides. Microsecond-domain fractional ablative CO2 and fully ablative erbium (Er):YAG lasers were also used for comparison. In the Franz diffusion cell study, pig or mouse skin was treated with a laser before exposure to palmitoyl tripeptide (PT)-1, PT-38, and copper tripeptide (CT)-1 at a concentration of 150 μM. Psoriasiform, atopic dermatitis (AD)-like, and photoaged skins were also developed as permeation barriers. The non-ablative laser elicited the ultrastructural disruption of the stratum corneum and epidermal vacuolation. All laser modalities significantly increased the skin permeation of peptides in vitro. The non-ablative laser chiefly enhanced peptide delivery to the receptor compartment, whereas the ablative laser mainly increased the intracutaneous peptide deposition. The picosecond- and nanosecond-domain Nd:YAG lasers elevated the amount of PT-1 in the receptor up to 40- and 22-fold compared with untreated skin, respectively. Laser treatment promoted peptide delivery in barrier-deficient and inflamed skins, although this enhancement effect was less than that observed in healthy skin. Fluorescence microscopy indicated the capability of the non-ablative laser to deliver peptides to deeper skin strata. The ablative laser confined the peptide distribution in the epidermis. Confocal microscopy showed that peptides penetrated the skin along the microdots created by the fractional Nd:YAG and CO2 lasers. The skin barrier function determined by transepidermal water loss suggested quick recovery when using a nanosecond-domain laser (within 4 h). A longer period was needed for the skin treated with the fully ablative Er:YAG laser (76−84 h). Nanosecond non-ablative laser-facilitated peptide delivery may become an efficient and safe approach for cosmeceutical applications. Full article
(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)
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14 pages, 4075 KiB  
Article
Development of Nanosuspension Formulations Compatible with Inkjet Printing for the Convenient and Precise Dispensing of Poorly Soluble Drugs
by Dennis H. Leung
Pharmaceutics 2022, 14(2), 449; https://doi.org/10.3390/pharmaceutics14020449 - 19 Feb 2022
Cited by 9 | Viewed by 2938
Abstract
The pharmaceutical industry has been challenged by the increasing number of poorly soluble drug candidates, resulting in significant issues with obtaining sufficient absorption and bioavailability, risk of exposure variability, and difficulties in achieving a safe therapeutic index. Additionally, the rapid and precise dispensing [...] Read more.
The pharmaceutical industry has been challenged by the increasing number of poorly soluble drug candidates, resulting in significant issues with obtaining sufficient absorption and bioavailability, risk of exposure variability, and difficulties in achieving a safe therapeutic index. Additionally, the rapid and precise dispensing of specific drug dosages is an important aspect that can enable personalized medicines for the patient. Herein, we report on the development of inkjet printing as a method for delivering precise quantities of poorly soluble drug molecules using commercially available equipment. Despite challenges due to low solubility making it difficult to prepare liquid solutions, stable suspensions of drug nanoparticles with the appropriate viscosity were successfully printed and dispensed onto a thin film suitable for delivery. The drug nanoparticles remained intact and could be reconstituted after printing, demonstrating that they remained stable and retained their advantageous particle size. This demonstrates that inkjet printing can be a practical and convenient approach for dispensing poorly soluble drug molecules when formulated as nanosuspensions. Full article
(This article belongs to the Special Issue Nanosuspensions for the Improvement of Drug Bioavailability)
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16 pages, 2521 KiB  
Article
Printing Drugs onto Nails for Effective Treatment of Onychomycosis
by Thomas D. Pollard, Margherita Bonetti, Adam Day, Simon Gaisford, Mine Orlu, Abdul W. Basit, Sudaxshina Murdan and Alvaro Goyanes
Pharmaceutics 2022, 14(2), 448; https://doi.org/10.3390/pharmaceutics14020448 - 19 Feb 2022
Cited by 10 | Viewed by 4259
Abstract
Inkjet printing (IJP) is an emerging technology for the precision dosing of medicines. We report, for the first time, the printing of the antifungal drug terbinafine hydrochloride directly onto nails for the treatment of onychomycosis. A commercial cosmetic nail printer was modified by [...] Read more.
