Pharmaceutics

22 pages, 4338 KiB

Open AccessEditor’s ChoiceArticle

Non-Invasive Delivery of Negatively Charged Nanobodies by Anodal Iontophoresis: When Electroosmosis Dominates Electromigration

by Phedra Firdaws Sahraoui, Oscar Vadas and Yogeshvar N. Kalia

Pharmaceutics 2024, 16(4), 539; https://doi.org/10.3390/pharmaceutics16040539 - 13 Apr 2024

Cited by 2 | Viewed by 2171

Abstract

Iontophoresis enables the non-invasive transdermal delivery of moderately-sized proteins and the needle-free cutaneous delivery of antibodies. However, simple descriptors of protein characteristics cannot accurately predict the feasibility of iontophoretic transport. This study investigated the cathodal and anodal iontophoretic transport of the negatively charged [...] Read more.

Iontophoresis enables the non-invasive transdermal delivery of moderately-sized proteins and the needle-free cutaneous delivery of antibodies. However, simple descriptors of protein characteristics cannot accurately predict the feasibility of iontophoretic transport. This study investigated the cathodal and anodal iontophoretic transport of the negatively charged M7D12H nanobody and a series of negatively charged variants with single amino acid substitutions. Surprisingly, M7D12H and its variants were only delivered transdermally by anodal iontophoresis. In contrast, transdermal permeation after cathodal iontophoresis and passive diffusion was <LOQ. The anodal iontophoretic delivery of these negatively charged proteins was achieved because electroosmosis was the dominant electrotransport mechanism. Cutaneous deposition after the anodal iontophoresis of M7D12H_WT (wild type), and the R54E and K65E variants, was statistically superior to that after cathodal iontophoresis (6.07 ± 2.11, 9.22 ± 0.80, and 14.45 ± 3.45 μg/cm², versus 1.12 ± 0.30, 0.72 ± 0.27, and 0.46 ± 0.07 µg/cm², respectively). This was not the case for S102E, where cutaneous deposition after anodal and cathodal iontophoresis was 11.89 ± 0.87 and 8.33 ± 2.62 µg/cm², respectively; thus, a single amino acid substitution appeared to be sufficient to impact the iontophoretic transport of a 17.5 kDa protein. Visualization studies using immunofluorescent labeling showed that skin transport of M7D12H_WT was achieved via the intercellular and follicular routes. Full article

(This article belongs to the Special Issue Transdermal Delivery: Challenges and Opportunities)

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32 pages, 12016 KiB

Open AccessEditor’s ChoiceReview

Cell Membrane-Coated Biomimetic Nanoparticles in Cancer Treatment

by Shu Zhang, Xiaojuan Zhang, Huan Gao, Xiaoqin Zhang, Lidan Sun, Yueyan Huang, Jie Zhang and Baoyue Ding

Pharmaceutics 2024, 16(4), 531; https://doi.org/10.3390/pharmaceutics16040531 - 12 Apr 2024

Cited by 27 | Viewed by 4420

Abstract

Nanoparticle-based drug delivery systems hold promise for cancer treatment by enhancing the solubility and stability of anti-tumor drugs. Nonetheless, the challenges of inadequate targeting and limited biocompatibility persist. In recent years, cell membrane nano-biomimetic drug delivery systems have emerged as a focal point [...] Read more.

Nanoparticle-based drug delivery systems hold promise for cancer treatment by enhancing the solubility and stability of anti-tumor drugs. Nonetheless, the challenges of inadequate targeting and limited biocompatibility persist. In recent years, cell membrane nano-biomimetic drug delivery systems have emerged as a focal point of research and development, due to their exceptional traits, including precise targeting, low toxicity, and good biocompatibility. This review outlines the categorization and advantages of cell membrane bionic nano-delivery systems, provides an introduction to preparation methods, and assesses their applications in cancer treatment, including chemotherapy, gene therapy, immunotherapy, photodynamic therapy, photothermal therapy, and combination therapy. Notably, the review delves into the challenges in the application of various cell membrane bionic nano-delivery systems and identifies opportunities for future advancement. Embracing cell membrane-coated biomimetic nanoparticles presents a novel and unparalleled avenue for personalized tumor therapy. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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24 pages, 3499 KiB

Open AccessEditor’s ChoiceReview

Mirk/Dyrk1B Kinase Inhibitors in Targeted Cancer Therapy

by Nikolaos Kokkorakis, Marios Zouridakis and Maria Gaitanou

Pharmaceutics 2024, 16(4), 528; https://doi.org/10.3390/pharmaceutics16040528 - 11 Apr 2024

Cited by 3 | Viewed by 2984

Abstract

During the last years, there has been an increased effort in the discovery of selective and potent kinase inhibitors for targeted cancer therapy. Kinase inhibitors exhibit less toxicity compared to conventional chemotherapy, and several have entered the market. Mirk/Dyrk1B kinase is a promising [...] Read more.

During the last years, there has been an increased effort in the discovery of selective and potent kinase inhibitors for targeted cancer therapy. Kinase inhibitors exhibit less toxicity compared to conventional chemotherapy, and several have entered the market. Mirk/Dyrk1B kinase is a promising pharmacological target in cancer since it is overexpressed in many tumors, and its overexpression is correlated with patients’ poor prognosis. Mirk/Dyrk1B acts as a negative cell cycle regulator, maintaining the survival of quiescent cancer cells and conferring their resistance to chemotherapies. Many studies have demonstrated the valuable therapeutic effect of Mirk/Dyrk1B inhibitors in cancer cell lines, mouse xenografts, and patient-derived 3D-organoids, providing a perspective for entering clinical trials. Since the majority of Mirk/Dyrk1B inhibitors target the highly conserved ATP-binding site, they exhibit off-target effects with other kinases, especially with the highly similar Dyrk1A. In this review, apart from summarizing the data establishing Dyrk1B as a therapeutic target in cancer, we highlight the most potent Mirk/Dyrk1B inhibitors recently reported. We also discuss the limitations and perspectives for the structure-based design of Mirk/Dyrk1B potent and highly selective inhibitors based on the accumulated structural data of Dyrk1A and the recent crystal structure of Dyrk1B with AZ191 inhibitor. Full article

(This article belongs to the Special Issue Kinase Inhibitor for Cancer Therapy, 2nd Edition)

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27 pages, 547 KiB

Open AccessEditor’s ChoiceReview

Progress in the Use of Hydrogels for Antioxidant Delivery in Skin Wounds

by Lidia Maeso, Pablo Edmundo Antezana, Ailen Gala Hvozda Arana, Pablo Andrés Evelson, Gorka Orive and Martín Federico Desimone

Pharmaceutics 2024, 16(4), 524; https://doi.org/10.3390/pharmaceutics16040524 - 10 Apr 2024

Cited by 16 | Viewed by 2510

Abstract

The skin is the largest organ of the body, and it acts as a protective barrier against external factors. Chronic wounds affect millions of people worldwide and are associated with significant morbidity and reduced quality of life. One of the main factors involved [...] Read more.

The skin is the largest organ of the body, and it acts as a protective barrier against external factors. Chronic wounds affect millions of people worldwide and are associated with significant morbidity and reduced quality of life. One of the main factors involved in delayed wound healing is oxidative injury, which is triggered by the overproduction of reactive oxygen species. Oxidative stress has been implicated in the pathogenesis of chronic wounds, where it is known to impair wound healing by causing damage to cellular components, delaying the inflammatory phase of healing, and inhibiting the formation of new blood vessels. Thereby, the treatment of chronic wounds requires a multidisciplinary approach that addresses the underlying causes of the wound, provides optimal wound care, and promotes wound healing. Among the promising approaches to taking care of chronic wounds, antioxidants are gaining interest since they offer multiple benefits related to skin health. Therefore, in this review, we will highlight the latest advances in the use of natural polymers with antioxidants to generate tissue regeneration microenvironments for skin wound healing. Full article

(This article belongs to the Special Issue Biopolymer Materials for Wound Healing, 2nd Edition)

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10 pages, 706 KiB

Open AccessEditor’s ChoiceCommunication

Therapeutic Aqueous Humor Concentrations of Latanoprost Attained in Rats by Administration in a Very-High-Molecular-Weight Hyaluronic Acid Eye Drop

by Kazunari Higa, Reona Kimoto, Takashi Kojima, Murat Dogru, Wolfgang G. K. Müller-Lierheim and Jun Shimazaki

Pharmaceutics 2024, 16(4), 523; https://doi.org/10.3390/pharmaceutics16040523 - 9 Apr 2024

Cited by 2 | Viewed by 1669

Abstract

The temporal change in concentration of a novel medicine, Latanoprost (LP), was evaluated in the aqueous humor of rats (6–8-week-old Jcl:Wister rats) when delivered in a very-high-molecular-weight hyaluronic acid (vHiHA) eye drop. Animals were randomly assigned to three treatment groups (LP + vHiHA [...] Read more.

The temporal change in concentration of a novel medicine, Latanoprost (LP), was evaluated in the aqueous humor of rats (6–8-week-old Jcl:Wister rats) when delivered in a very-high-molecular-weight hyaluronic acid (vHiHA) eye drop. Animals were randomly assigned to three treatment groups (LP + vHiHA (LPvHiHA), commercial LP (cLP), and diluted LP (dLP)) and after instilling the eye drops, the aqueous humor (AH) was collected at 0.5, 1, 2, 4, and 6 h to measure the LP concentration using an enzyme-linked immunosorbent assay (ELISA). Although the LP concentration in the LPvHiHA eye drop formulation was 3.57 times lower than in the commercial eye drops used (cLP), the LP concentration in the AH following LPvHiHA administration reached a value close to that of cLP. The cLP was diluted to the same concentration of LP as in the LPvHiHA eye drops for the dLP group, but the LP concentration in the AH of these animals was lower than that of the LPvHiHA rats at all time points. The higher LP concentration in the AH of the LPvHiHA rats suggests that vHiHA may aid the transport of LP across the ocular surface epithelium. Full article

(This article belongs to the Special Issue Advances in Ocular Drug Delivery)

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14 pages, 2287 KiB

Open AccessEditor’s ChoiceArticle

Interaction of γ-Polyglutamic Acid/Polyethyleneimine/Plasmid DNA Ternary Complexes with Serum Components Plays a Crucial Role in Transfection in Mice

by Tomotaka Ko, Shintaro Fumoto, Tomoaki Kurosaki, Moe Nakashima, Hirotaka Miyamoto, Hitoshi Sasaki and Koyo Nishida

Pharmaceutics 2024, 16(4), 522; https://doi.org/10.3390/pharmaceutics16040522 - 9 Apr 2024

Cited by 3 | Viewed by 1554

Abstract

Typical examples of non-viral vectors are binary complexes of plasmid DNA with cationic polymers such as polyethyleneimine (PEI). However, problems such as cytotoxicity and hemagglutination, owing to their positively charged surfaces, hinder their in vivo use. Coating binary complexes with anionic polymers, such [...] Read more.

Typical examples of non-viral vectors are binary complexes of plasmid DNA with cationic polymers such as polyethyleneimine (PEI). However, problems such as cytotoxicity and hemagglutination, owing to their positively charged surfaces, hinder their in vivo use. Coating binary complexes with anionic polymers, such as γ-polyglutamic acid (γ-PGA), can prevent cytotoxicity and hemagglutination. However, the role of interactions between these complexes and serum components in in vivo gene transfer remains unclear. In this study, we analyzed the contribution of serum components to in vivo gene transfer using PEI/plasmid DNA binary complexes and γ-PGA/PEI/plasmid DNA ternary complexes. In binary complexes, heat-labile components in the serum greatly contribute to the hepatic and splenic gene expression of the luciferase gene. In contrast, serum albumin and salts affected the hepatic and splenic gene expression in the ternary complexes. Changes in physicochemical characteristics, such as increased particle size and decreased absolute values of ζ-potential, might be involved in the enhanced gene expression. These findings would contribute to a better understanding of in vivo non-viral gene transfer using polymers, such as PEI and γ-PGA. Full article

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

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14 pages, 7480 KiB

Open AccessEditor’s ChoiceArticle

Size Tuning of Mesoporous Silica Adjuvant for One-Shot Vaccination with Long-Term Anti-Tumor Effect

by Xiupeng Wang, Yu Sogo and Xia Li

Pharmaceutics 2024, 16(4), 516; https://doi.org/10.3390/pharmaceutics16040516 - 8 Apr 2024

Cited by 1 | Viewed by 2068

Abstract

Despite recent clinical successes in cancer immunotherapy, it remains difficult to initiate a long-term anti-tumor effect. Therefore, repeated administrations of immune-activating agents are generally required in most cases. Herein, we propose an adjuvant particle size tuning strategy to initiate a long-term anti-tumor effect [...] Read more.

