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Pharmaceutics
Volume 14
Issue 8
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Pharmaceutics, Volume 14, Issue 8 (August 2022) – 229 articles

Cover Story (view full-size image): Cancer immunotherapy is a powerful strategy in the clinic to treat many cancers. The commonly applied immunotherapy strategies include blockade of immune checkpoints, adoptive transfer of engineered cells such as T cells, cytokine therapy, cancer vaccines, and oncolytic virotherapy. Many factors such as off-target side effects, immunosuppressive tumor microenvironment, and cancer cell heterogeneity impact the treatment efficacy and application of immunotherapies against cancers. In addition, some treatments such as chimeric antigen receptor (CAR) T cell therapy have limitations in application against solid tumors. To deal with these drawbacks, delivery systems such as nanoparticles, hydrogel matrix, and exosomes have been developed and applied in recent decades to deliver immunotherapeutic agents. View this paper
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21 pages, 27124 KiB  
Article
A Novel Laser-Based Zebrafish Model for Studying Traumatic Brain Injury and Its Molecular Targets
by Maria A. Tikhonova, Nikolai A. Maslov, Alim A. Bashirzade, Eugenyi V. Nehoroshev, Vladislav Y. Babchenko, Nadezhda D. Chizhova, Elena O. Tsibulskaya, Anna A. Akopyan, Evgeniya V. Markova, Yi-Ling Yang, Kwok-Tung Lu, Allan V. Kalueff, Lyubomir I. Aftanas and Tamara G. Amstislavskaya
Pharmaceutics 2022, 14(8), 1751; https://doi.org/10.3390/pharmaceutics14081751 - 22 Aug 2022
Cited by 6 | Viewed by 3366
Abstract
Traumatic brain injury (TBI) is a major public health problem. Here, we developed a novel model of non-invasive TBI induced by laser irradiation in the telencephalon of adult zebrafish (Danio rerio) and assessed their behavior and neuromorphology to validate the model and evaluate [...] Read more.
Traumatic brain injury (TBI) is a major public health problem. Here, we developed a novel model of non-invasive TBI induced by laser irradiation in the telencephalon of adult zebrafish (Danio rerio) and assessed their behavior and neuromorphology to validate the model and evaluate potential targets for neuroreparative treatment. Overall, TBI induced hypolocomotion and anxiety-like behavior in the novel tank test, strikingly recapitulating responses in mammalian TBI models, hence supporting the face validity of our model. NeuN-positive cell staining was markedly reduced one day, but not seven days, after TBI, suggesting increased neuronal damage immediately after the injury, and its fast recovery. The brain-derived neurotrophic factor (Bdnf) level in the brain dropped immediately after the trauma, but fully recovered seven days later. A marker of microglial activation, Iba1, was elevated in the TBI brain, albeit decreasing from Day 3. The levels of hypoxia-inducible factor 1-alpha (Hif1a) increased 30 min after the injury, and recovered by Day 7, further supporting the construct validity of the model. Collectively, these findings suggest that our model of laser-induced brain injury in zebrafish reproduces mild TBI and can be a useful tool for TBI research and preclinical neuroprotective drug screening. Full article
(This article belongs to the Special Issue Traumatic Brain Injury (TBI) Mechanisms and Novel Therapies)
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10 pages, 1742 KiB  
Article
Implementation of Model-Based Dose Adjustment of Tobramycin in Adult Patients with Cystic Fibrosis
by Jérémy Reverchon, Vianney Tuloup, Romain Garreau, Viviane Nave, Sabine Cohen, Philippe Reix, Stéphane Durupt, Raphaele Nove-Josserand, Isabelle Durieu, Quitterie Reynaud, Laurent Bourguignon, Sandrine Charles and Sylvain Goutelle
Pharmaceutics 2022, 14(8), 1750; https://doi.org/10.3390/pharmaceutics14081750 - 22 Aug 2022
Viewed by 1829
Abstract
Therapeutic drug monitoring (TDM) of tobramycin is widely performed in patients with cystic fibrosis (CF), but little is known about the value of model-informed precision dosing (MIPD) in this setting. We aim at reporting our experience with tobramycin MIPD in adult patients with [...] Read more.
Therapeutic drug monitoring (TDM) of tobramycin is widely performed in patients with cystic fibrosis (CF), but little is known about the value of model-informed precision dosing (MIPD) in this setting. We aim at reporting our experience with tobramycin MIPD in adult patients with CF. We analyzed data from adult patients with CF who received IV tobramycin and had model-guided TDM during the first year of implementation of MIPD. The predictive performance of a pharmacokinetic (PK) model was assessed. Observed maximal (Cmax) and minimal (Cmin) concentrations after initial dosing were compared with target values. We compared the initial doses and adjusted doses after model-based TDM, as well as renal function at the beginning and end of therapy. A total of 78 tobramycin courses were administered in 61 patients. After initial dosing set by physicians (mean, 9.2 ± 1.4 mg/kg), 68.8% of patients did not achieve the target Cmax ≥ 30 mg/L. The PK model fit the data very well, with a median absolute percentage error of 4.9%. MIPD was associated with a significant increase in tobramycin doses (p < 0.001) without significant change in renal function. Model-based dose suggestions were wellaccepted by the physicians and the expected target attainment for Cmax was 83%. To conclude, the implementation of MIPD was effective in changing prescribing practice and was not associated with nephrotoxic events in adult patients with CF. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy)
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40 pages, 5626 KiB  
Review
Fluoroquinolones Hybrid Molecules as Promising Antibacterial Agents in the Fight against Antibacterial Resistance
by Ioana-Andreea Lungu, Octavia-Laura Moldovan, Victoria Biriș and Aura Rusu
Pharmaceutics 2022, 14(8), 1749; https://doi.org/10.3390/pharmaceutics14081749 - 22 Aug 2022
Cited by 38 | Viewed by 6860
Abstract
The emergence of bacterial resistance has motivated researchers to discover new antibacterial agents. Nowadays, fluoroquinolones keep their status as one of the essential classes of antibacterial agents. The new generations of fluoroquinolones are valuable therapeutic tools with a spectrum of activity, including Gram-positive, [...] Read more.
The emergence of bacterial resistance has motivated researchers to discover new antibacterial agents. Nowadays, fluoroquinolones keep their status as one of the essential classes of antibacterial agents. The new generations of fluoroquinolones are valuable therapeutic tools with a spectrum of activity, including Gram-positive, Gram-negative, and atypical bacteria. This review article surveys the design of fluoroquinolone hybrids with other antibacterial agents or active compounds and underlines the new hybrids’ antibacterial properties. Antibiotic fluoroquinolone hybrids have several advantages over combined antibiotic therapy. Thus, some challenges related to joining two different molecules are under study. Structurally, the obtained hybrids may contain a cleavable or non-cleavable linker, an essential element for their pharmacokinetic properties and mechanism of action. The design of hybrids seems to provide promising antibacterial agents helpful in the fight against more virulent and resistant strains. These hybrid structures have proven superior antibacterial activity and less susceptibility to bacterial resistance than the component molecules. In addition, fluoroquinolone hybrids have demonstrated other biological effects such as anti-HIV, antifungal, antiplasmodic/antimalarial, and antitumor activity. Many fluoroquinolone hybrids are in various phases of clinical trials, raising hopes that new antibacterial agents will be approved shortly. Full article
(This article belongs to the Special Issue Drug Targeting towards Fighting Pathogen Bacteria)
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20 pages, 1515 KiB  
Review
An Updated Overview of Cyclodextrin-Based Drug Delivery Systems for Cancer Therapy
by Dan Nicolae Păduraru, Adelina-Gabriela Niculescu, Alexandra Bolocan, Octavian Andronic, Alexandru Mihai Grumezescu and Rodica Bîrlă
Pharmaceutics 2022, 14(8), 1748; https://doi.org/10.3390/pharmaceutics14081748 - 22 Aug 2022
Cited by 31 | Viewed by 4482
Abstract
Encompassing a group of complex and heterogeneous diseases, cancer continues to be a challenge for patients and healthcare systems worldwide. Thus, it is of vital importance to develop advanced treatment strategies that could reduce the trends of cancer-associated morbidity and mortality rates. Scientists [...] Read more.