Inkjet printing (IJP) is an emerging technology for the precision dosing of medicines. We report, for the first time, the printing of the antifungal drug terbinafine hydrochloride directly onto nails for the treatment of onychomycosis. A commercial cosmetic nail printer was modified by removing the ink from the cartridge and replacing it with an in-house prepared drug-loaded ink. The drug-loaded ink was designed so that it was comparable to the commercial ink for key printability properties. Linear drug dosing was shown by changing the lightness of the colour selected for printing (R2 = 0.977) and by printing multiple times (R2 = 0.989). The drug loads were measured for heart (271 µg), world (205 µg) and football (133 µg) shapes. A disc diffusion assay against Trpytophan rubrum showed inhibition of fungal growth with printed-on discs. In vitro testing with human nails showed substantial inhibition with printed-on nails. Hence, this is the first study to demonstrate the ability of a nail printer for drug delivery, thereby confirming its potential for onychomycosis treatment. Full article
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19 pages, 2088 KiB  
Article
Lipoaspirate Shows In Vitro Potential for Wound Healing
by Chiara Ceresa, Alessia Borrone, Letizia Fracchia, Maurizio Rinaldi, Alice Marchetti, Carlo Tremolada and Michela Bosetti
Pharmaceutics 2022, 14(2), 447; https://doi.org/10.3390/pharmaceutics14020447 - 19 Feb 2022
Cited by 5 | Viewed by 2765
Abstract
Mesenchymal stem cells (MSCs) are a promising therapy in wound healing, although extensive time and manipulation are necessary for their use. In our previous study on cartilage regeneration, we demonstrated that lipoaspirate acts as a natural scaffold for MSCs and gives rise to [...] Read more.
Mesenchymal stem cells (MSCs) are a promising therapy in wound healing, although extensive time and manipulation are necessary for their use. In our previous study on cartilage regeneration, we demonstrated that lipoaspirate acts as a natural scaffold for MSCs and gives rise to their spontaneous outgrowth, together with a paracrine effect on resident cells that overcome the limitations connected to MSC use. In this study, we aimed to investigate in vitro whether the microfragmented adipose tissue (lipoaspirate), obtained with Lipogems® technology, could promote and accelerate wound healing. We showed the ability of resident cells to outgrow from the clusters of lipoaspirate encapsulated in a 3D collagen substrate as capability of repopulating a culture of human skin. Moreover, we demonstrated that the in vitro lipoaspirate paracrine effect on fibroblasts and keratinocytes proliferation, migration, and contraction rate is mediated by the release of trophic/reparative proteins. Finally, an analysis of the paracrine antibacterial effect of lipoaspirate proved its ability to secrete antibacterial factors and its ability to modulate their secretion in culture media based on a bacterial stimulus. The results suggest that lipoaspirate may be a promising approach in wound healing showing in vitro regenerative and antibacterial activities that could improve current therapeutic strategies. Full article
(This article belongs to the Special Issue Biomaterials in Skin Wound Healing and Tissue Regenerations)
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20 pages, 4378 KiB  
Review
Polymer Conjugates of Antimicrobial Peptides (AMPs) with d-Amino Acids (d-aa): State of the Art and Future Opportunities
by Ottavia Bellotto, Sabrina Semeraro, Antonella Bandiera, Federica Tramer, Nicola Pavan and Silvia Marchesan
Pharmaceutics 2022, 14(2), 446; https://doi.org/10.3390/pharmaceutics14020446 - 19 Feb 2022
Cited by 20 | Viewed by 5607
Abstract
In recent years, antimicrobial peptides (AMPs) have enjoyed a renaissance, as the world is currently facing an emergency in terms of severe infections that evade antibiotics’ treatment. This is due to the increasing emergence and spread of resistance mechanisms. Covalent conjugation with polymers [...] Read more.