Despite recent clinical successes in cancer immunotherapy, it remains difficult to initiate a long-term anti-tumor effect. Therefore, repeated administrations of immune-activating agents are generally required in most cases. Herein, we propose an adjuvant particle size tuning strategy to initiate a long-term anti-tumor effect by one-shot vaccination. This strategy is based on the size-dependent immunostimulation mechanism of mesoporous silica particles. Hollow mesoporous silica (HMS) nanoparticles enhance the antigen uptake with dendritic cells around the immunization site in vivo. In contrast, hierarchically porous silica (HPS) microparticles prolong cancer antigen retention and release in vivo. The size tuning of the mesoporous silica adjuvant prepared by combining both nanoparticles and microparticles demonstrates the immunological properties of both components and has a long-term anti-tumor effect after one-shot vaccination. One-shot vaccination with HMS-HPS-ovalbumin (OVA)-Poly IC (PIC, a TLR3 agonist) increases CD4⁺ T cell, CD8⁺ T cell, and CD86⁺ cell populations in draining lymph nodes even 4 months after vaccination, as well as effector memory CD8⁺ T cell and tumor-specific tetramer⁺CD8⁺ T cell populations in splenocytes. The increases in the numbers of effector memory CD8⁺ T cells and tumor-specific tetramer⁺CD8⁺ T cells indicate that the one-shot vaccination with HMS-HPS-OVA-PIC achieved the longest survival time after a challenge with E.G7-OVA cells among all groups. The size tuning of the mesoporous silica adjuvant shows promise for one-shot vaccination that mimics multiple clinical vaccinations in future cancer immunoadjuvant development. This study may have important implications in the long-term vaccine design of one-shot vaccinations. Full article

(This article belongs to the Special Issue Anti-Cancer Drug Delivery Systems)

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20 pages, 3557 KiB

Open AccessEditor’s ChoiceArticle

Effect of Micromixer Design on Lipid Nanocarriers Manufacturing for the Delivery of Proteins and Nucleic Acids

by Enrica Chiesa, Alessandro Caimi, Marco Bellotti, Alessia Giglio, Bice Conti, Rossella Dorati, Ferdinando Auricchio and Ida Genta

Pharmaceutics 2024, 16(4), 507; https://doi.org/10.3390/pharmaceutics16040507 - 7 Apr 2024

Cited by 5 | Viewed by 2274

Abstract

Lipid-based nanocarriers have emerged as helpful tools to deliver sensible biomolecules such as proteins and oligonucleotides. To have a fast and robust microfluidic-based nanoparticle synthesis method, the setup of versatile equipment should allow for the rapid transfer to scale cost-effectively while ensuring tunable, [...] Read more.

Lipid-based nanocarriers have emerged as helpful tools to deliver sensible biomolecules such as proteins and oligonucleotides. To have a fast and robust microfluidic-based nanoparticle synthesis method, the setup of versatile equipment should allow for the rapid transfer to scale cost-effectively while ensuring tunable, precise and reproducible nanoparticle attributes. The present work aims to assess the effect of different micromixer geometries on the manufacturing of lipid nanocarriers taking into account the influence on the mixing efficiency by changing the fluid–fluid interface and indeed the mass transfer. Since the geometry of the adopted micromixer varies from those already published, a Design of Experiment (DoE) was necessary to identify the operating (total flow, flow rate ratio) and formulation (lipid concentration, lipid molar ratios) parameters affecting the nanocarrier quality. The suitable application of the platform was investigated by producing neutral, stealth and cationic liposomes, using DaunoXome^®, Myocet^®, Onivyde^® and Onpattro^® as the benchmark. The effect of condensing lipid (DOTAP, 3–10–20 mol%), coating lipids (DSPE-PEG550 and DSPE-PEG2000), as well as structural lipids (DSPC, eggPC) was pointed out. A very satisfactory encapsulation efficiency, always higher than 70%, was successfully obtained for model biomolecules (myoglobin, short and long nucleic acids). Full article

(This article belongs to the Special Issue Recent Advances in Nanotechnology Therapeutics)

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14 pages, 14092 KiB

Open AccessEditor’s ChoiceArticle

Polydopamine-Modified Copper Coordination Mesoporous Silica Nanoparticles Loaded with Disulfiram for Synergistic Chemo-Photothermal Therapy

by Junhong Ling, Yingying Cai, Haozhan Feng, Zhen Liu and Xiao-kun Ouyang

Pharmaceutics 2024, 16(4), 512; https://doi.org/10.3390/pharmaceutics16040512 - 7 Apr 2024

Cited by 5 | Viewed by 2388

Abstract

Disulfiram (DSF) degrades to diethyldithiocarbamate (DTC) in vivo and coordinates with copper ions to form CuET, which has higher antitumor activity. In this study, DSF@CuMSN-PDA nanoparticles were prepared using mesoporous silica with copper ions, DSF as a carrier, and polydopamine (PDA) as a [...] Read more.

Disulfiram (DSF) degrades to diethyldithiocarbamate (DTC) in vivo and coordinates with copper ions to form CuET, which has higher antitumor activity. In this study, DSF@CuMSN-PDA nanoparticles were prepared using mesoporous silica with copper ions, DSF as a carrier, and polydopamine (PDA) as a gate system. The nanoparticles selectively released CuET into tumor tissue by taking advantage of the tumor microenvironment, where PDA could be degraded. The release ratio reached 79.17% at pH 5.0, indicating pH-responsive drug release from the nanoparticles. The PDA-gated system provided the nanoparticles with unique photothermal conversion performance and significantly improved antitumor efficiency. In vivo, antitumor experiments showed that the designed DSF@CuMSN-PDA nanoparticles combined with near-infrared light (808 nm, 1 W/cm²) irradiation effectively inhibited tumor growth in HCT116 cells by harnessing the combined potential of chemotherapy and photothermal therapy; a synergistic effect was achieved. Taken together, these results suggest that the designed DSF@CuMSN-PDA construct can be employed as a promising candidate for combined chemo-photothermal therapy. Full article

(This article belongs to the Special Issue Anti-Cancer Drug Delivery Systems)

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16 pages, 3464 KiB

Open AccessEditor’s ChoiceArticle

Beyond One-Size-Fits-All: Tailoring Teicoplanin Regimens for Normal Renal Function Patients Using Population Pharmacokinetics and Monte Carlo Simulation

by Yong-Kyun Kim, Kyeong-Min Jo, Jae-Ha Lee, Ji-Hoon Jang, Eun-Jun Choe, Gaeun Kang, Dae-Young Zang and Dong-Hwan Lee

Pharmaceutics 2024, 16(4), 499; https://doi.org/10.3390/pharmaceutics16040499 - 5 Apr 2024

Cited by 2 | Viewed by 1930

Abstract

In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK [...] Read more.

In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK samples were obtained from 12 subjects and analyzed using a population approach. The derived parameters informed Monte Carlo simulations for dosing recommendations. The PK profile was best described using a three-compartment model, in which the estimated glomerular filtration rate calculated via the CKD-EPI equation and adjusted for body surface area was identified as a significant covariate affecting total clearance. For pathogens with a minimum inhibitory concentration of 1 mg/L, a loading dose (LD) of 14 mg/kg administered every 12 h for four doses, followed by a maintenance dose (MD) of 16 mg/kg administered every 24 h, is recommended. These findings indicate the need for dosage adjustments, such as increasing the LD and MD or decreasing the dosing interval of MD in patients with normal renal function. Because of the long half-life of teicoplanin and the requirement for long-term administration, therapeutic drug monitoring at strategic intervals is important to avoid nephrotoxicity associated with elevated trough concentrations. Full article

(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)

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29 pages, 1791 KiB

Open AccessEditor’s ChoiceArticle

Comparative Fitting of Mathematical Models to Carvedilol Release Profiles Obtained from Hypromellose Matrix Tablets

by Tadej Ojsteršek, Franc Vrečer and Grega Hudovornik

Pharmaceutics 2024, 16(4), 498; https://doi.org/10.3390/pharmaceutics16040498 - 4 Apr 2024

Cited by 8 | Viewed by 1804

Abstract

The mathematical models available in DDSolver were applied to experimental dissolution data obtained by analysing carvedilol release from hypromellose (HPMC)-based matrix tablets. Different carvedilol release profiles were generated by varying a comprehensive selection of fillers and carvedilol release modifiers in the formulation. Model [...] Read more.

The mathematical models available in DDSolver were applied to experimental dissolution data obtained by analysing carvedilol release from hypromellose (HPMC)-based matrix tablets. Different carvedilol release profiles were generated by varying a comprehensive selection of fillers and carvedilol release modifiers in the formulation. Model fitting was conducted for the entire relevant dissolution data, as determined by using a paired t-test, and independently for dissolution data up to approximately 60% of carvedilol released. The best models were selected based on the residual sum of squares (RSS) results used as a general measure of goodness of fit, along with the utilization of various criteria for visual assessment of model fit and determination of the acceptability of estimated model parameters indicating burst release or lag time concerning experimental dissolution results and previous research. In addition, a model-dependent analysis of carvedilol release mechanisms was carried out. Full article

(This article belongs to the Special Issue Feature Papers in Physical Pharmacy and Formulation)

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20 pages, 5222 KiB

Open AccessEditor’s ChoiceArticle

Unraveling Drug Delivery from Cyclodextrin Polymer-Coated Breast Implants: Integrating a Unidirectional Diffusion Mathematical Model with COMSOL Simulations

by Jacobo Hernandez-Montelongo, Javiera Salazar-Araya, Elizabeth Mas-Hernández, Douglas Soares Oliveira and Juan Paulo Garcia-Sandoval

Pharmaceutics 2024, 16(4), 486; https://doi.org/10.3390/pharmaceutics16040486 - 2 Apr 2024

Cited by 2 | Viewed by 2320

Abstract

Breast cancer ranks among the most commonly diagnosed cancers worldwide and bears the highest mortality rate. As an integral component of cancer treatment, mastectomy entails the complete removal of the affected breast. Typically, breast reconstruction, involving the use of silicone implants (augmentation mammaplasty), [...] Read more.

Breast cancer ranks among the most commonly diagnosed cancers worldwide and bears the highest mortality rate. As an integral component of cancer treatment, mastectomy entails the complete removal of the affected breast. Typically, breast reconstruction, involving the use of silicone implants (augmentation mammaplasty), is employed to address the aftermath of mastectomy. To mitigate postoperative risks associated with mammaplasty, such as capsular contracture or bacterial infections, the functionalization of breast implants with coatings of cyclodextrin polymers as drug delivery systems represents an excellent alternative. In this context, our work focuses on the application of a mathematical model for simulating drug release from breast implants coated with cyclodextrin polymers. The proposed model considers a unidirectional diffusion process following Fick’s second law, which was solved using the orthogonal collocation method, a numerical technique employed to approximate solutions for ordinary and partial differential equations. We conducted simulations to obtain release profiles for three therapeutic molecules: pirfenidone, used for preventing capsular contracture; rose Bengal, an anticancer agent; and the antimicrobial peptide KR-12. Furthermore, we calculated the diffusion profiles of these drugs through the cyclodextrin polymers, determining parameters related to diffusivity, solute solid–liquid partition coefficients, and the Sherwood number. Finally, integrating these parameters in COMSOL multiphysics simulations, the unidirectional diffusion mathematical model was validated. Full article

(This article belongs to the Special Issue Mathematical Modeling in Drug Delivery)

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30 pages, 6228 KiB

Open AccessEditor’s ChoiceArticle

The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine

by Khairulanwar Burhanuddin, Afzal Mohammed and Raj K. S. Badhan

Pharmaceutics 2024, 16(4), 489; https://doi.org/10.3390/pharmaceutics16040489 - 2 Apr 2024

Cited by 1 | Viewed by 2387

Abstract

The incidence of paediatric obesity continues to rise worldwide and contributes to a range of diseases including cardiovascular disease. Obesity in children has been shown to impact upon the plasma concentrations of various compounds, including amlodipine. Nonetheless, information on the influence of obesity [...] Read more.

