Pharmaceutics

20 pages, 14709 KB

Open AccessEditor’s ChoiceArticle

Characterizing Extracellular Vesicles Generated from the Integra CELLine Culture System and Their Endocytic Pathways for Intracellular Drug Delivery

by Tianjiao Geng, Lei Tian, Song Yee Paek, Euphemia Leung, Lawrence W. Chamley and Zimei Wu

Pharmaceutics 2024, 16(9), 1206; https://doi.org/10.3390/pharmaceutics16091206 - 13 Sep 2024

Cited by 1 | Viewed by 2221

Abstract

Extracellular vesicles (EVs) have attracted great attention as promising intracellular drug delivery carriers. While the endocytic pathways of small EVs (sEVs, <200 nm) have been reported, there is limited understanding of large EVs (lEVs, >200 nm), despite their potential applications for drug delivery. [...] Read more.

Extracellular vesicles (EVs) have attracted great attention as promising intracellular drug delivery carriers. While the endocytic pathways of small EVs (sEVs, <200 nm) have been reported, there is limited understanding of large EVs (lEVs, >200 nm), despite their potential applications for drug delivery. Additionally, the low yield of EVs during isolation remains a major challenge in their application. Herein, we aimed to compare the endocytic pathways of sEVs and lEVs using MIA PaCa-2 pancreatic cancer cell-derived EVs as models and to explore the efficiency of their production. The cellular uptake of EVs by MIA PaCa-2 cells was assessed and the pathways were investigated with the aid of endocytic inhibitors. The yield and protein content of sEVs and lEVs from the Integra CELLine culture system and the conventional flasks were compared. Our findings revealed that both sEVs and lEVs produced by the Integra CELLine system entered their parental cells via multiple routes, including caveolin-mediated endocytosis, clathrin-mediated endocytosis, and actin-dependent phagocytosis or macropinocytosis. Notably, caveolin- and clathrin-mediated endocytosis were more prominent in the uptake of sEVs, while actin-dependent phagocytosis and macropinocytosis were significant for both sEVs and lEVs. Compared with conventional flasks, the Integra CELLine system demonstrated a 9-fold increase in sEVs yield and a 6.5-fold increase in lEVs yield, along with 3- to 4-fold higher protein content per 10¹⁰ EVs. Given that different endocytic pathways led to distinct intracellular trafficking routes, this study highlights the unique potentials of sEVs and lEVs for intracellular cargo delivery. The Integra CELLine proves to be a highly productive and cost-effective system for generating EVs with favourable properties for drug delivery. Full article

(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)

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13 pages, 1958 KB

Open AccessEditor’s ChoiceArticle

Assessing α-Bisabolol as a Transmucosal Permeation Enhancer of Buccal Local Anesthetics

by Renê Oliveira do Couto, Douglas Vieira Thomaz, Maira Perez Ferreira Duarte, Renata Fonseca Vianna Lopez, Vinícius Pedrazzi, Osvaldo de Freitas and Gianluca Martino Tartaglia

Pharmaceutics 2024, 16(9), 1198; https://doi.org/10.3390/pharmaceutics16091198 - 12 Sep 2024

Viewed by 1949

Abstract

Needle-free buccal anesthesia improves dental treatment outcomes for both patients and dentists. In this study, we report on an assessment of the enhancement effects of α-bisabolol on the in vitro transmucosal permeation of prilocaine hydrochloride (PCl) and lidocaine hydrochloride (LCl) from needleless buccal [...] Read more.

Needle-free buccal anesthesia improves dental treatment outcomes for both patients and dentists. In this study, we report on an assessment of the enhancement effects of α-bisabolol on the in vitro transmucosal permeation of prilocaine hydrochloride (PCl) and lidocaine hydrochloride (LCl) from needleless buccal films. We also evaluated the mechanical properties of the film, which consisted of Methocel™ K100 LV as the film-forming polymer (3% m·m⁻¹), PEG 400 as a cosolvent (15% m·m⁻¹ based on drug loading), α-bisabolol (15 and 30% m·m⁻¹ based on drug loading), and the drugs combined at a 1:1 ratio (15 mg·unit⁻¹). The porcine esophageal epithelium was used as a membrane barrier, and artificial saliva was the release medium. After a 1 h experiment at 25 ± 2 °C, α-bisabolol significantly decreased, rather than enhanced, the permeation fluxes (five-fold), permeability coefficients (seven-fold), and retentions (two-fold) of both PCl and LCl through the epithelium, regardless of the concentration. Moreover, the resistance and flexibility of the films markedly decreased compared to those without α-bisabolol. Therefore, under the experimental conditions, using α-bisabolol as a buccal permeation enhancer for the hydrophilic local anesthetics PCl and LCl from buccal films is not feasible. Full article

(This article belongs to the Special Issue Site-Specific Drug Delivery: Formulation Strategies and Regulatory Challenges)

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15 pages, 2434 KB

Open AccessEditor’s ChoiceArticle

Powder Self-Emulsifying Drug Delivery System for Mitotane: In Vitro and In Vivo Evaluation

by Mohamed Skiba, Valentin Lefébure, Frederic Bounoure, Nicolas Milon, Michael Thomas, Herve Lefebvre and Lahiani-Skiba Malika

Pharmaceutics 2024, 16(9), 1194; https://doi.org/10.3390/pharmaceutics16091194 - 11 Sep 2024

Cited by 2 | Viewed by 1854

Abstract

Drug Delivery Systems (DDSs) of known drugs are prominent candidates for new and more effective treatments of various diseases, as they may increase drug solubility, dissolution velocity, and bioavailability. Mitotane (o,p′-dichlorodimethyl dichloroethane [o,p′-DDD]) is used for the treatment of adrenocortical cancer and, occasionally, [...] Read more.