Encompassing a group of complex and heterogeneous diseases, cancer continues to be a challenge for patients and healthcare systems worldwide. Thus, it is of vital importance to develop advanced treatment strategies that could reduce the trends of cancer-associated morbidity and mortality rates. Scientists have focused on creating performant delivery vehicles for anti-cancer agents. Among the possible materials, cyclodextrins (CDs) attracted increasing interest over the past few years, leading to the emergence of promising anti-tumor nanomedicines. Tackling their advantageous chemical structure, ease of modification, natural origin, biocompatibility, low immunogenicity, and commercial availability, researchers investigated CD-based therapeutical formulations against many types of cancer. In this respect, in this paper, we briefly present the properties of interest of CDs for designing performant nanocarriers, further reviewing some of the most recent potential applications of CD-based delivery systems in cancer management. Full article
(This article belongs to the Special Issue Cyclodextrin-Based Delivery Systems for Anticancer Drugs)
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25 pages, 3532 KiB  
Review
Amorphous Solid Dispersions: Role of the Polymer and Its Importance in Physical Stability and In Vitro Performance
by Qin Shi, Haibiao Chen, Yanan Wang, Ruoxun Wang, Jia Xu and Chen Zhang
Pharmaceutics 2022, 14(8), 1747; https://doi.org/10.3390/pharmaceutics14081747 - 22 Aug 2022
Cited by 24 | Viewed by 4835
Abstract
Amorphous solid dispersions stabilized by one or more polymer(s) have been widely used for delivering amorphous drugs with poor water solubilities, and they have gained great market success. Polymer selection is important for preparing robust amorphous solid dispersions, and considerations should be given [...] Read more.
Amorphous solid dispersions stabilized by one or more polymer(s) have been widely used for delivering amorphous drugs with poor water solubilities, and they have gained great market success. Polymer selection is important for preparing robust amorphous solid dispersions, and considerations should be given as to how the critical attributes of a polymer can enhance the physical stability, and the in vitro and in vivo performances of a drug. This article provides a comprehensive overview for recent developments in the understanding the role of polymers in amorphous solid dispersions from the aspects of nucleation, crystal growth, overall crystallization, miscibility, phase separation, dissolution, and supersaturation. The critical properties of polymers affecting the physical stability and the in vitro performance of amorphous solid dispersions are also highlighted. Moreover, a perspective regarding the current research gaps and novel research directions for better understanding the role of the polymer is provided. This review will provide guidance for the rational design of polymer-based amorphous pharmaceutical solids with desired physicochemical properties from the perspective of physical stability and in vitro performance. Full article
(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)
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21 pages, 4562 KiB  
Article
Enhanced Ocular Anti-Aspergillus Activity of Tolnaftate Employing Novel Cosolvent-Modified Spanlastics: Formulation, Statistical Optimization, Kill Kinetics, Ex Vivo Trans-Corneal Permeation, In Vivo Histopathological and Susceptibility Study
by Diana Aziz, Sally A. Mohamed, Saadia Tayel and Amal Makhlouf
Pharmaceutics 2022, 14(8), 1746; https://doi.org/10.3390/pharmaceutics14081746 - 22 Aug 2022
Cited by 9 | Viewed by 2417
Abstract
Tolnaftate (TOL) is a thiocarbamate fungicidal drug used topically in the form of creams and ointments. No ocular formulations of TOL are available for fungal keratitis (FK) treatment due to its poor water solubility and unique ocular barriers. Therefore, this study aimed at [...] Read more.
Tolnaftate (TOL) is a thiocarbamate fungicidal drug used topically in the form of creams and ointments. No ocular formulations of TOL are available for fungal keratitis (FK) treatment due to its poor water solubility and unique ocular barriers. Therefore, this study aimed at developing novel modified spanlastics by modulating spanlastics composition using different glycols for enhancing TOL ocular delivery. To achieve this goal, TOL basic spanlastics were prepared by ethanol injection method using a full 32 factorial design. By applying the desirability function, the optimal formula (BS6) was selected and used as a nucleus for preparing and optimizing TOL-cosolvent spanlastics according to the full 31.21 factorial design. The optimal formula (MS6) was prepared using 30% propylene glycol and showed entrapment efficiency percent (EE%) of 66.10 ± 0.57%, particle size (PS) of 231.20 ± 0.141 nm, and zeta potential (ZP) of −32.15 ± 0.07 mV. MS6 was compared to BS6 and both nanovesicles significantly increased the corneal permeation potential of TOL than drug suspension. Additionally, in vivo histopathological experiment was accomplished and confirmed the tolerability of MS6 for ocular use. The fungal susceptibility testing using Aspergillus niger confirmed that MS6 displayed more durable growth inhibition than drug suspension. Therefore, MS6 can be a promising option for enhanced TOL ocular delivery. Full article
(This article belongs to the Special Issue Nanoparticles in Ocular Drug Delivery Systems)
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19 pages, 4791 KiB  
Article
Development of Inhalable ATRA-Loaded PLGA Nanoparticles as Host-Directed Immunotherapy against Tuberculosis
by Ahmad Z. Bahlool, Sarinj Fattah, Andrew O’Sullivan, Brenton Cavanagh, Ronan MacLoughlin, Joseph Keane, Mary P. O’Sullivan and Sally-Ann Cryan
Pharmaceutics 2022, 14(8), 1745; https://doi.org/10.3390/pharmaceutics14081745 - 21 Aug 2022
Cited by 15 | Viewed by 3499
Abstract
Developing new effective treatment strategies to overcome the rise in multi-drug resistant tuberculosis cases (MDR-TB) represents a global challenge. A host-directed therapy (HDT), acting on the host immune response rather than Mtb directly, could address these resistance issues. We developed an HDT for [...] Read more.
Developing new effective treatment strategies to overcome the rise in multi-drug resistant tuberculosis cases (MDR-TB) represents a global challenge. A host-directed therapy (HDT), acting on the host immune response rather than Mtb directly, could address these resistance issues. We developed an HDT for targeted TB treatment, using All Trans Retinoic Acid (ATRA)-loaded nanoparticles (NPs) that are suitable for nebulization. Efficacy studies conducted on THP-1 differentiated cells infected with the H37Ra avirulent Mycobacterium tuberculosis (Mtb) strain, have shown a dose-dependent reduction in H37Ra growth as determined by the BACT/ALERT® system. Confocal microscopy images showed efficient and extensive cellular delivery of ATRA-PLGA NPs into THP-1-derived macrophages. A commercially available vibrating mesh nebulizer was used to generate nanoparticle-loaded droplets with a mass median aerodynamic diameter of 2.13 μm as measured by cascade impaction, and a volumetric median diameter of 4.09 μm as measured by laser diffraction. In an adult breathing simulation experiment, 65.1% of the ATRA PLGA-NP dose was inhaled. This targeted inhaled HDT could offer a new adjunctive TB treatment option that could enhance current dosage regimens leading to better patient prognosis and a decreasing incidence of MDR-TB. Full article
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14 pages, 2399 KiB  
Article
Population Pharmacokinetics and Dose Optimization Based on Renal Function of Rivaroxaban in Thai Patients with Non-Valvular Atrial Fibrillation
by Noppaket Singkham, Arintaya Phrommintikul, Phongsathon Pacharasupa, Lalita Norasetthada, Siriluck Gunaparn, Narawudt Prasertwitayakij, Wanwarang Wongcharoen and Baralee Punyawudho
Pharmaceutics 2022, 14(8), 1744; https://doi.org/10.3390/pharmaceutics14081744 - 21 Aug 2022
Cited by 6 | Viewed by 2932
Abstract
Low-dose rivaroxaban has been used in Asian patients with direct oral anticoagulants (DOACs) eligible for atrial fibrillation (AF). However, there are few pharmacokinetic (PK) data in Thai patients to support precise dosing. This study aimed to develop a population PK model and determine [...] Read more.