The incidence of paediatric obesity continues to rise worldwide and contributes to a range of diseases including cardiovascular disease. Obesity in children has been shown to impact upon the plasma concentrations of various compounds, including amlodipine. Nonetheless, information on the influence of obesity on amlodipine pharmacokinetics and the need for dose adjustment has not been studied previously. This study applied the physiologically based pharmacokinetic modelling and established a paediatric obesity population to assess the impact of obesity on amlodipine pharmacokinetics in children and explore the possible dose adjustments required to reach the same plasma concentration as non-obese paediatrics. The difference in predicted maximum concentration (C_max) and area under the curve (AUC) were significant between children with and without obesity across the age group 2 to 18 years old when a fixed-dose regimen was used. On the contrary, a weight-based dose regimen showed no difference in C_max between obese and non-obese from 2 to 9 years old. Thus, when a fixed-dose regimen is to be administered, a 1.25- to 1.5-fold increase in dose is required in obese children to achieve the same C_max concentration as non-obese children, specifically for children aged 5 years and above. Full article

(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)

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19 pages, 3966 KiB

Open AccessEditor’s ChoiceArticle

Membrane-Fusing Vehicles for Re-Sensitizing Transporter-Mediated Multiple-Drug Resistance in Cancer

by Sahel Vahdati and Alf Lamprecht

Pharmaceutics 2024, 16(4), 493; https://doi.org/10.3390/pharmaceutics16040493 - 2 Apr 2024

Cited by 3 | Viewed by 1497

Abstract

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three [...] Read more.

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three ABC transporters (ABCB1, ABCC1 and ABCG2) directly to the cell membrane using membrane-fusing vehicles (MFVs). Three different transfected MDCK II cell lines, along with parental cells, were used to investigate the inhibitory effect of cyclosporine A (CsA) in solution versus direct delivery to the cell membrane. CsA-loaded MFVs successfully reversed MDR for all three investigated efflux transporters at significantly lower concentrations compared with CsA in solution. Results showed a 15-fold decrease in the IC₅₀ value for ABCB1, a 7-fold decrease for ABCC1 and an 11-fold decrease for ABCG2. We observed binding site specificity for ABCB1 and ABCG2 transporters. Lower concentrations of empty MFVs along with CsA contribute to the inhibition of Hoechst 33342 efflux. However, higher concentrations of CsA along with the high amount of MFVs activated transport via the H-binding site. This supports the conclusion that MFVs can be useful beyond their role as delivery systems and also help to elucidate differences between these transporters and their binding sites. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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20 pages, 5181 KiB

Open AccessEditor’s ChoiceArticle

Ionic Liquid Transdermal Patches of Two Active Ingredients Based on Semi-Ionic Hydrogen Bonding for Rheumatoid Arthritis Treatment

by Faxing Zhang, Lu Li, Xinyuan Zhang, Hongyu Yang, Yingzhen Fan, Jian Zhang, Ting Fang, Yaming Liu, Zhihao Nie and Dongkai Wang

Pharmaceutics 2024, 16(4), 480; https://doi.org/10.3390/pharmaceutics16040480 - 1 Apr 2024

Cited by 5 | Viewed by 2326

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to deformities and disabilities in patients. Conventional treatment focuses on delaying progression; therefore, new treatments are necessary. The present study reported a novel ionic liquid transdermal platform for efficient RA treatment, and the [...] Read more.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to deformities and disabilities in patients. Conventional treatment focuses on delaying progression; therefore, new treatments are necessary. The present study reported a novel ionic liquid transdermal platform for efficient RA treatment, and the underlying mechanism was elucidated using FTIR, ¹H-NMR, Raman, XPS, and molecular simulations. The results showed that the reversibility of the semi-ionic hydrogen bonding facilitated high drug loading and enhanced drug permeability. Actarit’s drug loading had an approximately 11.34-times increase. The in vitro permeability of actarit and ketoprofen was improved by 5.46 and 2.39 times, respectively. And they had the same significant effect in vivo. Furthermore, through the integration of network pharmacology, Western blotting (WB), and radiology analyses, the significant osteoprotective effects of SIHDD-PSA (semi-ionic H-bond double-drug pressure-sensitive adhesive transdermal patch) were revealed through the modulation of the JAK-STAT pathway. The SIHDD-PSA significantly reduced paw swelling and inflammation in the rat model, and stimulatory properties evaluation confirmed the safety of SIHDD-PSA. In conclusion, these findings provide a novel approach for the effective treatment of RA, and the semi-ionic hydrogen bonding strategy contributes a new theoretical basis for developing TDDS. Full article

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

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16 pages, 5552 KiB

Open AccessEditor’s ChoiceReview

Engineering Nanomedicine for Non-Viral RNA-Based Gene Therapy of Glioblastoma

by Wenya He, Ningyang Wang, Yaping Wang, Mengyao Liu, Qian Qing, Qihang Su, Yan Zou and Yang Liu

Pharmaceutics 2024, 16(4), 482; https://doi.org/10.3390/pharmaceutics16040482 - 1 Apr 2024

Cited by 2 | Viewed by 3094

Abstract

Glioblastoma multiforme (GBM) is the most common type of malignant tumor of the central nervous system, characterized by aggressiveness, genetic instability, heterogenesis, and unpredictable clinical behavior. Disappointing results from the current clinical therapeutic methods have fueled a search for new therapeutic targets and [...] Read more.

Glioblastoma multiforme (GBM) is the most common type of malignant tumor of the central nervous system, characterized by aggressiveness, genetic instability, heterogenesis, and unpredictable clinical behavior. Disappointing results from the current clinical therapeutic methods have fueled a search for new therapeutic targets and treatment modalities. GBM is characterized by various genetic alterations, and RNA-based gene therapy has raised particular attention in GBM therapy. Here, we review the recent advances in engineered non-viral nanocarriers for RNA drug delivery to treat GBM. Therapeutic strategies concerning the brain-targeted delivery of various RNA drugs involving siRNA, microRNA, mRNA, ASO, and short-length RNA and the therapeutical mechanisms of these drugs to tackle the challenges of chemo-/radiotherapy resistance, recurrence, and incurable stem cell-like tumor cells of GBM are herein outlined. We also highlight the progress, prospects, and remaining challenges of non-viral nanocarriers-mediated RNA-based gene therapy. Full article

(This article belongs to the Special Issue Nanocarriers: A Novel Strategy for Cell and Gene Delivery)

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28 pages, 5511 KiB

Open AccessEditor’s ChoiceReview

Evaluation of Advanced Nanomaterials for Cancer Diagnosis and Treatment

by Nkanyiso L. Ndlovu, Wendy B. Mdlalose, Bulelwa Ntsendwana and Thomas Moyo

Pharmaceutics 2024, 16(4), 473; https://doi.org/10.3390/pharmaceutics16040473 - 28 Mar 2024

Cited by 8 | Viewed by 4383

Abstract

Cancer is a persistent global disease and a threat to the human species, with numerous cases reported every year. Over recent decades, a steady but slowly increasing mortality rate has been observed. While many attempts have been made using conventional methods alone as [...] Read more.

Cancer is a persistent global disease and a threat to the human species, with numerous cases reported every year. Over recent decades, a steady but slowly increasing mortality rate has been observed. While many attempts have been made using conventional methods alone as a theragnostic strategy, they have yielded very little success. Most of the shortcomings of such conventional methods can be attributed to the high demands of industrial growth and ever-increasing environmental pollution. This requires some high-tech biomedical interventions and other solutions. Thus, researchers have been compelled to explore alternative methods. This has brought much attention to nanotechnology applications, specifically magnetic nanomaterials, as the sole or conjugated theragnostic methods. The exponential growth of nanomaterials with overlapping applications in various fields is due to their potential properties, which depend on the type of synthesis route used. Either top-down or bottom-up strategies synthesize various types of NPs. The top-down only branches out to one method, i.e., physical, and the bottom-up has two methods, chemical and biological syntheses. This review highlights some synthesis techniques, the types of nanoparticle properties each technique produces, and their potential use in the biomedical field, more specifically for cancer. Despite the evident drawbacks, the success achieved in furthering nanoparticle applications to more complex cancer stages and locations is unmatched. Full article

(This article belongs to the Special Issue Research on New Strategies for Tumor Therapy Based on Nanostructured Materials)

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14 pages, 3576 KiB

Open AccessEditor’s ChoiceArticle

Influenza Virus Inactivated by Heavy Ion Beam Irradiation Stimulates Antigen-Specific Immune Responses

by Kai Schulze, Ulrich Weber, Christoph Schuy, Marco Durante and Carlos Alberto Guzmán

Pharmaceutics 2024, 16(4), 465; https://doi.org/10.3390/pharmaceutics16040465 - 27 Mar 2024

Cited by 1 | Viewed by 2919

Abstract

The COVID-19 pandemic has made clear the need for effective and rapid vaccine development methods. Conventional inactivated virus vaccines, together with new technologies like vector and mRNA vaccines, were the first to be rolled out. However, the traditional methods used for virus inactivation [...] Read more.

The COVID-19 pandemic has made clear the need for effective and rapid vaccine development methods. Conventional inactivated virus vaccines, together with new technologies like vector and mRNA vaccines, were the first to be rolled out. However, the traditional methods used for virus inactivation can affect surface-exposed antigen, thereby reducing vaccine efficacy. Gamma rays have been used in the past to inactivate viruses. We recently proposed that high-energy heavy ions may be more suitable as an inactivation method because they increase the damage ratio between the viral nucleic acid and surface proteins. Here, we demonstrate that irradiation of the influenza virus using heavy ion beams constitutes a suitable method to develop effective vaccines, since immunization of mice by the intranasal route with the inactivated virus resulted in the stimulation of strong antigen-specific humoral and cellular immune responses. Full article

(This article belongs to the Special Issue Emerging Pharmaceutical Strategies against Infectious Diseases)

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18 pages, 3281 KiB

Open AccessEditor’s ChoiceArticle

AmBisome^® Formulations for Pediatrics: Stability, Cytotoxicity, and Cost-Effectiveness Studies

by Guendalina Zuccari, Carla Villa, Valentina Iurilli, Paola Barabino, Alessia Zorzoli, Danilo Marimpietri, Debora Caviglia and Eleonora Russo

Pharmaceutics 2024, 16(4), 466; https://doi.org/10.3390/pharmaceutics16040466 - 27 Mar 2024

Cited by 7 | Viewed by 4046

Abstract

Liposomal amphotericin B (Ambisome^®) is the gold standard for the treatment and prevention of fungal infections both in the adult and pediatric populations. The lyophilized dosage form has to be reconstituted and diluted by hospital staff, but its management can be [...] Read more.

Liposomal amphotericin B (Ambisome^®) is the gold standard for the treatment and prevention of fungal infections both in the adult and pediatric populations. The lyophilized dosage form has to be reconstituted and diluted by hospital staff, but its management can be challenging due to the spontaneous tendency of amphotericin B to form aggregates with different biological activity. In this study, the colloidal stability of the liposomes and the chemical stability of amphotericin B were investigated over time at storage conditions. Three liposomal formulations of amphotericin B at 4.0 mg/mL, 2.0 mg/mL, and 0.2 mg/mL were prepared and assayed for changes regarding the dimensional distribution, zeta potential, drug aggregation state, and onset of by-products. Our analyses highlighted that the most diluted formulation, kept at room temperature, showed the greatest changes in the aggregation state of the drug and accordingly the highest cytotoxicity. These findings are clinically relevant since the lower dosages are addressed to the more vulnerable patients. Therefore, the centralization of the dilution of AmBisome^® at the pharmacy is of fundamental importance for assuring patient safety, and at the same time for reducing medication waste, as we demonstrated using the cost-saving analysis of drug expense per therapy carried out at the G. Gaslini children hospital. Full article

(This article belongs to the Special Issue Recent Advances in Therapeutic Strategies for the Treatment of Pediatric Diseases)

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18 pages, 9211 KiB

Open AccessEditor’s ChoiceArticle

Nanonization and Deformable Behavior of Fattigated Peptide Drug in Mucoadhesive Buccal Films

by Woojun Kim, Hai V. Ngo, Hy D. Nguyen, Ji-Min Park, Kye Wan Lee, Chulhun Park, Jun-Bom Park and Beom-Jin Lee

Pharmaceutics 2024, 16(4), 468; https://doi.org/10.3390/pharmaceutics16040468 - 27 Mar 2024

Cited by 5 | Viewed by 2097

Abstract

This study was tasked with the design of mucoadhesive buccal films (MBFs) containing a peptide drug, leuprolide (LEU), or its diverse nanoparticles (NPs), for enhanced membrane permeability via self-assembled nanonization and deformable behavior. An LEU-oleic acid conjugate (LOC) and its self-assembled NPs (LON) [...] Read more.