In recent years, antimicrobial peptides (AMPs) have enjoyed a renaissance, as the world is currently facing an emergency in terms of severe infections that evade antibiotics’ treatment. This is due to the increasing emergence and spread of resistance mechanisms. Covalent conjugation with polymers is an interesting strategy to modulate the pharmacokinetic profile of AMPs and enhance their biocompatibility profile. It can also be an effective approach to develop active coatings for medical implants and devices, and to avoid biofilm formation on their surface. In this concise review, we focus on the last 5 years’ progress in this area, pertaining in particular to AMPs that contain d-amino acids, as well as their role, and the advantages that may arise from their introduction into AMPs. Full article
(This article belongs to the Special Issue Antimicrobial Peptide-Polymer Conjugates)
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20 pages, 3711 KiB  
Systematic Review
Prevalence and Risk Factors of Augmented Renal Clearance: A Systematic Review and Meta-Analysis
by Fatma Hefny, Anna Stuart, Janice Y. Kung and Sherif Hanafy Mahmoud
Pharmaceutics 2022, 14(2), 445; https://doi.org/10.3390/pharmaceutics14020445 - 19 Feb 2022
Cited by 27 | Viewed by 4576
Abstract
Kidney function assessment in the critically ill overlooks the possibility for hyperfunctioning kidneys, known as augmented renal clearance (ARC), which could contribute to therapeutic failures in the intensive care unit (ICU). The aim of this research is to conduct a systematic review and [...] Read more.
Kidney function assessment in the critically ill overlooks the possibility for hyperfunctioning kidneys, known as augmented renal clearance (ARC), which could contribute to therapeutic failures in the intensive care unit (ICU). The aim of this research is to conduct a systematic review and meta-analysis of prevalence and risk factors of ARC in the critically ill. MEDLINE, Embase, Cochrane Library, CINAHL, Scopus, ProQuest Dissertations and Theses Global databases were searched on 27 October 2020. We included studies conducted in critically ill adults who reported the prevalence and/or risk factors of ARC. We evaluated study quality using the Joanna Briggs Institute appraisal tool. Case reports, reviews, editorials and commentaries were excluded. We generated a random-effects meta-analytic model using the inverse variance method and visualized the pooled estimates using forest plots. Seventy studies were included. The pooled prevalence (95% CI) was 39% (34.9–43.3). Prevalence for neuro, trauma, mixed and sepsis ICUs were 74 (55–87), 58 (48–67), 36 (31–41) and 33 (21–48), respectively. Age, male sex and trauma were associated with ARC with pooled OR (95% CI) of 0.95 (0.93–0.96), 2.36 (1.28–4.36), 2.60 (1.21–5.58), respectively. Limitations included variations in ARC definition, inclusion and exclusion criteria and studies design. In conclusion, ARC is prevalent in critically ill patients, especially those in the neurocritical care and trauma ICU population. Young age, male sex and trauma are risk factors for ARC in those with apparently normal renal function. Further research on optimal dosing of drugs in the setting of ARC is warranted. (Prospero registration: CRD42021246417). Full article
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14 pages, 3023 KiB  
Article
Focused Ultrasound-Induced Blood–Brain Barrier Opening Enhanced α-Synuclein Expression in Mice for Modeling Parkinson’s Disease
by Chung-Yin Lin, Ching-Yun Huang, Chiung-Mei Chen and Hao-Li Liu
Pharmaceutics 2022, 14(2), 444; https://doi.org/10.3390/pharmaceutics14020444 - 18 Feb 2022
Cited by 8 | Viewed by 2652
Abstract
Parkinson’s disease (PD) is characterized by α-synuclein (αSNCA) aggregation in dopaminergic neurons. Gradual accumulation of αSNCA aggregates in substantia nigra (SN) diminishes the normal functioning of soluble αSNCA, leading to a loss of dopamine (DA) neurons. In this study, we developed focused ultrasound-targeted [...] Read more.