Low-dose rivaroxaban has been used in Asian patients with direct oral anticoagulants (DOACs) eligible for atrial fibrillation (AF). However, there are few pharmacokinetic (PK) data in Thai patients to support precise dosing. This study aimed to develop a population PK model and determine the optimal rivaroxaban doses in Thai patients. A total of 240 Anti-Xa levels of rivaroxaban from 60 Thai patients were analyzed. A population PK model was established using the nonlinear mixed-effect modeling approach. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. Proportions of patients having rivaroxaban exposure within typical exposure ranges were determined. A one-compartment model with first-order absorption best described the data. Creatinine clearance (CrCl) and body weight significantly affected CL/F and V/F, respectively. Regardless of body weight, a higher proportion of patients with CrCl < 50 mL/min receiving the 10-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. In contrast, a higher proportion of patients with CrCl ≥ 50 mL/min receiving the 15-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. The study’s findings suggested that low-dose rivaroxaban would be better suited for Thai patients and suggested adjusting the medication’s dose in accordance with renal function. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy)
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18 pages, 2278 KiB  
Article
Nanoassemblies from Amphiphilic Sb Complexes Target Infection Sites in Models of Visceral and Cutaneous Leishmaniases
by Juliane S. Lanza, Virginia M. R. Vallejos, Guilherme S. Ramos, Ana Carolina B. de Oliveira, Cynthia Demicheli, Luis Rivas, Sébastien Pomel, Philippe M. Loiseau and Frédéric Frézard
Pharmaceutics 2022, 14(8), 1743; https://doi.org/10.3390/pharmaceutics14081743 - 21 Aug 2022
Cited by 1 | Viewed by 1956
Abstract
This work aims to evaluate whether nanoassemblies (NanoSb) made from antimony(V) complexes with octanoyl-N-methylglucamide (SbL8) or decanoyl-N-methylglucamide (SbL10) would effectively target the infection sites in visceral and cutaneous leishmaniases (VL and CL). NanoSb were investigated regarding stability at different [...] Read more.
This work aims to evaluate whether nanoassemblies (NanoSb) made from antimony(V) complexes with octanoyl-N-methylglucamide (SbL8) or decanoyl-N-methylglucamide (SbL10) would effectively target the infection sites in visceral and cutaneous leishmaniases (VL and CL). NanoSb were investigated regarding stability at different pHs, accumulation of Sb in the macrophage host cell and liver, and in vitro and in vivo activities in models of leishmaniasis. The kinetic stability assay showed that NanoSb are stable at neutral pH, but release incorporated lipophilic substance after conformational change in media that mimic the gastric fluid and the parasitophorous vacuole. NanoSb promoted greater accumulation of Sb in macrophages and in the liver of mice after parenteral administration, when compared to conventional antimonial Glucantime®. SbL10 was much more active than Glucantime® against intramacrophage Leishmania amastigotes and less cytotoxic than SbL8 against macrophages. The in vitro SbL10 activity was further enhanced with co-incorporated miltefosine. NanoSb showed high antileishmanial activity in the L. donovani murine VL after parenteral administration and moderate activity in the L. amazonensis murine CL after topical treatment. This study supports the ability of NanoSb to effectively deliver a combination of Sb and co-incorporated drug to host cell and infected tissues, in a better way than Glucantime® does. Full article
(This article belongs to the Special Issue Lipid-Based Formulations for Therapy of Vector-Borne Protozoan Diseases)
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21 pages, 3806 KiB  
Article
Development and In Vitro-Ex Vivo Evaluation of Novel Polymeric Nasal Donepezil Films for Potential Use in Alzheimer’s Disease Using Experimental Design
by Paraskevi Papakyriakopoulou, Dimitrios M. Rekkas, Gaia Colombo and Georgia Valsami
Pharmaceutics 2022, 14(8), 1742; https://doi.org/10.3390/pharmaceutics14081742 - 21 Aug 2022
Cited by 6 | Viewed by 2727
Abstract
The objective and novelty of the present study is the development and optimization of innovative nasal film of Donepezil hydrochloride (DH) for potential use in Alzheimer’s disease. Hydroxypropyl-methyl-cellulose E50 (factor A) nasal films, with Polyethylene glycol 400 as plasticizer (factor B), and Methyl-β-Cyclodextrin, [...] Read more.
The objective and novelty of the present study is the development and optimization of innovative nasal film of Donepezil hydrochloride (DH) for potential use in Alzheimer’s disease. Hydroxypropyl-methyl-cellulose E50 (factor A) nasal films, with Polyethylene glycol 400 as plasticizer (factor B), and Methyl-β-Cyclodextrin, as permeation enhancer (factor C), were prepared and characterized in vitro and ex vivo. An experimental design was used to determine the effects of the selected factors on permeation profile of DH through rabbit nasal mucosa (response 1), and on film flexibility/foldability (response 2). A face centered central composite design with three levels was applied and 17 experiments were performed in triplicate. The prepared films exhibited good uniformity of DH content (90.0 ± 1.6%–99.8 ± 4.9%) and thickness (19.6 ± 1.9–170.8 ± 11.5 μm), storage stability characteristics, and % residual humidity (<3%), as well as favourable swelling and mucoadhesive properties. Response surface methodology determined the optimum composition for flexible nasal film with maximized DH permeation. All selected factors interacted with each other and the effect of these interactions on responses is strongly related to the factor’s concentration ratios. Based on these encouraging results, in vivo serum and brain pharmacokinetic study of the optimized nasal film, in comparison to DH oral administration, is ongoing in an animal model. Full article
(This article belongs to the Special Issue Advances and Challenges in Nasal Formulation Developments)
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18 pages, 3666 KiB  
Article
Hydrochlorothiazide/Losartan Potassium Tablet Prepared by Direct Compression
by Qiuhua Luo, Qianying Zhang and Puxiu Wang
Pharmaceutics 2022, 14(8), 1741; https://doi.org/10.3390/pharmaceutics14081741 - 21 Aug 2022
Cited by 8 | Viewed by 2655
Abstract
Hydrochlorothiazide (HCTZ)/losartan potassium (LOS-K) was used as a model drug to prepare compound tablets through the investigation of the compression and mechanical properties of mixed powders to determine the formulation and preparation factors, followed by D-optimal mixture experimental design to optimize the final [...] Read more.