This study was tasked with the design of mucoadhesive buccal films (MBFs) containing a peptide drug, leuprolide (LEU), or its diverse nanoparticles (NPs), for enhanced membrane permeability via self-assembled nanonization and deformable behavior. An LEU-oleic acid conjugate (LOC) and its self-assembled NPs (LON) were developed. Additionally, a deformable variant of LON (d-LON) was originally developed by incorporating l-α-phosphatidylcholine into LON as an edge activator. The physicochemical properties of LON and d-LON, encompassing particle size, zeta potential, and deformability index (DI), were evaluated. MBFs containing LEU, LOC, and NPs (LON, d-LON) were prepared using the solvent casting method by varying the ratio of Eudragit RLPO and hydroxypropyl methylcellulose, with propylene glycol used as a plasticizer. The optimization of MBF formulations was based on their physicochemical properties, including in vitro residence time, dissolution, and permeability. The dissolution results demonstrated that the conjugation of oleic acid to LEU exhibited a more sustained LEU release pattern by cleaving the ester bond of the conjugate, as compared to the native LEU, with reduced variability. Moreover, the LOC and its self-assembled NPs (LON, d-LON), equivalent to 1 mg LEU doses in MBF, exhibited an amorphous state and demonstrated better permeability through the nanonization process than LEU alone, regardless of membrane types. The incorporation of lauroyl-L-carnitine into the films as a permeation enhancer synergistically augmented drug permeability. Most importantly, the d-LON-loaded buccal films showed the highest permeability, due to the deformability of NPs. Overall, MBF-containing peptide NPs and permeation enhancers have the potential to replace parenteral LEU administration by improving LEU druggability and patient compliance. Full article

(This article belongs to the Special Issue Mucoadhesive and Mucosal Drug Delivery Systems, 2nd Edition)

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40 pages, 20578 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Alginate-Based Hydrogels for Cell Transplantation Applications

by Alireza Kavand, François Noverraz and Sandrine Gerber-Lemaire

Pharmaceutics 2024, 16(4), 469; https://doi.org/10.3390/pharmaceutics16040469 - 27 Mar 2024

Cited by 17 | Viewed by 6820

Abstract

With its exceptional biocompatibility, alginate emerged as a highly promising biomaterial for a large range of applications in regenerative medicine. Whether in the form of microparticles, injectable hydrogels, rigid scaffolds, or bioinks, alginate provides a versatile platform for encapsulating cells and fostering an [...] Read more.

With its exceptional biocompatibility, alginate emerged as a highly promising biomaterial for a large range of applications in regenerative medicine. Whether in the form of microparticles, injectable hydrogels, rigid scaffolds, or bioinks, alginate provides a versatile platform for encapsulating cells and fostering an optimal environment to enhance cell viability. This review aims to highlight recent studies utilizing alginate in diverse formulations for cell transplantation, offering insights into its efficacy in treating various diseases and injuries within the field of regenerative medicine. Full article

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

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21 pages, 4411 KiB

Open AccessEditor’s ChoiceReview

Polysaccharides as a Hydrophilic Building Block of Amphiphilic Block Copolymers for the Conception of Nanocarriers

by Aijing Lu and Suming Li

Pharmaceutics 2024, 16(4), 467; https://doi.org/10.3390/pharmaceutics16040467 - 27 Mar 2024

Cited by 3 | Viewed by 1859

Abstract

Polysaccharides are gaining increasing attention for their relevance in the production of sustainable materials. In the domain of biomaterials, polysaccharides play an important role as hydrophilic components in the design of amphiphilic block copolymers for the development of drug delivery systems, in particular [...] Read more.

Polysaccharides are gaining increasing attention for their relevance in the production of sustainable materials. In the domain of biomaterials, polysaccharides play an important role as hydrophilic components in the design of amphiphilic block copolymers for the development of drug delivery systems, in particular nanocarriers due to their outstanding biocompatibility, biodegradability, and structural versatility. The presence of a reducing end in polysaccharide chains allows for the synthesis of polysaccharide-based block copolymers. Compared with polysaccharide-based graft copolymers, the structure of block copolymers can be more precisely controlled. In this review, the synthesis methods of polysaccharide-based amphiphilic block copolymers are discussed in detail, taking into consideration the structural characteristics of polysaccharides. Various synthetic approaches, including reductive amination, oxime ligation, and other chain-end modification reactions, are explored. This review also focuses on the advantages of polysaccharides as hydrophilic blocks in polymeric nanocarriers. The structure and unique properties of different polysaccharides such as cellulose, hyaluronic acid, chitosan, alginate, and dextran are described along with examples of their applications as hydrophilic segments in the synthesis of amphiphilic copolymers to construct nanocarriers for sustained drug delivery. Full article

(This article belongs to the Special Issue Design of Novel Polymeric Systems for Controlled Drug Delivery, 2nd Edition)

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19 pages, 2919 KiB

Open AccessEditor’s ChoiceArticle

Optimizing Nanosuspension Drug Release and Wound Healing Using a Design of Experiments Approach: Improving the Drug Delivery Potential of NDH-4338 for Treating Chemical Burns

by Tomas L. Roldan, Shike Li, Christophe Guillon, Ned D. Heindel, Jeffrey D. Laskin, In Heon Lee, Dayuan Gao and Patrick J. Sinko

Pharmaceutics 2024, 16(4), 471; https://doi.org/10.3390/pharmaceutics16040471 - 27 Mar 2024

Cited by 4 | Viewed by 2511

Abstract

NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in [...] Read more.

NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in the presence of a Vitamin E TPGS aqueous stabilizer solution. Critical processing parameters and material attributes were optimized to reduce particle size and determine the effect on dissolution rate and burn healing efficacy. The antisolvent/solvent ratio (A/S), dose concentration (DC), and drug/stabilizer ratio (D/S) were the critical sonoprecipitation factors that control particle size. These factors were subjected to a Box–Behnken design and response surface analysis, and model quality was assessed. Maximize desirability and simulation experiment optimization approaches were used to determine nanosuspension parameters with the smallest size and the lowest defect rate within the 10–50 nm specification limits. Optimized and unoptimized nanosuspensions were prepared and characterized. An established depilatory double-disc mouse model was used to evaluate the healing of nitrogen mustard-induced dermal injuries. Optimized nanosuspensions (A/S = 6.2, DC = 2% w/v, D/S = 2.8) achieved a particle size of 31.46 nm with a narrow size range (PDI = 0.110) and a reduced defect rate (42.2 to 6.1%). The optimized nanosuspensions were stable and re-dispersible, and they showed a ~45% increase in cumulative drug release and significant edema reduction in mice. Optimized NDH-4338 nanosuspensions were smaller with more uniform sizes that led to improved physical stability, faster dissolution, and enhanced burn healing efficacy compared to unoptimized nanosuspensions. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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14 pages, 4006 KiB

Open AccessEditor’s ChoiceArticle

The Impact of Polymers on Enzalutamide Solid Self-Nanoemulsifying Drug Delivery System and Improved Bioavailability

by Su-Min Lee, Jeong-Gyun Lee, Tae-Han Yun, Chul-Ho Kim, Jung-Hyun Cho and Kyeong-Soo Kim

Pharmaceutics 2024, 16(4), 457; https://doi.org/10.3390/pharmaceutics16040457 - 26 Mar 2024

Cited by 2 | Viewed by 2660

Abstract

Enzalutamide (ENZ), marketed under the brand name Xtandi^® as a soft capsule, is an androgen receptor signaling inhibitor drug actively used in clinical settings for treating prostate cancer. However, ENZ’s low solubility and bioavailability significantly hinder the achievement of optimal therapeutic outcomes. [...] Read more.

Enzalutamide (ENZ), marketed under the brand name Xtandi^® as a soft capsule, is an androgen receptor signaling inhibitor drug actively used in clinical settings for treating prostate cancer. However, ENZ’s low solubility and bioavailability significantly hinder the achievement of optimal therapeutic outcomes. In previous studies, a liquid self-nanoemulsifying drug delivery system (L-SNEDDS) containing ENZ was developed among various solubilization technologies. However, powder formulations that included colloidal silica rapidly formed crystal nuclei in aqueous solutions, leading to a significant decrease in dissolution. Consequently, this study evaluated the efficacy of adding a polymer as a recrystallization inhibitor to a solid SNEDDS (S-SNEDDS) to maintain the drug in a stable, amorphous state in aqueous environments. Polymers were selected based on solubility tests, and the S-SNEDDS formulation was successfully produced via spray drying. The optimized S-SNEDDS formulation demonstrated through X-ray diffraction and differential scanning calorimetry data that it significantly reduced drug crystallinity and enhanced its dissolution rate in simulated gastric and intestinal fluid conditions. In an in vivo study, the bioavailability of orally administered formulations was increased compared to the free drug. Our results highlight the effectiveness of solid-SNEDDS formulations in enhancing the bioavailability of ENZ and outline the potential translational directions for oral drug development. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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21 pages, 3903 KiB

Open AccessEditor’s ChoiceArticle

Daptomycin Liposomes Exhibit Enhanced Activity against Staphylococci Biofilms Compared to Free Drug

by Foteini Gkartziou, Maria Plota, Charikleia Kypraiou, Iti Gauttam, Fevronia Kolonitsiou, Pavlos Klepetsanis, Iris Spiliopoulou and Sophia G. Antimisiaris

Pharmaceutics 2024, 16(4), 459; https://doi.org/10.3390/pharmaceutics16040459 - 26 Mar 2024

Cited by 5 | Viewed by 1900

Abstract

The purpose of the present study was to investigate the anti-staphylococcal activity of liposomal daptomycin against four biofilm-producing S. aureus and S. epidermidis clinical strains, three of which are methicillin-resistant. Neutral and negatively charged daptomycin-loaded liposomes were prepared using three methods, namely, thin-film [...] Read more.

The purpose of the present study was to investigate the anti-staphylococcal activity of liposomal daptomycin against four biofilm-producing S. aureus and S. epidermidis clinical strains, three of which are methicillin-resistant. Neutral and negatively charged daptomycin-loaded liposomes were prepared using three methods, namely, thin-film hydration (TFH), a dehydration–rehydration vesicle (DRV) method, and microfluidic mixing (MM); moreover, they were characterized for drug encapsulation (EE%), size distribution, zeta-potential, vesicle stability, drug release, and drug integrity. Interestingly, whilst drug loading in THF and DRV nanosized (by extrusion) vesicles was around 30–35, very low loading (~4%) was possible in MM vesicles, requiring further explanatory investigations. Liposomal encapsulation protected daptomycin from degradation and preserved its bioactivity. Biofilm mass (crystal violet, CV), biofilm viability (MTT), and growth curve (GC) assays evaluated the antimicrobial activity of neutral and negatively charged daptomycin-liposomes towards planktonic bacteria and biofilms. Neutral liposomes exhibited dramatically enhanced inhibition of bacterial growth (compared to the free drug) for all species studied, while negatively charged liposomes were totally inactive. Biofilm prevention and treatment studies revealed high antibiofilm activity of liposomal daptomycin. Neutral liposomes were more active for prevention and negative charge ones for treating established biofilms. Planktonic bacteria as well as the matured biofilms of low daptomycin-susceptible, methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) strains were almost completely eradicated by liposomal-daptomycin, indicating the need for their further exploration as antimicrobial therapeutics. Full article

(This article belongs to the Special Issue Advances in Liposomes for Drug Delivery)

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30 pages, 2633 KiB

Open AccessEditor’s ChoiceReview

Polymersomes as Innovative, Stimuli-Responsive Platforms for Cancer Therapy

by Irina Negut and Bogdan Bita

Pharmaceutics 2024, 16(4), 463; https://doi.org/10.3390/pharmaceutics16040463 - 26 Mar 2024

Cited by 9 | Viewed by 2659

Abstract

This review addresses the urgent need for more targeted and less toxic cancer treatments by exploring the potential of multi-responsive polymersomes. These advanced nanocarriers are engineered to deliver drugs precisely to tumor sites by responding to specific stimuli such as pH, temperature, light, [...] Read more.