Parkinson’s disease (PD) is characterized by α-synuclein (αSNCA) aggregation in dopaminergic neurons. Gradual accumulation of αSNCA aggregates in substantia nigra (SN) diminishes the normal functioning of soluble αSNCA, leading to a loss of dopamine (DA) neurons. In this study, we developed focused ultrasound-targeted microbubble destruction (UTMD)-mediated PD model that could generate the disease phenotype via αSNCA CNS gene delivery. The formation of neuronal aggregates was analyzed with immunostaining. To evaluate the DA cell loss, we used tyrosine hydroxylase immunostaining and HPLC analysis on DA and its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This loss of DA was associated with a dose-dependent impairment in motor function, as assessed by the rotarod motor assessment. We demonstrate that UTMD-induced SNCA expression initiates αSNCA aggregation and results in a 50% loss of DA in SN. UTMD-related dose-dependent neuronal loss was identified, and it correlates with the degree of impairment of motor function. In comparison to chemical neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated and conventional intracerebral (IC)-injected animal models of PD, the UTMD-mediated αSNCA-based mouse model offers the advantage of mimicking the rapid development of the PD phenotype. The PD models that we created using UTMD also prove valuable in assessing specific aspects of PD pathogenesis and can serve as a useful PD model for the development of new therapeutic strategies. Full article
(This article belongs to the Special Issue Ultrasonic Technologies in Imaging and Drug Delivery)
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18 pages, 5513 KiB  
Article
‘Tablet-in-Syringe’: A Novel Dosing Mechanism for Dysphagic Patients Containing Fast-Disintegrating Tablets Fabricated Using Semisolid Extrusion 3D Printing
by Pattaraporn Panraksa, Bin Zhang, Pornchai Rachtanapun, Kittisak Jantanasakulwong, Sheng Qi and Pensak Jantrawut
Pharmaceutics 2022, 14(2), 443; https://doi.org/10.3390/pharmaceutics14020443 - 18 Feb 2022
Cited by 21 | Viewed by 4552
Abstract
With the ability to fabricate personalized dosage forms and considerably shorter manufacturing time, semisolid extrusion (SSE) 3D printing has rapidly grown in popularity in recent years as a novel, versatile manufacturing method that powers a wide range of applications in the pharmaceutical field. [...] Read more.
With the ability to fabricate personalized dosage forms and considerably shorter manufacturing time, semisolid extrusion (SSE) 3D printing has rapidly grown in popularity in recent years as a novel, versatile manufacturing method that powers a wide range of applications in the pharmaceutical field. In this work, the feasibility of using SSE 3D printing to fabricate fast-disintegrating tablets (FDTs) that are pre-filled in dosing syringes was evaluated. The novel design approach, ‘tablet-in-syringe’, was aimed to ease the oral drug administration and improve the dosing accuracy for dysphagic patients. The effect of varying polymer (hydroxypropyl methylcellulose E15) concentrations and printing parameters (e.g., extrusion rate) on dimensional accuracy, physicochemical properties, disintegration time, and content uniformity of 3D-printed FDTs was studied. An overall comparison of results demonstrated that the best FDT formulation among those developed was with a polymer:drug ratio (w/w) of 1:30, printed at extrusion rate of 3.5 μL/s. The diameter of printed filaments of this formulation was observed to be similar to the nozzle diameter (22G), proving that good printing accuracy was achieved. This FDTs also had the fastest disintegration time (0.81 ± 0.14 min) and a drug (phenytoin sodium, as the model drug) content uniformity that met pharmacopeial specifications. Although the flow characteristics of the dissolved formulation still need improvement, our findings suggested that the novel ‘tablet-in-syringe’ could potentially be considered as a promising fast-disintegrating drug delivery system that can be personalized and manufactured at—or close to—the point of care for dysphagic patients using SSE. Full article
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13 pages, 2201 KiB  
Article
Free and Open-Source Posologyr Software for Bayesian Dose Individualization: An Extensive Validation on Simulated Data
by Cyril Leven, Anne Coste and Camille Mané
Pharmaceutics 2022, 14(2), 442; https://doi.org/10.3390/pharmaceutics14020442 - 18 Feb 2022
Cited by 5 | Viewed by 2891
Abstract
Model-informed precision dosing is being increasingly used to improve therapeutic drug monitoring. To meet this need, several tools have been developed, but open-source software remains uncommon. Posologyr is a free and open-source R package developed to enable Bayesian individual parameter estimation and dose [...] Read more.