Hydrochlorothiazide (HCTZ)/losartan potassium (LOS-K) was used as a model drug to prepare compound tablets through the investigation of the compression and mechanical properties of mixed powders to determine the formulation and preparation factors, followed by D-optimal mixture experimental design to optimize the final parameters. The type and amount of lactose monohydrate (SuperTab®14SD, 19.53–26.91%), microcrystalline cellulose (MCC PH102, 32.86–43.31%), pre-gelatinized starch (Starch-1500, 10.96–15.91%), and magnesium stearate (0.7%) were determined according to the compressive work, stress relaxation curves, and Py value. Then, the compression mechanism of the mixed powder was investigated by the Kawakita equation, Shapiro equation, and Heckel analysis, and the mixed powder was classified as a Class-II powder. The compaction pressure (150–300 MPa) and tableting speed (1200–2400 Tab/h) were recommended. A D-optimal mixture experimental design was utilized to select the optimal formulation (No 1, 26.027% lactose monohydrate, 32.811% MCC PH102, and 15.462% pregelatinized starch) according to the drug dissolution rate, using Hyzaar® tablets as a control. Following oral administration in beagle dogs, there were no significant differences in bioavailability between the No. 1 tablet and the Hyzaar® tablet in HCTZ, losartan carboxylic acid (E-3174), and LOS-K (F < F0.05). Thus, formulation and preparation factors were determined according to the combination of the compression and mechanical properties of the mixed powder and quality of tablets, which was demonstrated to be a feasible method in direct powder compression. Full article
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17 pages, 3880 KiB  
Article
Association of Indocyanine Green with Chitosan Oleate Coated PLGA Nanoparticles for Photodynamic Therapy
by Dalila Miele, Milena Sorrenti, Laura Catenacci, Paolo Minzioni, Giorgio Marrubini, Valeria Amendola, Marcello Maestri, Paolo Giunchedi and Maria Cristina Bonferoni
Pharmaceutics 2022, 14(8), 1740; https://doi.org/10.3390/pharmaceutics14081740 - 20 Aug 2022
Cited by 7 | Viewed by 2319
Abstract
Indocyanine green (ICG) is a safe dye widely used in the biomedical field. Its photodynamic effect (PDT), originating from laser irradiation at 803 nm, opens interesting perspectives in theranostic applications. To overcome its low water stability, ICG can be shielded with nanoparticles (NPs). [...] Read more.
Indocyanine green (ICG) is a safe dye widely used in the biomedical field. Its photodynamic effect (PDT), originating from laser irradiation at 803 nm, opens interesting perspectives in theranostic applications. To overcome its low water stability, ICG can be shielded with nanoparticles (NPs). In this work, previously developed NPs based on poly lactic-co-glycolic acid (PLGA) coated with chitosan oleate (CS-OA) and loaded with resveratrol as a hydrophobic model drug have been proposed as an ICG carrier. These systems have been selected for their observed immunostimulatory properties. The possible loading of the dye by adsorption onto NP surface by electrostatic interaction was studied here in comparison with the encapsulation into the PLGA core. The ICG-chitosan (CS) interaction has been characterized by spectrophotometry, spectroscopy and in-cell in vitro assays. Fluorescence quenching was observed due to the ionic interaction between ICG and CS and was studied considering the dye:polymer stoichiometry and the effect of the NP dilution in cell culture medium (DMEM). The NP systems have been compared in vitro, assessing their behaviour in Caco-2 cell lines. A reduction in cell viability was observed after irradiation of ICG associated with NPs, evident also for the samples loaded by adsorption. These findings open the opportunity to exploit the association of PDT’s effect on ICG with the properties of CS-OA coated NPs, whose immunostimulatory effect can be associated with PDT mechanism in cancer therapy. Full article
(This article belongs to the Special Issue Study of Nanoparticles for Photodynamic Therapy and Imaging)
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20 pages, 3169 KiB  
Article
Degradable and Non-Degradable Chondroitin Sulfate Particles with the Controlled Antibiotic Release for Bacterial Infections
by Selin S. Suner, Mehtap Sahiner, Ramesh S. Ayyala and Nurettin Sahiner
Pharmaceutics 2022, 14(8), 1739; https://doi.org/10.3390/pharmaceutics14081739 - 20 Aug 2022
Cited by 6 | Viewed by 2090
Abstract
Non-degradable, slightly degradable, and completely degradable micro/nanoparticles derived from chondroitin sulfate (CS) were synthesized through crosslinking reactions at 50%, 40%, and 20% mole ratios, respectively. The CS particles with a 20% crosslinking ratio show total degradation within 48 h, whereas 50% CS particles [...] Read more.
Non-degradable, slightly degradable, and completely degradable micro/nanoparticles derived from chondroitin sulfate (CS) were synthesized through crosslinking reactions at 50%, 40%, and 20% mole ratios, respectively. The CS particles with a 20% crosslinking ratio show total degradation within 48 h, whereas 50% CS particles were highly stable for up to 240 h with only 7.0 ± 2.8% weight loss in physiological conditions (pH 7.4, 37 °C). Tobramycin and amikacin antibiotics were encapsulated into non-degradable CS particles with high loading at 250 g/mg for the treatment of corneal bacterial ulcers. The highest release capacity of 92 ± 2% was obtained for CS-Amikacin particles with sustainable and long-term release profiles. The antibacterial effects of CS particles loaded with 2.5 mg of antibiotic continued to render a prolonged release time of 240 h with 24 ± 2 mm inhibition zones against Pseudomonas aeruginosa. Furthermore, as a carrier, CS particles significantly improved the compatibility of the antibiotics even at high particle concentrations of 1000 g/mL with a minimum of 71 ± 7% fibroblast cell viability. In summary, the sustainable delivery of antibiotics and long-term treatment of bacterial keratitis were shown to be afforded by the design of tunable degradation ability of CS particles with improved biocompatibility for the encapsulated drugs. Full article
(This article belongs to the Special Issue Biopolymer Micro/Nanogel Particles as Smart Drug Delivery and Theranostic Systems)
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18 pages, 3256 KiB  
Article
Investigations on Cellular Uptake Mechanisms and Immunogenicity Profile of Novel Bio-Hybrid Nanovesicles
by Yi-Hsuan Ou, Jeremy Liang, Wei Heng Chng, Ram Pravin Kumar Muthuramalingam, Zi Xiu Ng, Choon Keong Lee, Yub Raj Neupane, Jia Ning Nicolette Yau, Sitong Zhang, Charles Kang Liang Lou, Chenyuan Huang, Jiong-Wei Wang and Giorgia Pastorin
Pharmaceutics 2022, 14(8), 1738; https://doi.org/10.3390/pharmaceutics14081738 - 20 Aug 2022
Cited by 9 | Viewed by 3092
Abstract
In drug delivery, the development of nanovesicles that combine both synthetic and cellular components provides added biocompatibility and targeting specificity in comparison to conventional synthetic carriers such as liposomes. Produced through the fusion of U937 monocytes’ membranes and synthetic lipids, our nano-cell vesicle [...] Read more.