This review addresses the urgent need for more targeted and less toxic cancer treatments by exploring the potential of multi-responsive polymersomes. These advanced nanocarriers are engineered to deliver drugs precisely to tumor sites by responding to specific stimuli such as pH, temperature, light, hypoxia, and redox conditions, thereby minimizing the side effects associated with traditional chemotherapy. We discuss the design, synthesis, and recent applications of polymersomes, emphasizing their ability to improve therapeutic outcomes through controlled drug release and targeted delivery. Moreover, we highlight the critical areas for future research, including the optimization of polymersome–biological interactions and biocompatibility, to facilitate their clinical adoption. Multi-responsive polymersomes emerge as a promising development in nanomedicine, offering a pathway to safer and more effective cancer treatments. Full article

(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery, 2nd Edition)

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44 pages, 2418 KiB

Open AccessEditor’s ChoiceReview

Recent Approaches for the Topical Treatment of Psoriasis Using Nanoparticles

by Krisztina Bodnár, Pálma Fehér, Zoltán Ujhelyi, Ildikó Bácskay and Liza Józsa

Pharmaceutics 2024, 16(4), 449; https://doi.org/10.3390/pharmaceutics16040449 - 25 Mar 2024

Cited by 23 | Viewed by 9507

Abstract

Psoriasis (PSO) is a chronic autoimmune skin condition characterized by the rapid and excessive growth of skin cells, which leads to the formation of thick, red, and scaly patches on the surface of the skin. These patches can be itchy and painful, and [...] Read more.

Psoriasis (PSO) is a chronic autoimmune skin condition characterized by the rapid and excessive growth of skin cells, which leads to the formation of thick, red, and scaly patches on the surface of the skin. These patches can be itchy and painful, and they may cause discomfort for patients affected by this condition. Therapies for psoriasis aim to alleviate symptoms, reduce inflammation, and slow down the excessive skin cell growth. Conventional topical treatment options are non-specific, have low efficacy and are associated with adverse effects, which is why researchers are investigating different delivery mechanisms. A novel approach to drug delivery using nanoparticles (NPs) shows promise in reducing toxicity and improving therapeutic efficacy. The unique properties of NPs, such as their small size and large surface area, make them attractive for targeted drug delivery, enhanced drug stability, and controlled release. In the context of PSO, NPs can be designed to deliver active ingredients with anti-inflammatory effect, immunosuppressants, or other therapeutic compounds directly to affected skin areas. These novel formulations offer improved access to the epidermis and facilitate better absorption, thus enhancing the therapeutic efficacy of conventional anti-psoriatic drugs. NPs increase the surface-to-volume ratio, resulting in enhanced penetration through the skin, including intracellular, intercellular, and trans-appendage routes. The present review aims to discuss the latest approaches for the topical therapy of PSO using NPs. It is intended to summarize the results of the in vitro and in vivo examinations carried out in the last few years regarding the effectiveness and safety of nanoparticles. Full article

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

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28 pages, 3797 KiB

Open AccessEditor’s ChoiceArticle

Gold(I) and Silver(I) Complexes Containing Hybrid Sulfonamide/Thiourea Ligands as Potential Leishmanicidal Agents

by Alice P. Borges, Malu M. S. Obata, Silvia H. Libardi, Rafael O. Trevisan, Victor M. Deflon, Ulrich Abram, Francis B. Ferreira, Luiz Antônio S. Costa, Antonio O. T. Patrocínio, Marcos V. da Silva, Júlio C. Borges and Pedro I. S. Maia

Pharmaceutics 2024, 16(4), 452; https://doi.org/10.3390/pharmaceutics16040452 - 25 Mar 2024

Cited by 3 | Viewed by 1908

Abstract

Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from [...] Read more.

Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from M^I metal ions with thioureas, aiming to obtain potential leishmanicidal agents. The thiourea ligands (HL^R) were obtained by reactions of p-toluenesulfohydrazide with R-isothiocyanates and were used in complexation reactions with Ag^I and Au^I, leading to the formation of complexes of composition [M(HL^R)₂]X (M = Ag or Au; X = NO₃⁻ or Cl⁻). All compounds were characterized by FTIR, ¹H NMR, UV-vis, emission spectroscopy and elemental analysis. Some representatives were additionally studied by ESI-MS and single-crystal XRD. Their properties were further analyzed by DFT calculations. Their cytotoxicity on Vero cells and the extracellular leishmanicidal activity on Leishmania infantum and Leishmania braziliensis cells were evaluated. Additionally, the interaction of the complexes with the Old Yellow enzyme of the L. braziliensis (LbOYE) was examined. The biological tests showed that some compounds present remarkable leishmanicidal activity, even higher than that of the standard drug Glucantime, with different selectivity for the two species of Leishmania. Finally, the interaction studies with LbOYE revealed that this enzyme could be one of their biological targets. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of Metal Complexes and Derived Materials)

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27 pages, 4839 KiB

Open AccessEditor’s ChoiceArticle

Investigating the Effects of Mixing Dynamics on Twin-Screw Granule Quality Attributes via the Development of a Physics-Based Process Map

by Lalith Kotamarthy, Subhodh Karkala, Ashley Dan, Andrés D. Román-Ospino and Rohit Ramachandran

Pharmaceutics 2024, 16(4), 456; https://doi.org/10.3390/pharmaceutics16040456 - 25 Mar 2024

Cited by 2 | Viewed by 2157

Abstract

Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing [...] Read more.

Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing dynamics on the granule quality attributes (PSD, content uniformity, and microstructure). Mixing is an important dynamic process that simultaneously occurs along with the granulation rate mechanisms during the wet granulation process. An improved mechanistic understanding was achieved by identifying and quantifying the physically relevant intermediate parameters that affect the mixing dynamics in TSG, and then their effects on the granule attributes were analyzed by investigating their effects on the granulation rate mechanisms. The fill level, granule liquid saturation, extent of nucleation, and powder wettability were found to be the key physically relevant intermediate parameters that affect the mixing inside the twin-screw granulator. An improved geometrical model for the fill level was developed and validated against existing experimental data. Finally, a process map was developed to depict the effects of mixing on the temporal and spatial evolution of the materials inside the twin-screw granulator. This process map illustrates the mechanism of nucleation and the growth of the granules based on the fundamental material properties of the primary powders (solubility and wettability), liquid binders (viscosity), and mixing dynamics present in the system. Furthermore, it was shown that the process map can be used to predict the granule product quality based on the granule growth mechanism. Full article

(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling)

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16 pages, 937 KiB

Open AccessEditor’s ChoiceReview

Impact of Drug-Mediated Inhibition of Intestinal Transporters on Nutrient and Endogenous Substrate Disposition…an Afterthought?

by Kshitee Kharve, Andrew S. Engley, Mary F. Paine and Jason A. Sprowl

Pharmaceutics 2024, 16(4), 447; https://doi.org/10.3390/pharmaceutics16040447 - 24 Mar 2024

Cited by 1 | Viewed by 2364

Abstract

A large percentage (~60%) of prescription drugs and new molecular entities are designed for oral delivery, which requires passage through a semi-impervious membrane bilayer in the gastrointestinal wall. Passage through this bilayer can be dependent on membrane transporters that regulate the absorption of [...] Read more.

A large percentage (~60%) of prescription drugs and new molecular entities are designed for oral delivery, which requires passage through a semi-impervious membrane bilayer in the gastrointestinal wall. Passage through this bilayer can be dependent on membrane transporters that regulate the absorption of nutrients or endogenous substrates. Several investigations have provided links between nutrient, endogenous substrate, or drug absorption and the activity of certain membrane transporters. This knowledge has been key in the development of new therapeutics that can alleviate various symptoms of select diseases, such as cholestasis and diabetes. Despite this progress, recent studies revealed potential clinical dangers of unintended altered nutrient or endogenous substrate disposition due to the drug-mediated disruption of intestinal transport activity. This review outlines reports of glucose, folate, thiamine, lactate, and bile acid (re)absorption changes and consequent adverse events as examples. Finally, the need to comprehensively expand research on intestinal transporter-mediated drug interactions to avoid the unwanted disruption of homeostasis and diminish therapeutic adverse events is highlighted. Full article

(This article belongs to the Special Issue New Insights into Transporters in Drug Development)

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14 pages, 16075 KiB

Open AccessEditor’s ChoiceArticle

Intranasal Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Hypoxic-Ischemic Brain Injury

by Takuma Ikeda, Masahito Kawabori, Yuyuan Zheng, Sho Yamaguchi, Shuho Gotoh, Yo Nakahara, Erika Yoshie and Miki Fujimura

Pharmaceutics 2024, 16(4), 446; https://doi.org/10.3390/pharmaceutics16040446 - 23 Mar 2024

Cited by 15 | Viewed by 5596

Abstract

Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous [...] Read more.

Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a promising approach. In this study, we investigate the effects of intranasally administered exosomes in an animal model. Exosomes were isolated from the cell supernatants using the ultracentrifugation method. Brain injury was induced in Sprague-Dawley rats through a transient four-vessel occlusion model. Intranasal administration was conducted with 3 × 10⁸ exosome particles in 20 µL of PBS or PBS alone, administered daily for 7 days post-injury. Long-term cognitive behavioral assessments, biodistribution of exosomes, and histological evaluations of apoptosis and neuroinflammation were conducted. Exosomes were primarily detected in the olfactory bulb one hour after intranasal administration, subsequently distributing to the striatum and midbrain. Rats treated with exosomes exhibited substantial improvement in cognitive function up to 28 days after the insult, and demonstrated significantly fewer apoptotic cells along with higher neuronal cell survival in the hippocampus. Exosomes were found to be taken up by microglia, leading to a decrease in the expression of cytotoxic inflammatory markers. Full article

(This article belongs to the Special Issue Pharmaceutical Formulations and Bioavailability Enhancement Techniques for Transmucosal Drug Delivery)

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26 pages, 2897 KiB

Open AccessEditor’s ChoiceReview

3D Printing Direct Powder Extrusion in the Production of Drug Delivery Systems: State of the Art and Future Perspectives

by Ángela Aguilar-de-Leyva, Marta Casas, Carmen Ferrero, Vicente Linares and Isidoro Caraballo

Pharmaceutics 2024, 16(4), 437; https://doi.org/10.3390/pharmaceutics16040437 - 22 Mar 2024

Cited by 13 | Viewed by 4221

Abstract

The production of tailored, on-demand drug delivery systems has gained attention in pharmaceutical development over the last few years, thanks to the application of 3D printing technology in the pharmaceutical field. Recently, direct powder extrusion (DPE) has emerged among the extrusion-based additive manufacturing [...] Read more.

The production of tailored, on-demand drug delivery systems has gained attention in pharmaceutical development over the last few years, thanks to the application of 3D printing technology in the pharmaceutical field. Recently, direct powder extrusion (DPE) has emerged among the extrusion-based additive manufacturing techniques. It is a one-step procedure that allows the direct processing of powdered formulations. The aim of this systematic literature review is to analyze the production of drug delivery systems using DPE. A total of 27 articles have been identified through scientific databases (Scopus, PubMed, and ScienceDirect). The main characteristics of the three types of 3D printers based on DPE have been discussed. The selection of polymers and auxiliary excipients, as well as the flowability of the powder mixture, the rheological properties of the molten material, and the printing temperatures have been identified as the main critical parameters for successful printing. A wide range of drug delivery systems with varied geometries and different drug release profiles intended for oral, buccal, parenteral, and transdermal routes have been produced. The ability of this technique to manufacture personalized, on-demand drug delivery systems has been proven. For all these reasons, its implementation in hospital settings in the near future seems promising. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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22 pages, 2106 KiB

Open AccessEditor’s ChoiceReview

In Vivo Applications of Dendrimers: A Step toward the Future of Nanoparticle-Mediated Therapeutics

by Krzysztof Sztandera, José Luis Rodríguez-García and Valentín Ceña

Pharmaceutics 2024, 16(4), 439; https://doi.org/10.3390/pharmaceutics16040439 - 22 Mar 2024

Cited by 16 | Viewed by 3255

Abstract

Over the last few years, the development of nanotechnology has allowed for the synthesis of many different nanostructures with controlled sizes, shapes, and chemical properties, with dendrimers being the best-characterized of them. In this review, we present a succinct view of the structure [...] Read more.