Model-informed precision dosing is being increasingly used to improve therapeutic drug monitoring. To meet this need, several tools have been developed, but open-source software remains uncommon. Posologyr is a free and open-source R package developed to enable Bayesian individual parameter estimation and dose individualization. Before using it for clinical practice, performance validation is mandatory. The estimation functions implemented in posologyr were benchmarked against reference software products on a wide variety of models and pharmacokinetic profiles: 35 population pharmacokinetic models, with 4.000 simulated subjects by model. Maximum A Posteriori (MAP) estimates were compared to NONMEM post hoc estimates, and full posterior distributions were compared to Monolix conditional distribution estimates. The performance of MAP estimation was excellent in 98.7% of the cases. Considering the full posterior distributions of individual parameters, the bias on dosage adjustment proposals was acceptable in 97% of cases with a median bias of 0.65%. These results confirmed the ability of posologyr to serve as a basis for the development of future Bayesian dose individualization tools. Full article
(This article belongs to the Special Issue Model-Informed Precision Dosing)
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27 pages, 12947 KiB  
Article
Genipin-Crosslinked, Proteosaccharide Scaffolds for Potential Neural Tissue Engineering Applications
by Henna Cassimjee, Pradeep Kumar, Philemon Ubanako and Yahya E. Choonara
Pharmaceutics 2022, 14(2), 441; https://doi.org/10.3390/pharmaceutics14020441 - 18 Feb 2022
Cited by 15 | Viewed by 3549
Abstract
Traumatic brain injuries (TBIs) are still a challenge for the field of modern medicine. Many treatment options such as autologous grafts and stem cells show limited promise for the treatment and the reversibility of damage caused by TBIs. Injury beyond the critical size [...] Read more.
Traumatic brain injuries (TBIs) are still a challenge for the field of modern medicine. Many treatment options such as autologous grafts and stem cells show limited promise for the treatment and the reversibility of damage caused by TBIs. Injury beyond the critical size necessitates the implementation of scaffolds that function as surrogate extracellular matrices. Two scaffolds were synthesised utilising polysaccharides, chitosan and hyaluronic acid in conjunction with gelatin. Both scaffolds were chemically crosslinked using a naturally derived crosslinker, Genipin. The polysaccharides increased the mechanical strength of each scaffold, while gelatin provided the bioactive sequence, which promoted cellular interactions. The effect of crosslinking was investigated, and the crosslinked hydrogels showed higher thermal decomposition temperatures, increased resistance to degradation, and pore sizes ranging from 72.789 ± 16.85 µm for the full interpenetrating polymer networks (IPNs) and 84.289 ± 7.658 μm for the semi-IPN. The scaffolds were loaded with Dexamethasone-21-phosphate to investigate their efficacy as a drug delivery vehicle, and the full IPN showed a 100% release in 10 days, while the semi-IPN showed a burst release in 6 h. Both scaffolds stimulated the proliferation of rat pheochromocytoma (PC12) and human glioblastoma multiforme (A172) cell cultures and also provided signals for A172 cell migration. Both scaffolds can be used as potential drug delivery vehicles and as artificial extracellular matrices for potential neural regeneration. Full article
(This article belongs to the Special Issue Application of Chitosan and Hyaluronan in Medicine)
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17 pages, 2774 KiB  
Article
Preclinical PET Imaging of Granzyme B Shows Promotion of Immunological Response Following Combination Paclitaxel and Immune Checkpoint Inhibition in Triple Negative Breast Cancer
by Tiara S. Napier, Chanelle L. Hunter, Patrick N. Song, Benjamin M. Larimer and Anna G. Sorace
Pharmaceutics 2022, 14(2), 440; https://doi.org/10.3390/pharmaceutics14020440 - 18 Feb 2022
Cited by 12 | Viewed by 3241
Abstract
Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to [...] Read more.
Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to IMT with chemotherapy in TNBC. TNBC mouse models received the paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 (anti-PD1) and anti-cytotoxic T-lymphocyte 4 (anti-CTLA4). GZP-PET imaging was performed on treatment days 0, 3, and 6. Mean standard uptake value (SUVmean), effector cell fractions, and SUV histograms were compared. Mice were sacrificed at early imaging timepoints for cytokine and histological analyses. GZP-PET imaging data revealed differences prior to tumor volume changes. By day six, responders had SUVmean ≥ 2.2-fold higher (p < 0.0037) and effector cell fractions ≥ 1.9-fold higher (p = 0.03) compared to non-responders. IMT/PTX resulted in a significantly different SUV distribution compared to control, indicating broader distribution of activated intratumoral T-cells. IMT/PTX resulted in significantly more necrotic tumor tissue and increased levels of IL-2, 4, and 12 compared to control. Results implicate immunogenic cell death through upregulation of key Th1/Th2 cytokines by IMT/PTX. Noninvasive PET imaging can provide data on the TNBC tumor microenvironment, specifically intratumoral effector cell activation, predicting response to IMT plus chemotherapy. Full article
(This article belongs to the Special Issue Molecular Imaging of the Immune System)
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