In drug delivery, the development of nanovesicles that combine both synthetic and cellular components provides added biocompatibility and targeting specificity in comparison to conventional synthetic carriers such as liposomes. Produced through the fusion of U937 monocytes’ membranes and synthetic lipids, our nano-cell vesicle technology systems (nCVTs) showed promising results as targeted cancer treatment. However, no investigation has been conducted yet on the immunogenic profile and the uptake mechanisms of nCVTs. Hence, this study was aimed at exploring the potential cytotoxicity and immune cells’ activation by nCVTs, as well as the routes through which cells internalize these biohybrid systems. The endocytic pathways were selectively inhibited to establish if the presence of cellular components in nCVTs affected the internalization route in comparison to both liposomes (made up of synthetic lipids only) and nano-cellular membranes (made up of biological material only). As a result, nCVTs showed an 8-to-40-fold higher cellular internalization than liposomes within the first hour, mainly through receptor-mediated processes (i.e., clathrin- and caveolae-mediated endocytosis), and low immunostimulatory potential (as indicated by the level of IL-1α, IL-6, and TNF-α cytokines) both in vitro and in vivo. These data confirmed that nCVTs preserved surface cues from their parent U937 cells and can be rationally engineered to incorporate ligands that enhance the selective uptake and delivery toward target cells and tissues. Full article
(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)
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20 pages, 3051 KiB  
Review
New Strategies for Stroke Therapy: Nanoencapsulated Neuroglobin
by Santos Blanco, Esther Martínez-Lara, Eva Siles and María Ángeles Peinado
Pharmaceutics 2022, 14(8), 1737; https://doi.org/10.3390/pharmaceutics14081737 - 19 Aug 2022
Cited by 6 | Viewed by 2491
Abstract
Stroke is a global health and socio-economic problem. However, no efficient preventive and/or palliative treatments have yet been found. Neuroglobin (Ngb) is an endogen neuroprotective protein, but it only exerts its beneficial action against stroke after increasing its basal levels. Therefore, its systemic [...] Read more.
Stroke is a global health and socio-economic problem. However, no efficient preventive and/or palliative treatments have yet been found. Neuroglobin (Ngb) is an endogen neuroprotective protein, but it only exerts its beneficial action against stroke after increasing its basal levels. Therefore, its systemic administration appears to be an efficient therapy applicable to stroke and other neurodegenerative pathologies. Unfortunately, Ngb cannot cross the blood-brain barrier (BBB), making its direct pharmacological use unfeasible. Thus, the association of Ngb with a drug delivery system (DDS), such as nanoparticles (NPs), appears to be a good strategy for overcoming this handicap. NPs are a type of DDS which efficiently transport Ngb and increase its bioavailability in the infarcted area. Hence, we previously built hyaluronate NPS linked to Ngb (Ngb-NPs) as a therapeutic tool against stroke. This nanoformulation induced an improvement of the cerebral infarct prognosis. However, this innovative therapy is still in development, and a more in-depth study focusing on its long-lasting neuroprotectant and neuroregenerative capabilities is needed. In short, this review aims to update the state-of-the-art of stroke therapies based on Ngb, paying special attention to the use of nanotechnological drug-delivering tools. Full article
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28 pages, 818 KiB  
Review
Promising Strategies for Transdermal Delivery of Arthritis Drugs: Microneedle Systems
by Jitong Wang, Jia Zeng, Zhidan Liu, Qin Zhou, Xin Wang, Fan Zhao, Yu Zhang, Jiamiao Wang, Minchen Liu and Ruofei Du
Pharmaceutics 2022, 14(8), 1736; https://doi.org/10.3390/pharmaceutics14081736 - 19 Aug 2022
Cited by 23 | Viewed by 5165
Abstract
Arthritis is a general term for various types of inflammatory joint diseases. The most common clinical conditions are mainly represented by rheumatoid arthritis and osteoarthritis, which affect more than 4% of people worldwide and seriously limit their mobility. Arthritis medication generally requires long-term [...] Read more.
Arthritis is a general term for various types of inflammatory joint diseases. The most common clinical conditions are mainly represented by rheumatoid arthritis and osteoarthritis, which affect more than 4% of people worldwide and seriously limit their mobility. Arthritis medication generally requires long-term application, while conventional administrations by oral delivery or injections may cause gastrointestinal side effects and are inconvenient for patients during long-term application. Emerging microneedle (MN) technology in recent years has created new avenues of transdermal delivery for arthritis drugs due to its advantages of painless skin perforation and efficient local delivery. This review summarizes various types of arthritis and current therapeutic agents. The current development of MNs in the delivery of arthritis drugs is highlighted, demonstrating their capabilities in achieving different drug release profiles through different self-enhancement methods or the incorporation of nanocarriers. Furthermore, the challenges of translating MNs from laboratory studies to the clinical practice and the marketplace are discussed. This promising technology provides a new approach to the current drug delivery paradigm in treating arthritis in transdermal delivery. Full article
(This article belongs to the Special Issue New Trends for Transdermal and Dermal Delivery)
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33 pages, 3857 KiB  
Review
High Drug-Loading Nanomedicines for Tumor Chemo–Photo Combination Therapy: Advances and Perspectives
by Ya Wang, Yujie Zhang, Xiaojiang Zhang, Zhe Zhang, Junjun She, Daocheng Wu and Wei Gao
Pharmaceutics 2022, 14(8), 1735; https://doi.org/10.3390/pharmaceutics14081735 - 19 Aug 2022
Cited by 4 | Viewed by 2802
Abstract
The combination of phototherapy and chemotherapy (chemo–photo combination therapy) is an excellent attempt for tumor treatment. The key requirement of this technology is the high drug-loading nanomedicines, which can load either chemotherapy drugs or phototherapy agents at the same nanomedicines and simultaneously deliver [...] Read more.
The combination of phototherapy and chemotherapy (chemo–photo combination therapy) is an excellent attempt for tumor treatment. The key requirement of this technology is the high drug-loading nanomedicines, which can load either chemotherapy drugs or phototherapy agents at the same nanomedicines and simultaneously deliver them to tumors, and play a multimode therapeutic role for tumor treatment. These nanomedicines have high drug-loading efficiency (>30%) and good tumor combination therapeutic effect with important clinical application potential. Although there are many reports of high drug-loading nanomedicines for tumor therapy at present, systematic analyses on those nanomedicines remain lacking and a comprehensive review is urgently needed. In this review, we systematically analyze the current status of developed high drug-loading nanomedicines for tumor chemo–photo combination therapy and summarize their types, methods, drug-loading properties, in vitro and in vivo applications. The shortcomings of the existing high drug-loading nanomedicines for tumor chemo–photo combination therapy and the possible prospective development direction are also discussed. We hope to attract more attention for researchers in different academic fields, provide new insights into the research of tumor therapy and drug delivery system and develop these nanomedicines as the useful tool for tumor chemo–photo combination therapy in the future. Full article
(This article belongs to the Special Issue Advanced Nanomaterials for Drug Delivery)
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20 pages, 3158 KiB  
Article
Physiologically Based Pharmacokinetic Modeling to Describe the CYP2D6 Activity Score-Dependent Metabolism of Paroxetine, Atomoxetine and Risperidone
by Simeon Rüdesheim, Dominik Selzer, Thomas Mürdter, Svitlana Igel, Reinhold Kerb, Matthias Schwab and Thorsten Lehr
Pharmaceutics 2022, 14(8), 1734; https://doi.org/10.3390/pharmaceutics14081734 - 18 Aug 2022
Cited by 6 | Viewed by 3155
Abstract
The cytochrome P450 2D6 (CYP2D6) genotype is the single most important determinant of CYP2D6 activity as well as interindividual and interpopulation variability in CYP2D6 activity. Here, the CYP2D6 activity score provides an established tool to categorize the large number of CYP2D6 [...] Read more.