Over the last few years, the development of nanotechnology has allowed for the synthesis of many different nanostructures with controlled sizes, shapes, and chemical properties, with dendrimers being the best-characterized of them. In this review, we present a succinct view of the structure and the synthetic procedures used for dendrimer synthesis, as well as the cellular uptake mechanisms used by these nanoparticles to gain access to the cell. In addition, the manuscript reviews the reported in vivo applications of dendrimers as drug carriers for drugs used in the treatment of cancer, neurodegenerative diseases, infections, and ocular diseases. The dendrimer-based formulations that have reached different phases of clinical trials, including safety and pharmacokinetic studies, or as delivery agents for therapeutic compounds are also presented. The continuous development of nanotechnology which makes it possible to produce increasingly sophisticated and complex dendrimers indicates that this fascinating family of nanoparticles has a wide potential in the pharmaceutical industry, especially for applications in drug delivery systems, and that the number of dendrimer-based compounds entering clinical trials will markedly increase during the coming years. Full article

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

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38 pages, 7322 KiB

Open AccessEditor’s ChoiceSystematic Review

Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers

by Patrizia Garbati, Cristiana Picco, Raffaella Magrassi, Paolo Signorello, Ludovica Cacopardo, Mauro Dalla Serra, Maria Grazia Faticato, Maria De Luca, Francesco Balestra, Maria Principia Scavo and Federica Viti

Pharmaceutics 2024, 16(3), 431; https://doi.org/10.3390/pharmaceutics16030431 - 21 Mar 2024

Cited by 19 | Viewed by 5260

Abstract

The intestine is essential for the modulation of nutrient absorption and the removal of waste. Gut pathologies, such as cancer, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and celiac disease, which extensively impact gut functions, are thus critical for human health. Targeted [...] Read more.

The intestine is essential for the modulation of nutrient absorption and the removal of waste. Gut pathologies, such as cancer, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and celiac disease, which extensively impact gut functions, are thus critical for human health. Targeted drug delivery is essential to tackle these diseases, improve therapy efficacy, and minimize side effects. Recent strategies have taken advantage of both active and passive nanocarriers, which are designed to protect the drug until it reaches the correct delivery site and to modulate drug release via the use of different physical–chemical strategies. In this systematic review, we present a literature overview of the different nanocarriers used for drug delivery in a set of chronic intestinal pathologies, highlighting the rationale behind the controlled release of intestinal therapies. The overall aim is to provide the reader with useful information on the current approaches for gut targeting in novel therapeutic strategies. Full article

(This article belongs to the Special Issue Nanotechnology-Based Pharmaceutical Treatments)

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24 pages, 3524 KiB

Open AccessEditor’s ChoiceArticle

NLC-Based Sunscreen Formulations with Optimized Proportion of Encapsulated and Free Filters Exhibit Enhanced UVA and UVB Photoprotection

by Margarete M. de Araújo, Andressa C. Schneid, Mariana S. Oliveira, Samuel V. Mussi, Miller N. de Freitas, Flávia C. Carvalho, Edson A. Bernes Junior, Renato Faro and Hatylas Azevedo

Pharmaceutics 2024, 16(3), 427; https://doi.org/10.3390/pharmaceutics16030427 - 20 Mar 2024

Cited by 9 | Viewed by 4227

Abstract

The topical use of sunscreens is recommended for avoiding the damaging effects of UV radiation. However, improvements are still needed in the existing products to enhance their photoprotection effectiveness and safety. This involves minimizing the use of chemical UV filters while providing enhanced [...] Read more.

The topical use of sunscreens is recommended for avoiding the damaging effects of UV radiation. However, improvements are still needed in the existing products to enhance their photoprotection effectiveness and safety. This involves minimizing the use of chemical UV filters while providing enhanced and prolonged photoprotection. This work investigated novel sunscreen formulations and their UV protection effects by encapsulating Uvinul^® A, Tinosorb^® S, and Uvinul^® T150 into nanostructured lipid carriers (NLCs) based on bacuri butter and raspberry seed oil. First, the impact of critical formulation and process parameters on NLCs’ particle size was evaluated using a 2² Face Centered Central Composite Design. Then, formulations were evaluated in terms of critical quality factors, in vitro skin permeation, and in vitro and in vivo photoprotection activities. The developed NLCs-containing formulations exhibited appropriate size (122–135 nm), PdI (<0.3), encapsulation efficiency (>90%), and drug content (>80%), which were preserved for at least 90 days under different stability conditions. Moreover, these NLCs-based formulations had equivalent skin permeation to emulsion-based controls, and the addition of NLCs into sunscreen cream bases in the optimum proportion of 20% (w/w) resulted in enhanced UVA and UVB photoprotection levels, despite a 10% reduction in the total filters content. Altogether, these results describe the application of nanoencapsulated organic UV filters in innovative sunscreen formulations to achieve superior photoprotection and cosmeceutical properties. Full article

(This article belongs to the Special Issue Quality Requirements for Nanomedicines: From Early Development to the Market)

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12 pages, 3738 KiB

Open AccessEditor’s ChoiceArticle

Mannose-Decorated Solid-Lipid Nanoparticles for Alveolar Macrophage Targeted Delivery of Rifampicin

by Hriday Bera, Caizhu Zhao, Xidong Tian, Dongmei Cun and Mingshi Yang

Pharmaceutics 2024, 16(3), 429; https://doi.org/10.3390/pharmaceutics16030429 - 20 Mar 2024

Cited by 8 | Viewed by 2983

Abstract

Alveolar macrophages play a vital role in a variety of lung diseases, including tuberculosis. Thus, alveolar macrophage targeted anti-tubercular drug delivery through nanocarriers could improve its therapeutic response against tuberculosis. The current study aimed at exploring the efficacy of glyceryl monostearate (GMS)-based solid-lipid [...] Read more.

Alveolar macrophages play a vital role in a variety of lung diseases, including tuberculosis. Thus, alveolar macrophage targeted anti-tubercular drug delivery through nanocarriers could improve its therapeutic response against tuberculosis. The current study aimed at exploring the efficacy of glyceryl monostearate (GMS)-based solid-lipid nanoparticles (SLNs) and their mannose functionalized forms on the alveolar macrophage targeting ability of an anti-tubercular model drug, rifampicin (Rif). Rif-loaded SLNs were accomplished by the solvent diffusion method. These carriers with unimodal particle size distribution (~170 nm) were further surface-modified with mannose via Schiff-base reaction, leading to slight enhancement of particle diameter and a decline of drug loading capacity. The encapsulated Rif, which was molecularly dispersed within the matrices as indicated by their XRD patterns, was eluted in a sustained manner with an initial burst release effect. The uptake efficiency of mannose-modified SLNs was remarkably higher than that of corresponding native forms on murine macrophage Raw 264.7 cells and human lung adenocarcinoma A549 cells. Eventually, the mannose-modified SLNs showed a greater cytotoxicity on Raw 264.7 and A549 cells relative to their unmodified forms. Overall, our study demonstrated that mannose modification of SLNs had an influence on their uptake by alveolar macrophages, which could provide guidance for the future development of alveolar macrophage targeted nanoformulations. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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11 pages, 2714 KiB

Open AccessEditor’s ChoiceArticle

Novel Fluorescent Strategy for Discriminating T and B Lymphocytes Using Transport System

by Heewon Cho, Na-Kyeong Hong and Young-Tae Chang

Pharmaceutics 2024, 16(3), 424; https://doi.org/10.3390/pharmaceutics16030424 - 19 Mar 2024

Cited by 1 | Viewed by 1882

Abstract

Fluorescent bioprobes are invaluable tools for visualizing live cells and deciphering complex biological processes by targeting intracellular biomarkers without disrupting cellular functions. In addition to protein-binding concepts, fluorescent probes utilize various mechanisms, including membrane, metabolism, and gating-oriented strategies. This study introduces a novel [...] Read more.

Fluorescent bioprobes are invaluable tools for visualizing live cells and deciphering complex biological processes by targeting intracellular biomarkers without disrupting cellular functions. In addition to protein-binding concepts, fluorescent probes utilize various mechanisms, including membrane, metabolism, and gating-oriented strategies. This study introduces a novel fluorescent mechanism distinct from existing ways. Here, we developed a B cell selective probe, CDrB, with unique transport mechanisms. Through SLC-CRISPRa screening, we identified two transporters, SLCO1B3 and SLC25A41, by sorting out populations exhibiting higher and lower fluorescence intensities, respectively, demonstrating contrasting activities. We confirmed that SLCO1B3, with comparable expression levels in T and B cells, facilitates the transport of CDrB into cells, while SLC25A41, overexpressed in T lymphocytes, actively exports CDrB. This observation suggests that SLC25A41 plays a crucial role in discriminating between T and B lymphocytes. Furthermore, it reveals the potential for the reversible localization of SLC25A41 to demonstrate its distinct activity. This study is the first report to unveil a novel strategy of SLC by exporting the probe. We anticipate that this research will open up new avenues for developing fluorescent probes. Full article

(This article belongs to the Special Issue Transport and Metabolism of Small-Molecule Drugs, 2nd Edition)

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14 pages, 4923 KiB

Open AccessEditor’s ChoiceArticle

Intracellular Delivery of Therapeutic Protein via Ultrathin Layered Double Hydroxide Nanosheets

by He Zhang, Anle Ge, Yulin Wang, Boran Xia, Xichu Wang, Zhonghui Zheng, Changsheng Wei, Bo Ma, Lin Zhu, Rose Amal, Sung Lai Jimmy Yun and Zi Gu

Pharmaceutics 2024, 16(3), 422; https://doi.org/10.3390/pharmaceutics16030422 - 19 Mar 2024

Cited by 1 | Viewed by 2369

Abstract

The therapeutic application of biofunctional proteins relies on their intracellular delivery, which is hindered by poor cellular uptake and transport from endosomes to cytoplasm. Herein, we constructed a two-dimensional (2D) ultrathin layered double hydroxide (LDH) nanosheet for the intracellular delivery of a cell-impermeable [...] Read more.

The therapeutic application of biofunctional proteins relies on their intracellular delivery, which is hindered by poor cellular uptake and transport from endosomes to cytoplasm. Herein, we constructed a two-dimensional (2D) ultrathin layered double hydroxide (LDH) nanosheet for the intracellular delivery of a cell-impermeable protein, gelonin, towards efficient and specific cancer treatment. The LDH nanosheet was synthesized via a facile method without using exfoliation agents and showed a high loading capacity of proteins (up to 182%). Using 2D and 3D 4T1 breast cancer cell models, LDH–gelonin demonstrated significantly higher cellular uptake efficiency, favorable endosome escape ability, and deep tumor penetration performance, leading to a higher anticancer efficiency, in comparison to free gelonin. This work provides a promising strategy and a generalized nanoplatform to efficiently deliver biofunctional proteins to unlock their therapeutic potential for cancer treatment. Full article

(This article belongs to the Special Issue Smart Drug Delivery Strategies Based on Porous Materials)

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21 pages, 1305 KiB

Open AccessEditor’s ChoiceReview

Nanomedicine for the Treatment of Viral Diseases: Smaller Solution to Bigger Problems

by Suvankar Ghorai, Harshita Shand, Soumendu Patra, Kingshuk Panda, Maria J. Santiago, Md. Sohanur Rahman, Srinivasan Chinnapaiyan and Hoshang J. Unwalla

Pharmaceutics 2024, 16(3), 407; https://doi.org/10.3390/pharmaceutics16030407 - 16 Mar 2024

Cited by 5 | Viewed by 3009

Abstract

The continuous evolution of new viruses poses a danger to world health. Rampant outbreaks may advance to pandemic level, often straining financial and medical resources to breaking point. While vaccination remains the gold standard to prevent viral illnesses, these are mostly prophylactic and [...] Read more.