The cytochrome P450 2D6 (CYP2D6) genotype is the single most important determinant of CYP2D6 activity as well as interindividual and interpopulation variability in CYP2D6 activity. Here, the CYP2D6 activity score provides an established tool to categorize the large number of CYP2D6 alleles by activity and facilitates the process of genotype-to-phenotype translation. Compared to the broad traditional phenotype categories, the CYP2D6 activity score additionally serves as a superior scale of CYP2D6 activity due to its finer graduation. Physiologically based pharmacokinetic (PBPK) models have been successfully used to describe and predict the activity score-dependent metabolism of CYP2D6 substrates. This study aimed to describe CYP2D6 drug–gene interactions (DGIs) of important CYP2D6 substrates paroxetine, atomoxetine and risperidone by developing a substrate-independent approach to model their activity score-dependent metabolism. The models were developed in PK-Sim®, using a total of 57 plasma concentration–time profiles, and showed good performance, especially in DGI scenarios where 10/12, 5/5 and 7/7 of DGI AUClast ratios and 9/12, 5/5 and 7/7 of DGI Cmax ratios were within the prediction success limits. Finally, the models were used to predict their compound’s exposure for different CYP2D6 activity scores during steady state. Here, predicted DGI AUCss ratios were 3.4, 13.6 and 2.0 (poor metabolizers; activity score = 0) and 0.2, 0.5 and 0.95 (ultrarapid metabolizers; activity score = 3) for paroxetine, atomoxetine and risperidone active moiety (risperidone + 9-hydroxyrisperidone), respectively. Full article
(This article belongs to the Section Clinical Pharmaceutics)
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38 pages, 5257 KiB  
Review
An Overview of the Supramolecular Systems for Gene and Drug Delivery in Tissue Regeneration
by Saketh Reddy Ranamalla, Alina Silvia Porfire, Ioan Tomuță and Manuela Banciu
Pharmaceutics 2022, 14(8), 1733; https://doi.org/10.3390/pharmaceutics14081733 - 18 Aug 2022
Cited by 3 | Viewed by 2845
Abstract
Tissue regeneration is a prominent area of research, developing biomaterials aimed to be tunable, mechanistic scaffolds that mimic the physiological environment of the tissue. These biomaterials are projected to effectively possess similar chemical and biological properties, while at the same time are required [...] Read more.
Tissue regeneration is a prominent area of research, developing biomaterials aimed to be tunable, mechanistic scaffolds that mimic the physiological environment of the tissue. These biomaterials are projected to effectively possess similar chemical and biological properties, while at the same time are required to be safely and quickly degradable in the body once the desired restoration is achieved. Supramolecular systems composed of reversible, non-covalently connected, self-assembly units that respond to biological stimuli and signal cells have efficiently been developed as preferred biomaterials. Their biocompatibility and the ability to engineer the functionality have led to promising results in regenerative therapy. This review was intended to illuminate those who wish to envisage the niche translational research in regenerative therapy by summarizing the various explored types, chemistry, mechanisms, stimuli receptivity, and other advancements of supramolecular systems. Full article
(This article belongs to the Special Issue Supramolecular Systems for Gene and Drug Delivery, 2nd Edition)
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36 pages, 15663 KiB  
Review
Innovations in Chewable Formulations: The Novelty and Applications of 3D Printing in Drug Product Design
by Lucía Rodríguez-Pombo, Atheer Awad, Abdul W. Basit, Carmen Alvarez-Lorenzo and Alvaro Goyanes
Pharmaceutics 2022, 14(8), 1732; https://doi.org/10.3390/pharmaceutics14081732 - 18 Aug 2022
Cited by 23 | Viewed by 11942
Abstract
Since their introduction, chewable dosage forms have gained traction due to their ability to facilitate swallowing, especially in paediatric, geriatric and dysphagia patients. Their benefits stretch beyond human use to also include veterinary applications, improving administration and palatability in different animal species. Despite [...] Read more.
Since their introduction, chewable dosage forms have gained traction due to their ability to facilitate swallowing, especially in paediatric, geriatric and dysphagia patients. Their benefits stretch beyond human use to also include veterinary applications, improving administration and palatability in different animal species. Despite their advantages, current chewable formulations do not account for individualised dosing and palatability preferences. In light of this, three-dimensional (3D) printing, and in particular the semi-solid extrusion technology, has been suggested as a novel manufacturing method for producing customised chewable dosage forms. This advanced approach offers flexibility for selecting patient-specific doses, excipients, and organoleptic properties, which are critical for ensuring efficacy, safety and adherence to the treatment. This review provides an overview of the latest advancements in chewable dosage forms for human and veterinary use, highlighting the motivations behind their use and covering formulation considerations, as well as regulatory aspects. Full article
(This article belongs to the Special Issue New Pharmaceutical Applications through 3D Printing Processes)
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15 pages, 4103 KiB  
Article
Efficient Sustained-Release Nanoparticle Delivery System Protects Nigral Neurons in a Toxin Model of Parkinson’s Disease
by Qun Wang, Rui Ma, Piaoxue Liu, Guowang Cheng, Qi Yang, Xiaojia Chen, Zhenfeng Wu, Dongsheng Yuan and Tongkai Chen
Pharmaceutics 2022, 14(8), 1731; https://doi.org/10.3390/pharmaceutics14081731 - 18 Aug 2022
Cited by 12 | Viewed by 2480
Abstract
Parkinson’s disease (PD) is a serious neurodegenerative disease wherein the progressive destruction of dopaminergic neurons results in a series of related movement disorders. Effective oral delivery of anti-Parkinson’s drugs is challenging owing to the blood-brain barrier (BBB) and the limited plasma exposure. However, [...] Read more.
Parkinson’s disease (PD) is a serious neurodegenerative disease wherein the progressive destruction of dopaminergic neurons results in a series of related movement disorders. Effective oral delivery of anti-Parkinson’s drugs is challenging owing to the blood-brain barrier (BBB) and the limited plasma exposure. However, polymeric nanoparticles possess great potential to enhance oral bioavailability, thus improving drug accumulation within the brain. In this work, biodegradable poly(ethylene glycol)-b-poly(trimethylene carbonate) (PEG-PTMC) nanoparticles (PPNPs) were developed to deliver Ginkgolide B (GB) as a potent treatment for PD, aiming to enhance its accumulation within both the blood and the brain. The resultant GB-PPNPs were able to facilitate sustained GB release for 48 h and to protect against 1-methyl-4-phenylpyridine (MPP+)-induced neuronal cytotoxicity without causing any toxic damage. Subsequent pharmacokinetic studies revealed that GB-PPNPs accumulated at significantly higher concentrations in the plasma and brain relative to free GB. Oral GB-PPNP treatment was also linked to desirable outcomes in an animal model of PD, as evidenced by improvements in locomotor activity, levels of dopamine and its metabolites, and tyrosine hydroxylase activity. Together, these data suggest that PPNPs may represent promising tools for the effective remediation of PD and other central nervous system disorders. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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13 pages, 1340 KiB  
Review
The New Role of SGLT2 Inhibitors in the Management of Heart Failure: Current Evidence and Future Perspective
by Saverio Muscoli, Francesco Barillà, Rojin Tajmir, Marco Meloni, David Della Morte, Alfonso Bellia, Nicola Di Daniele, Davide Lauro and Aikaterini Andreadi
Pharmaceutics 2022, 14(8), 1730; https://doi.org/10.3390/pharmaceutics14081730 - 18 Aug 2022
Cited by 22 | Viewed by 6947
Abstract
The sodium-glucose transporter 2 inhibitors (SGLT2i) are a relatively new class of medication used in the management of type 2 diabetes. Recent clinical trials and research have demonstrated this class’s effectiveness in treating heart failure, since they reduce the risk of cardiovascular events, [...] Read more.