The continuous evolution of new viruses poses a danger to world health. Rampant outbreaks may advance to pandemic level, often straining financial and medical resources to breaking point. While vaccination remains the gold standard to prevent viral illnesses, these are mostly prophylactic and offer minimal assistance to those who have already developed viral illnesses. Moreover, the timeline to vaccine development and testing can be extensive, leading to a lapse in controlling the spread of viral infection during pandemics. Antiviral therapeutics can provide a temporary fix to tide over the time lag when vaccines are not available during the commencement of a disease outburst. At times, these medications can have negative side effects that outweigh the benefits, and they are not always effective against newly emerging virus strains. Several limitations with conventional antiviral therapies may be addressed by nanotechnology. By using nano delivery vehicles, for instance, the pharmacokinetic profile of antiviral medications can be significantly improved while decreasing systemic toxicity. The virucidal or virus-neutralizing qualities of other special nanomaterials can be exploited. This review focuses on the recent advancements in nanomedicine against RNA viruses, including nano-vaccines and nano-herbal therapeutics. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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25 pages, 1517 KiB

Open AccessEditor’s ChoiceArticle

Effects of Combined Treatment with Sodium Dichloroacetate and Sodium Valproate on the Genes in Inflammation- and Immune-Related Pathways in T Lymphocytes from Patients with SARS-CoV-2 Infection with Pneumonia: Sex-Related Differences

by Donatas Stakišaitis, Linas Kapočius, Vacis Tatarūnas, Dovydas Gečys, Auksė Mickienė, Tomas Tamošuitis, Rasa Ugenskienė, Arūnas Vaitkevičius, Ingrida Balnytė and Vaiva Lesauskaitė

Pharmaceutics 2024, 16(3), 409; https://doi.org/10.3390/pharmaceutics16030409 - 16 Mar 2024

Cited by 2 | Viewed by 2201

Abstract

The study presents data on the anti-inflammatory effects of a combination of sodium dichloroacetate and sodium valproate (DCA–VPA) on the expression of inflammation- and immune response-related genes in T lymphocytes of SARS-CoV-2 patients. The study aimed to assess the effects of DCA–VPA on [...] Read more.

The study presents data on the anti-inflammatory effects of a combination of sodium dichloroacetate and sodium valproate (DCA–VPA) on the expression of inflammation- and immune response-related genes in T lymphocytes of SARS-CoV-2 patients. The study aimed to assess the effects of DCA–VPA on the genes of cytokine activity, chemokine-mediated signaling, neutrophil chemotaxis, lymphocyte chemotaxis, T-cell chemotaxis, and regulation of T-cell proliferation pathways. The study included 21 patients with SARS-CoV-2 infection and pneumonia: 9 male patients with a mean age of 68.44 ± 15.32 years and 12 female patients with a mean age of 65.42 ± 15.74 years. They were hospitalized between December 2022 and March 2023. At the time of testing, over 90% of sequences analyzed in Lithuania were found to be of the omicron variant of SARS-CoV-2. The T lymphocytes from patients were treated with 5 mmol DCA and 2 mmol VPA for 24 h in vitro. The effect of the DCA–VPA treatment on gene expression in T lymphocytes was analyzed via gene sequencing. The study shows that DCA–VPA has significant anti-inflammatory effects and apparent sex-related differences. The effect is more potent in T cells from male patients with SARS-CoV-2 infection and pneumonia than in females. Full article

(This article belongs to the Special Issue Antiviral and Antibacterial: Focus on Novel Therapeutic Agents and Drug Delivery Systems)

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18 pages, 1449 KiB

Open AccessEditor’s ChoiceReview

Role of Biofunctionalized Nanoparticles in Digestive Cancer Vaccine Development

by Razvan Zdrehus, Cristian Delcea and Lucian Mocan

Pharmaceutics 2024, 16(3), 410; https://doi.org/10.3390/pharmaceutics16030410 - 16 Mar 2024

Cited by 2 | Viewed by 2432

Abstract

Nanotechnology has provided an opportunity for unparalleled development of the treatment of various severe diseases. The unique properties of nanoparticles offer a promising strategy for enhancing antitumor immunity by enhancing immunogenicity and presentation of tumor autoantigens for cancer immunotherapy. Polymeric, liposomal, carbon or [...] Read more.

Nanotechnology has provided an opportunity for unparalleled development of the treatment of various severe diseases. The unique properties of nanoparticles offer a promising strategy for enhancing antitumor immunity by enhancing immunogenicity and presentation of tumor autoantigens for cancer immunotherapy. Polymeric, liposomal, carbon or silica-based nanoparticles are among those with major immunomodulatory roles in various cancer treatments. Cancer vaccines, in particular digestive cancer vaccines, have been researched and developed on nanotechnological platforms. Due to their safety, controlled release, targeting of dendritic cells (DCs) and improved antigen uptake, as well as enhanced immunogenicity, nanoparticles have been used as carriers, as adjuvants for increased effect at the tumor level, for their immunomodulating effect, or for targeting the tumor microenvironment, thereby increasing tumor immunogenicity and reducing tumor inflammatory response. This review looks at digestive cancer vaccines developed on nanoparticle platforms and the impact nanoparticles have on the effects of these vaccines. Full article

(This article belongs to the Special Issue Functionalized Nanoparticles in Cancer Therapeutics, 2nd Edition)

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15 pages, 3907 KiB

Open AccessEditor’s ChoiceArticle

Designing a Placebo Microneedle Stamp: Modeling and Validation in a Clinical Control Trial

by Seung-Yeon Jeong, Ye-Seul Lee, Ji-Yeun Park, Jung-Hwan Park, Hi-Joon Park and Song-Yi Kim

Pharmaceutics 2024, 16(3), 395; https://doi.org/10.3390/pharmaceutics16030395 - 14 Mar 2024

Cited by 1 | Viewed by 1943

Abstract

Recently, several clinical studies have been conducted using microneedles (MNs), and various devices have been developed. This study aimed to propose and confirm the feasibility of a placebo control for activating MN clinical research. A 0.5 mm MN stamp with 42 needles was [...] Read more.

Recently, several clinical studies have been conducted using microneedles (MNs), and various devices have been developed. This study aimed to propose and confirm the feasibility of a placebo control for activating MN clinical research. A 0.5 mm MN stamp with 42 needles was used as a treatment intervention, and a placebo stamp with four acupressure-type needles that did not penetrate was proposed and designed as a control for comparison. First, to check whether the placebo stamp did not invade the skin and to set an appropriate level of pressure to be provided during skin stimulation, two participants were stimulated with five different forces on the forearm, and then the skin was dyed. Secondly, to evaluate the validity of the placebo control group, a blinded study between the MN and placebo stamps was performed on 15 participants. We confirmed that the placebo stamp did not penetrate the skin at any intensity or location. Both types of stamps reported relatively low pain levels, but the MN stamp induced higher pain compared to the placebo stamp. Based on the speculation regarding the type of intervention received, the MN stamp was successfully blinded (random guess), whereas the placebo stamp was unblinded. However, according to a subgroup analysis, it was confirmed that the group with low skin sensitivity was completely blind. Blinding the placebo MN stamp had limited success in participants with low skin sensitivity. Future research on suitable placebo controls, considering the variations in MN stamp length and needle count, is warranted. Full article

(This article belongs to the Special Issue Recent Advances in Microneedle-Mediated Drug Delivery, 2nd Edition)

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46 pages, 4899 KiB

Open AccessEditor’s ChoiceReview

Lipid Nanocarriers-Enabled Delivery of Antibiotics and Antimicrobial Adjuvants to Overcome Bacterial Biofilms

by Anam Ahsan, Nicky Thomas, Timothy J. Barnes, Santhni Subramaniam, Thou Chen Loh, Paul Joyce and Clive A. Prestidge

Pharmaceutics 2024, 16(3), 396; https://doi.org/10.3390/pharmaceutics16030396 - 14 Mar 2024

Cited by 23 | Viewed by 4490

Abstract

The opportunistic bacteria growing in biofilms play a decisive role in the pathogenesis of chronic infectious diseases. Biofilm-dwelling bacteria behave differently than planktonic bacteria and are likely to increase resistance and tolerance to antimicrobial therapeutics. Antimicrobial adjuvants have emerged as a promising strategy [...] Read more.

The opportunistic bacteria growing in biofilms play a decisive role in the pathogenesis of chronic infectious diseases. Biofilm-dwelling bacteria behave differently than planktonic bacteria and are likely to increase resistance and tolerance to antimicrobial therapeutics. Antimicrobial adjuvants have emerged as a promising strategy to combat antimicrobial resistance (AMR) and restore the efficacy of existing antibiotics. A combination of antibiotics and potential antimicrobial adjuvants, (e.g., extracellular polymeric substance (EPS)-degrading enzymes and quorum sensing inhibitors (QSI) can improve the effects of antibiotics and potentially reduce bacterial resistance). In addition, encapsulation of antimicrobials within nanoparticulate systems can improve their stability and their delivery into biofilms. Lipid nanocarriers (LNCs) have been established as having the potential to improve the efficacy of existing antibiotics in combination with antimicrobial adjuvants. Among them, liquid crystal nanoparticles (LCNPs), liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) are promising due to their superior properties compared to traditional formulations, including their greater biocompatibility, higher drug loading capacity, drug protection from chemical or enzymatic degradation, controlled drug release, targeted delivery, ease of preparation, and scale-up feasibility. This article reviews the recent advances in developing various LNCs to co-deliver some well-studied antimicrobial adjuvants combined with antibiotics from different classes. The efficacy of various combination treatments is compared against bacterial biofilms, and synergistic therapeutics that deserve further investigation are also highlighted. This review identifies promising LNCs for the delivery of combination therapies that are in recent development. It discusses how LNC-enabled co-delivery of antibiotics and adjuvants can advance current clinical antimicrobial treatments, leading to innovative products, enabling the reuse of antibiotics, and providing opportunities for saving millions of lives from bacterial infections. Full article

(This article belongs to the Special Issue Photodynamic, Photothermal and Photoimmune Therapy and Other Antimicrobial Nanomedicine-Related Applications)

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23 pages, 8398 KiB

Open AccessEditor’s ChoiceArticle

Cellular Uptake and Transport Mechanism Investigations of PEGylated Niosomes for Improving the Oral Delivery of Thymopentin

by Mengyang Liu, Darren Svirskis, Thomas Proft, Jacelyn Loh, Yuan Huang and Jingyuan Wen

Pharmaceutics 2024, 16(3), 397; https://doi.org/10.3390/pharmaceutics16030397 - 14 Mar 2024

Cited by 7 | Viewed by 2332

Abstract

Background: Although its immunomodulatory properties make thymopentin (TP5) appealing, its rapid metabolism and inactivation in the digestive system pose significant challenges for global scientists. PEGylated niosomal nanocarriers are hypothesized to improve the physicochemical stability of TP5, and to enhance its intestinal permeability for [...] Read more.

Background: Although its immunomodulatory properties make thymopentin (TP5) appealing, its rapid metabolism and inactivation in the digestive system pose significant challenges for global scientists. PEGylated niosomal nanocarriers are hypothesized to improve the physicochemical stability of TP5, and to enhance its intestinal permeability for oral administration. Methods: TP5-loaded PEGylated niosomes were fabricated using the thin film hydration method. Co-cultured Caco-2 and HT29 cells with different ratios were screened as in vitro intestinal models. The cytotoxicity of TP5 and its formulations were evaluated using an MTT assay. The cellular uptake and transport studies were investigated in the absence or presence of variable inhibitors or enhancers, and their mechanisms were explored. Results and Discussion: All TP5 solutions and their niosomal formulations were nontoxic to Caco-2 and HT-29 cells. The uptake of TP5-PEG-niosomes by cells relied on active endocytosis, exhibiting dependence on time, energy, and concentration, which has the potential to significantly enhance its cellular uptake compared to TP5 in solution. Nevertheless, cellular transport rates were similar between TP5 in solution and its niosomal groups. The cellular transport of TP5 in solution was carried out mainly through MRP5 endocytosis and a passive pathway and effluxed by MRP5 transporters, while that of TP5-niosomes and TP5-PEG-niosomes was carried out through adsorptive- and clathrin-mediated endocytosis requiring energy. The permeability and transport rate was further enhanced when EDTA and sodium taurocholate were used as the penetration enhancers. Conclusions: This research has illustrated that PEG-niosomes were able to enhance the cellular uptake and maintain the cellular transport of TP5. This study also shows this formulation’s potential to serve as an effective carrier for improving the oral delivery of peptides. Full article

(This article belongs to the Special Issue Advances in Oral Administration)

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21 pages, 9487 KiB

Open AccessEditor’s ChoiceArticle

The Effect of Formulation Variables on the Manufacturability of Clopidogrel Tablets via Fluidized Hot-Melt Granulation—From the Lab Scale to the Pilot Scale

by Béla Kovács, Erzsébet-Orsolya Tőkés, Éva Katalin Kelemen, Katalin Zöldi, Francisc Boda, Edit Suba, Boglárka Kovács-Deák and Tibor Casian

Pharmaceutics 2024, 16(3), 391; https://doi.org/10.3390/pharmaceutics16030391 - 13 Mar 2024

Cited by 2 | Viewed by 2277

Abstract

Solid pharmaceutical formulations with class II active pharmaceutical ingredients (APIs) face dissolution challenges due to limited solubility, affecting in vivo behavior. Robust computational tools, via data mining, offer valuable insights into product performance, complementing traditional methods and aiding in scale-up decisions. This study [...] Read more.

Solid pharmaceutical formulations with class II active pharmaceutical ingredients (APIs) face dissolution challenges due to limited solubility, affecting in vivo behavior. Robust computational tools, via data mining, offer valuable insights into product performance, complementing traditional methods and aiding in scale-up decisions. This study utilizes the design of experiments (DoE) to understand fluidized hot-melt granulation manufacturing technology. Exploratory data analysis (MVDA) highlights similarities and differences in tablet manufacturability and dissolution profiles at both the lab and pilot scales. The study sought to gain insights into the application of multivariate data analysis by identifying variations among batches produced at different manufacturing scales for this technology. DoE and MVDA findings show that the granulation temperature, time, and Macrogol type significantly impact product performance. These factors, by influencing particle size distribution, become key predictors of product quality attributes such as resistance to crushing, disintegration time, and early-stage API dissolution in the profile. Software-aided data mining, with its multivariate and versatile nature, complements the empirical approach, which is reliant on trial and error during product scale-up. Full article

(This article belongs to the Special Issue Pharmaceutical Solids: Advanced Manufacturing and Characterization)

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13 pages, 3110 KiB

Open AccessEditor’s ChoiceArticle

In Vitro Profile of Hydrocortisone Release from Three-Dimensionally Printed Paediatric Mini-Tablets

by Chrystalla Protopapa, Angeliki Siamidi, Siva Satyanarayana Kolipaka, Laura Andrade Junqueira, Dennis Douroumis and Marilena Vlachou

Pharmaceutics 2024, 16(3), 385; https://doi.org/10.3390/pharmaceutics16030385 - 11 Mar 2024

Cited by 7 | Viewed by 2402

Abstract

Three-dimensional (3D) printing is quickly being adopted in pharmaceutics due to the many advantages it offers, including treatment, adaptability, the reduction in waste and the accelerated development of new formulations. In this study, micro-extrusion printing was implemented for the production of modified-release hydrocortisone [...] Read more.

Three-dimensional (3D) printing is quickly being adopted in pharmaceutics due to the many advantages it offers, including treatment, adaptability, the reduction in waste and the accelerated development of new formulations. In this study, micro-extrusion printing was implemented for the production of modified-release hydrocortisone (HCT) mini-tablets for paediatric patients. For the developed formulations, Gelucire^® 44/14 and Precirol^® ATO 5 were used as the main inks at three different ratios: 70%/30%, 60%/40% and 50%/50%, respectively. The printing parameters (temperature and pressure) were altered accordingly for each ratio to achieve printability. The printed mini-tablets exhibited excellent printing quality, featuring consistent layer thicknesses and smooth surfaces. Dissolution tests were performed, and the results indicated a successful modified release of HCT from the mini-tablets. In summary, micro-extrusion exhibited favourable processing abilities for powder blends, facilitating quick printing and the fabrication of potential personalized dosages. Full article

(This article belongs to the Special Issue 3D-Printed Solid Pharmaceutical Formulations: Physicochemical Properties and Modified Release (Volume II))

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16 pages, 3245 KiB

Open AccessEditor’s ChoiceArticle

Enhanced Skin Permeation of 5-Fluorouracil through Drug-in-Adhesive Topical Patches

by Sangseo Kim, Souha H. Youssef, Kyung Min Kirsten Lee, Yunmei Song, Sachin Vaidya and Sanjay Garg

Pharmaceutics 2024, 16(3), 379; https://doi.org/10.3390/pharmaceutics16030379 - 10 Mar 2024

Cited by 2 | Viewed by 2900

Abstract

5-fluorouracil (5-FU), commercially available as a topical product, is approved for non-melanoma skin cancer (NMSC) treatment with several clinical limitations. This work aimed to develop 5-FU-loaded topical patches as a potential alternative to overcome such drawbacks. The patches offer accurate dosing, controlled drug [...] Read more.

5-fluorouracil (5-FU), commercially available as a topical product, is approved for non-melanoma skin cancer (NMSC) treatment with several clinical limitations. This work aimed to develop 5-FU-loaded topical patches as a potential alternative to overcome such drawbacks. The patches offer accurate dosing, controlled drug release and improved patient compliance. Our study highlights the development of Eudragit^® E (EuE)-based drug-in-adhesive (DIA) patches containing a clinically significant high level of 5-FU (approximately 450 µg/cm²) formulated with various chemical permeation enhancers. The patches containing Transcutol^® (Patch-TRAN) or oleic acid (Patch-OA) demonstrated significantly higher skin penetration ex vivo than their control counterpart, reaching 5-FU concentrations of 76.39 ± 27.7 µg/cm² and 82.56 ± 8.2 µg/cm², respectively. Furthermore, the findings from in vitro permeation studies also validated the superior skin permeation of 5-FU achieved by Patch-OA and Patch-TRAN over 72 h. Moreover, the EuE-based DIA patch platform demonstrated suitable adhesive and mechanical properties with an excellent safety profile evaluated through an inaugural in vivo human study involving 11 healthy volunteers. In conclusion, the DIA patches could be a novel alternative option for NMSC as the patches effectively deliver 5-FU into the dermis layer and receptor compartment ex vivo for an extended period with excellent mechanical and safety profiles. Full article

(This article belongs to the Special Issue Biomedical Applications of Topical Formulations for Skin and Mucosal Disorders)

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29 pages, 4222 KiB

Open AccessEditor’s ChoiceArticle

Continuous Microfluidic Antisolvent Crystallization as a Bottom-Up Solution for the Development of Long-Acting Injectable Formulations

by Snehashis Nandi, Laura Verstrepen, Mariana Hugo Silva, Luis Padrela, Lidia Tajber and Alain Collas

Pharmaceutics 2024, 16(3), 376; https://doi.org/10.3390/pharmaceutics16030376 - 8 Mar 2024

Cited by 5 | Viewed by 2626

Abstract

A bottom-up approach was investigated to produce long-acting injectable (LAI) suspension-based formulations to overcome specific limitations of top-down manufacturing methods by tailoring drug characteristics while making the methods more sustainable and cost-efficient. A Secoya microfluidic crystallization technology-based continuous liquid antisolvent crystallization (SCT-CLASC) process [...] Read more.

A bottom-up approach was investigated to produce long-acting injectable (LAI) suspension-based formulations to overcome specific limitations of top-down manufacturing methods by tailoring drug characteristics while making the methods more sustainable and cost-efficient. A Secoya microfluidic crystallization technology-based continuous liquid antisolvent crystallization (SCT-CLASC) process was optimized and afterward compared to an earlier developed microchannel reactor-based continuous liquid antisolvent crystallization (MCR-CLASC) setup, using itraconazole (ITZ) as the model drug. After operating parameter optimization and downstream processing (i.e., concentrating the suspensions), stable microsuspensions were generated with a final solid loading of 300 mg ITZ/g suspension. The optimized post-precipitation feed suspension consisted of 40 mg ITZ/g suspension with a drug-to-excipient ratio of 53:1. Compared to the MCR-CLASC setup, where the post-precipitation feed suspensions contained 10 mg ITZ/g suspension and had a drug-to-excipient ratio of 2:1, a higher drug concentration and lower excipient use were successfully achieved to produce LAI microsuspensions using the SCT-CLASC setup. To ensure stability during drug crystallization and storage, the suspensions’ quality was monitored for particle size distribution (PSD), solid-state form, and particle morphology. The PSD of the ITZ crystals in suspension was maintained within the target range of 1–10 µm, while the crystals displayed an elongated plate-shaped morphology and the solid state was confirmed to be form I, which is the most thermodynamically stable form of ITZ. In conclusion, this work lays the foundation for the SCT-CLASC process as an energy-efficient, robust, and reproducible bottom-up approach for the manufacture of LAI microsuspensions using ITZ at an industrial scale. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

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16 pages, 3283 KiB

Open AccessEditor’s ChoiceArticle

Silver Nanoparticles Selectively Treat Neurofibromatosis Type 1-Associated Plexiform Neurofibroma Cells at Doses That Do Not Affect Patient-Matched Schwann Cells

by Bashnona Attiah, Garrett Alewine, Mary-Kate Easter, Robert A. Coover and Cale D. Fahrenholtz

Pharmaceutics 2024, 16(3), 371; https://doi.org/10.3390/pharmaceutics16030371 - 7 Mar 2024

Cited by 1 | Viewed by 1975

Abstract

Neurofibromatosis Type 1 (NF1) is a common neurogenic condition characterized by heterozygous loss of function mutations in the neurofibromin gene. NF1 patients are susceptible to the development of neurofibromas, including plexiform neurofibromas (pNFs), which occurs in about half of all cases. Plexiform neurofibroma [...] Read more.

Neurofibromatosis Type 1 (NF1) is a common neurogenic condition characterized by heterozygous loss of function mutations in the neurofibromin gene. NF1 patients are susceptible to the development of neurofibromas, including plexiform neurofibromas (pNFs), which occurs in about half of all cases. Plexiform neurofibroma are benign peripheral nerve sheath tumors originating from Schwann cells after complete loss of neurofibromin; they can be debilitating and also transform into deadly malignant peripheral nerve sheath tumors (MPNSTs). Here, our data indicates that silver nanoparticles (AgNPs) may be useful in the treatment of pNFs. We assessed the cytotoxicity of AgNPs using pNF cells and Schwann cells derived from the same NF1 patient. We found that AgNPs are selectively cytotoxic to pNF cells relative to isogenic Schwann cells. We then examined the role of neurofibromin expression on AgNP-mediated cytotoxicity; restoration of neurofibromin expression in pNF cells decreased sensitivity to AgNP, and knockdown of neurofibromin in isogenic Schwann cells increased sensitivity to AgNP, outlining a correlation between neurofibromin expression and AgNP-mediated cytotoxicity. AgNP was able to selectively remove pNF cells from a co-culture with patient-matched Schwann cells. Therefore, AgNPs represent a new approach for clinical management of NF1-associated pNF to address significant clinical need. Full article

(This article belongs to the Special Issue Metal and Carbon Nanomaterials for Pharmaceutical Applications)

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14 pages, 5171 KiB

Open AccessEditor’s ChoiceArticle

Curcumin/Carrier Coprecipitation by Supercritical Antisolvent Route

by Stefania Mottola and Iolanda De Marco

Pharmaceutics 2024, 16(3), 352; https://doi.org/10.3390/pharmaceutics16030352 - 2 Mar 2024

Cited by 3 | Viewed by 1421

Abstract

In this work, polyvinylpyrrolidone (PVP)- and β-cyclodextrin (β-CD)-based composite powders containing curcumin (CURC) were obtained through the supercritical antisolvent (SAS) technique. Pressure, total concentration of CURC/carrier in dimethylsulfoxide, and CURC/carrier ratio effects on the morphology and size of the precipitated powders were investigated. [...] Read more.

In this work, polyvinylpyrrolidone (PVP)- and β-cyclodextrin (β-CD)-based composite powders containing curcumin (CURC) were obtained through the supercritical antisolvent (SAS) technique. Pressure, total concentration of CURC/carrier in dimethylsulfoxide, and CURC/carrier ratio effects on the morphology and size of the precipitated powders were investigated. Using PVP as the carrier, spherical particles with a mean diameter of 1.72 μm were obtained at 12.0 MPa, 20 mg/mL, and a CURC/PVP molar ratio equal to 1/2 mol/mol; using β-CD as the carrier, the optimal operating conditions were 9.0 MPa and 200 mg/mL; well-defined micrometric particles with mean diameters equal to 2.98 and 3.69 μm were obtained at molar ratios of 1/2 and 1/1 mol/mol, respectively. FT-IR spectra of CURC/ β-CD inclusion complexes and coprecipitated CURC/PVP powders revealed the presence of some peaks of the active compounds. The stoichiometry of the complexes evaluated through the Job method revealed that β-CD formed inclusion complexes with CURC at a molar ratio equal to 1/1. Dissolution profiles revealed that in comparison with the curve of the pure ingredient, the SAS-processed powders obtained using both PVP and β-CD have an improved release rate. Full article

(This article belongs to the Special Issue Supercritical Techniques for Pharmaceutical Applications)

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