The sodium-glucose transporter 2 inhibitors (SGLT2i) are a relatively new class of medication used in the management of type 2 diabetes. Recent clinical trials and research have demonstrated this class’s effectiveness in treating heart failure, since they reduce the risk of cardiovascular events, hospitalization, and mortality. The mechanism by which they do so is unclear; however, SGLT2i inhibit the tubular reabsorption of glucose, lowering the interstitial volume. This mechanism leads to a reduction in blood pressure and an improvement of endothelial function. As a result, improvements in hospitalization and mortality rate have been shown. In this review, we focus on the primary outcome of the clinical trials designed to investigate the effect of SGLT2i in heart failure, regardless of patients’ diabetic status. Furthermore, we compare the various SGLT2i regarding their risk reduction to investigate their potential as a treatment option for patients with reduced ejection fraction and preserved ejection fraction. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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38 pages, 1239 KiB  
Review
In Vitro Models of the Blood–Cerebrospinal Fluid Barrier and Their Applications in the Development and Research of (Neuro)Pharmaceuticals
by Fatemeh Dabbagh, Horst Schroten and Christian Schwerk
Pharmaceutics 2022, 14(8), 1729; https://doi.org/10.3390/pharmaceutics14081729 - 18 Aug 2022
Cited by 9 | Viewed by 3435
Abstract
The pharmaceutical research sector has been facing the challenge of neurotherapeutics development and its inherited high-risk and high-failure-rate nature for decades. This hurdle is partly attributable to the presence of brain barriers, considered both as obstacles and opportunities for the entry of drug [...] Read more.
The pharmaceutical research sector has been facing the challenge of neurotherapeutics development and its inherited high-risk and high-failure-rate nature for decades. This hurdle is partly attributable to the presence of brain barriers, considered both as obstacles and opportunities for the entry of drug substances. The blood–cerebrospinal fluid (CSF) barrier (BCSFB), an under-studied brain barrier site compared to the blood–brain barrier (BBB), can be considered a potential therapeutic target to improve the delivery of CNS therapeutics and provide brain protection measures. Therefore, leveraging robust and authentic in vitro models of the BCSFB can diminish the time and effort spent on unproductive or redundant development activities by a preliminary assessment of the desired physiochemical behavior of an agent toward this barrier. To this end, the current review summarizes the efforts and progresses made to this research area with a notable focus on the attribution of these models and applied techniques to the pharmaceutical sector and the development of neuropharmacological therapeutics and diagnostics. A survey of available in vitro models, with their advantages and limitations and cell lines in hand will be provided, followed by highlighting the potential applications of such models in the (neuro)therapeutics discovery and development pipelines. Full article
(This article belongs to the Special Issue Crossing the Blood–Brain Barrier and Targeting the Brain to Meet the Challenge of CNS Diseases)
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18 pages, 1525 KiB  
Review
Host Response Modulation Therapy in the Diabetes Mellitus—Periodontitis Conjuncture: A Narrative Review
by Irina-Georgeta Sufaru, Silvia Teslaru, Liliana Pasarin, Gianina Iovan, Simona Stoleriu and Sorina Mihaela Solomon
Pharmaceutics 2022, 14(8), 1728; https://doi.org/10.3390/pharmaceutics14081728 - 18 Aug 2022
Cited by 4 | Viewed by 3023
Abstract
The inflammatory response of the host in periodontitis is the phenomenon that underlies the onset and evolution of periodontal destructive phenomena. A number of systemic factors, such as diabetes mellitus (DM), can negatively affect the patient with periodontitis, just as the periodontal disease [...] Read more.
The inflammatory response of the host in periodontitis is the phenomenon that underlies the onset and evolution of periodontal destructive phenomena. A number of systemic factors, such as diabetes mellitus (DM), can negatively affect the patient with periodontitis, just as the periodontal disease can aggravate the status of the DM patient. Host response modulation therapy involves the use of anti-inflammatory and anti-oxidant products aimed at resolving inflammation, stopping destructive processes, and promoting periodontal healing, all important aspects in patients with high tissue loss rates, such as diabetic patients. This paper reviews the data available in the literature on the relationship between DM and periodontitis, the main substances modulating the inflammatory response (nonsteroidal anti-inflammatory drugs, sub-antimicrobial doses of doxycycline, or omega-3 fatty acids and their products, specialized pro-resolving mediators), as well as their application in diabetic patients. Full article
(This article belongs to the Special Issue Targeted Therapies in Diabetes and Its Complications)
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21 pages, 3749 KiB  
Article
Combinatorial Therapy of Letrozole- and Quercetin-Loaded Spanlastics for Enhanced Cytotoxicity against MCF-7 Breast Cancer Cells
by Aml I. Mekkawy, Nermin E. Eleraky, Ghareb M. Soliman, Mohamed G. Elnaggar and Marwa G. Elnaggar
Pharmaceutics 2022, 14(8), 1727; https://doi.org/10.3390/pharmaceutics14081727 - 18 Aug 2022
Cited by 25 | Viewed by 3021
Abstract
Breast cancer is the most widespread cancer in women with rising incidence, prevalence, and mortality in developed regions. Most breast cancers (80%) are estrogen receptor–positive, indicating that disease progression could be controlled by estrogen inhibition in the breast tissue. However, drug resistance limits [...] Read more.
Breast cancer is the most widespread cancer in women with rising incidence, prevalence, and mortality in developed regions. Most breast cancers (80%) are estrogen receptor–positive, indicating that disease progression could be controlled by estrogen inhibition in the breast tissue. However, drug resistance limits the benefits of this approach. Combinatorial treatment could overcome the resistance and improve the outcome of breast cancer treatment. In the current study, we prepared letrozole-(LTZSPs) and quercetin-loaded spanlastics (QuSPs) using different edge activators—Tween 80, Brij 35, and Cremophor RH40—with different concentrations. The spanlastics were evaluated for their average particles size, surface charge, and percent encapsulation efficiency. The optimized formulations were further examined using transmission electron microscopy, Fourier transform infrared spectroscopy, in vitro drug release and ex vivo skin permeation studies. The prepared spherical LTZSPs and QuSPs had average particle sizes ranged between 129–310 nm and 240–560 nm, respectively, with negative surface charge and high LTZ and Qu encapsulation (94.3–97.2% and 97.9–99.6%, respectively). The in vitro release study of LTZ and Qu from the selected formulations showed a sustained drug release for 24 h with reasonable flux and permeation through the rat skin. Further, we evaluated the in vitro cytotoxicity, cell cycle analysis, and intracellular reactive oxygen species (ROS) of the combination therapy of letrozole and quercetin either in soluble form or loaded in spanlastics against MCF-7 breast cancer cells. The LTZSPs and QuSPs combination was superior to the individual treatments and the soluble free drugs in terms of in vitro cytotoxicity, cell cycle analysis, and ROS studies. These results confirm the potential of LTZSPs and QuSPs combination for transdermal delivery of drugs for enhanced breast cancer management. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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17 pages, 1004 KiB  
Review
Combination-Based Strategies for the Treatment of Actinic Keratoses with Photodynamic Therapy: An Evidence-Based Review
by Stefano Piaserico, Roberto Mazzetto, Emma Sartor and Carlotta Bortoletti
Pharmaceutics 2022, 14(8), 1726; https://doi.org/10.3390/pharmaceutics14081726 - 18 Aug 2022
Cited by 10 | Viewed by 2926
Abstract
Photodynamic therapy (PDT) is a highly effective and widely adopted treatment strategy for many skin diseases, particularly for multiple actinic keratoses (AKs). However, PDT is ineffective in some cases, especially if AKs occur in the acral part of the body. Several methods to [...] Read more.
Photodynamic therapy (PDT) is a highly effective and widely adopted treatment strategy for many skin diseases, particularly for multiple actinic keratoses (AKs). However, PDT is ineffective in some cases, especially if AKs occur in the acral part of the body. Several methods to improve the efficacy of PDT without significantly increasing the risks of side effects have been proposed. In this study, we reviewed the combination-based PDT treatments described in the literature for treating AKs; both post-treatment and pretreatment were considered including topical (i.e., diclofenac, imiquimod, adapalene, 5-fluorouracil, and calcitriol), systemic (i.e., acitretin, methotrexate, and polypodium leucotomos), and mechanical–physical (i.e., radiofrequency, thermomechanical fractional injury, microneedling, microdermabrasion, and laser) treatment strategies. Topical pretreatments with imiquimod, adapalene, 5-fluorouracil, and calcipotriol were more successful than PDT alone in treating AKs, while the effect of diclofenac gel was less clear. Both mechanical laser treatment with CO2 and Er:YAG (Erbium:Yttrium–Aluminum–Garnet) as well as systemic treatment with Polypodium leucotomos were also effective. Different approaches were relatively more effective in particular situations such as in immunosuppressed patients, AKs in the extremities, or thicker AKs. Conclusions: Several studies showed that a combination-based approach enhanced the effectiveness of PDT. However, more studies are needed to further understand the effectiveness of combination therapy in clinical practice and to investigate the role of acitretin, methotrexate, vitamin D, thermomechanical fractional injury, and microdermabrasion in humans. Full article
(This article belongs to the Special Issue Special Issue in Honor of Dr. Michael Weber’s 70th Birthday: Photodynamic Therapy: Rising Star in Pharmaceutical Applications)
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10 pages, 2772 KiB  
Article
Tumor Microenvironment-Responsive Polymeric iRGD and Doxorubicin Conjugates Reduce Spontaneous Lung Metastasis in an Orthotopic Breast Cancer Model
by Zheng-Hong Peng, Chinmay M. Jogdeo, Jing Li, Ying Xie, Yazhe Wang, Yuri M. Sheinin, Jindřich Kopeček and David Oupický
Pharmaceutics 2022, 14(8), 1725; https://doi.org/10.3390/pharmaceutics14081725 - 18 Aug 2022
Cited by 3 | Viewed by 2665
Abstract
Tremendous progress has been made in the field of nanomedicine for cancer treatment. However, most of the research to date has been focused on inhibiting primary tumor growth with comparatively less efforts directed towards managing tumor metastasis. Here, we introduce a polymeric conjugate [...] Read more.
Tremendous progress has been made in the field of nanomedicine for cancer treatment. However, most of the research to date has been focused on inhibiting primary tumor growth with comparatively less efforts directed towards managing tumor metastasis. Here, we introduce a polymeric conjugate P-DOX-iRGD that not only significantly suppressed primary tumor growth but also substantially inhibited pulmonary metastasis in an orthotopic mouse model of breast cancer. In addition, treatment with P-DOX-iRGD markedly reduced breast cancer-induced splenomegaly and liver hematopoiesis. Interestingly, contrasting results were seen for the free form and polymeric form of DOX in vitro and in vivo, which may be attributed to the enhanced permeability and retention (EPR) effect. Full article
(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)
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16 pages, 28938 KiB  
Article
Redox-Responsive Polymersomes as Smart Doxorubicin Delivery Systems
by Carmen Ferrero, Marta Casas and Isidoro Caraballo
Pharmaceutics 2022, 14(8), 1724; https://doi.org/10.3390/pharmaceutics14081724 - 18 Aug 2022
Cited by 9 | Viewed by 2372
Abstract
Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments [...] Read more.
Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120–190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells. Full article
(This article belongs to the Special Issue Stimuli-Responsive Nanomedicine for the Effective and Controlled Delivery of Drug Molecules to the Tumor Microenvironment)
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13 pages, 2207 KiB  
Article
Formulation Development of Fluconazole-Loaded Lactose Agglomerate Tablets as a Disinfectant for Candida-Associated Dentures
by Rapee Jarungsirawat, Wanassnant Kajthunyakarn, Chaipat Siriwachirachai and Thaned Pongjanyakul
Pharmaceutics 2022, 14(8), 1723; https://doi.org/10.3390/pharmaceutics14081723 - 18 Aug 2022
Cited by 5 | Viewed by 2145
Abstract
Denture stomatitis is induced by irritation or an inflammatory response when wearing a denture for a long time. Candida species are the leading cause of biofilm formation on the surfaces and fissures of dentures. Thus, this study aimed to formulate and evaluate fluconazole [...] Read more.
Denture stomatitis is induced by irritation or an inflammatory response when wearing a denture for a long time. Candida species are the leading cause of biofilm formation on the surfaces and fissures of dentures. Thus, this study aimed to formulate and evaluate fluconazole tablets for use in preparing a disinfectant mixture with anticandidal activity. For size enlargement of lactose, a tablet diluent, using polyvinylpyrrolidone (PVP) as an agglomerating agent, was developed to enhance the flowability and compactability of the tablet preparation using direct compression. Lactose agglomerates with 6% PVP were used as a diluent for the fluconazole tablets. Furthermore, other excipients were used, such as a buffering agent, disintegrant, surfactant, and lubricant. The fluconazole tablets obtained could be dispersed and dissolved within 10 min in distilled water to achieve a clear mixture, providing a neutral pH and 96% transmittance. Furthermore, the fluconazole mixtures displayed anticandidal efficiency against C. albicans with a similar effect to the standard fluconazole solution. These findings suggest that the fluconazole-loaded lactose agglomerate tablets show strong potential when prepared using direct compression. The fluconazole mixtures made by dispersing the tablets can be used as a disinfectant for Candida-associated dentures, particularly in patients with oral candidiasis. Full article
(This article belongs to the Special Issue Advance in Development of Patient-Centric Dosage Form)
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28 pages, 3970 KiB  
Review
Beyond Formulation: Contributions of Nanotechnology for Translation of Anticancer Natural Products into New Drugs
by Rodrigo dos A. Miguel, Amanda S. Hirata, Paula C. Jimenez, Luciana B. Lopes and Leticia V. Costa-Lotufo
Pharmaceutics 2022, 14(8), 1722; https://doi.org/10.3390/pharmaceutics14081722 - 17 Aug 2022
Cited by 24 | Viewed by 3788
Abstract
Nature is the largest pharmacy in the world. Doxorubicin (DOX) and paclitaxel (PTX) are two examples of natural-product-derived drugs employed as first-line treatment of various cancer types due to their broad mechanisms of action. These drugs are marketed as conventional and nanotechnology-based formulations, [...] Read more.
Nature is the largest pharmacy in the world. Doxorubicin (DOX) and paclitaxel (PTX) are two examples of natural-product-derived drugs employed as first-line treatment of various cancer types due to their broad mechanisms of action. These drugs are marketed as conventional and nanotechnology-based formulations, which is quite curious since the research and development (R&D) course of nanoformulations are even more expensive and prone to failure than the conventional ones. Nonetheless, nanosystems are cost-effective and represent both novel and safer dosage forms with fewer side effects due to modification of pharmacokinetic properties and tissue targeting. In addition, nanotechnology-based drugs can contribute to dose modulation, reversion of multidrug resistance, and protection from degradation and early clearance; can influence the mechanism of action; and can enable drug administration by alternative routes and co-encapsulation of multiple active agents for combined chemotherapy. In this review, we discuss the contribution of nanotechnology as an enabling technology taking the clinical use of DOX and PTX as examples. We also present other nanoformulations approved for clinical practice containing different anticancer natural-product-derived drugs. Full article
(This article belongs to the Special Issue Recent Advances in Natural Product Drugs)
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