Drug Delivery Systems (DDSs) of known drugs are prominent candidates for new and more effective treatments of various diseases, as they may increase drug solubility, dissolution velocity, and bioavailability. Mitotane (o,p′-dichlorodimethyl dichloroethane [o,p′-DDD]) is used for the treatment of adrenocortical cancer and, occasionally, Cushing’s syndrome. However, the efficacy of mitotane is limited by its low oral bioavailability, caused by its extremely poor aqueous solubility. This research explores the development of a new powder self-emulsifying drug delivery system (P-SEDDS) for mitotane to improve its oral bioavailability. The study focuses on the new concept of a mitotane-loaded P-SEDDS to overcome the challenges associated with its limited solubility and high logP, thereby improving its therapeutic efficacy, reducing off-target toxicity, and avoiding first-pass metabolism. The P-SEDDS formulations were meticulously designed using only α-cyclodextrin and oil, with the goal of achieving a stable and efficient P-SEDDS. The optimized formulation was characterized for pharmaceutical properties, and its pharmacokinetic behavior was examined in rats. The results demonstrated a significant enhancement in the bioavailability of mitotane when delivered through the P-SEDDS, attributed to the increased dissolution velocity and improved absorption of the poorly water-soluble drug. The results suggest that a mitotane-loaded P-SEDDS has distinctly enhanced in vitro and in vivo performance compared with conventional mitotane formulations (Lysodren^®), which leads to the conclusion that the P-SEDDS formulation could be a viable and effective strategy for improving the dissolution rate and bioavailability of poorly aqueous-soluble ingredients. Full article

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39 pages, 2469 KB

Open AccessEditor’s ChoiceReview

Exploring the Therapeutic Implications of Co-Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer

by Mafalda Calheiros-Lobo, João P. N. Silva, Bárbara Pinto, Luís Monteiro, Patrícia M. A. Silva and Hassan Bousbaa

Pharmaceutics 2024, 16(9), 1196; https://doi.org/10.3390/pharmaceutics16091196 - 11 Sep 2024

Cited by 3 | Viewed by 2254

Abstract

Head and neck cancer (HNC), the sixth most common cancer worldwide, is increasing in incidence, with oral squamous cell carcinoma (OSCC) as the predominant subtype. OSCC mainly affects middle-aged to elderly males, often occurring on the posterior lateral border of the tongue, leading [...] Read more.

Head and neck cancer (HNC), the sixth most common cancer worldwide, is increasing in incidence, with oral squamous cell carcinoma (OSCC) as the predominant subtype. OSCC mainly affects middle-aged to elderly males, often occurring on the posterior lateral border of the tongue, leading to significant disfigurement and functional impairments, such as swallowing and speech difficulties. Despite advancements in understanding OSCC’s genetic and epigenetic variations, survival rates for advanced stages remain low, highlighting the need for new treatment options. Primary treatment includes surgery, often combined with radiotherapy (RT) and chemotherapy (CT). Cetuximab-based chemotherapy, targeting the overexpressed epidermal growth factor receptor (EGFR) in 80–90% of HNCs, is commonly used but correlates with poor prognosis. Additionally, monopolar spindle 1 (MPS1), a spindle assembly checkpoint (SAC) component, is a significant target due to its role in genomic fidelity during mitosis and its overexpression in several cancers. This review explores EGFR and MPS1 as therapeutic targets in HNC, analyzing their molecular mechanisms and the effects of their inhibition on cancer cells. It also highlights the promise of combinatorial approaches, such as microtubule-targeting agents (MTAs) and antimitotic agents, in improving HNC therapies, patient outcomes, and survival rates. Full article

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28 pages, 7409 KB

Open AccessEditor’s ChoiceReview

Advances in Nanoparticles as Non-Viral Vectors for Efficient Delivery of CRISPR/Cas9

by Minse Kim, Youngwoo Hwang, Seongyu Lim, Hyeon-Ki Jang and Hyun-Ouk Kim

Pharmaceutics 2024, 16(9), 1197; https://doi.org/10.3390/pharmaceutics16091197 - 11 Sep 2024

Cited by 20 | Viewed by 6377

Abstract

The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is a gene-editing technology. Nanoparticle delivery systems have attracted attention because of the limitations of conventional viral vectors. In this review, we assess the efficiency of various nanoparticles, including lipid-based, polymer-based, inorganic, and extracellular [...] Read more.

The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is a gene-editing technology. Nanoparticle delivery systems have attracted attention because of the limitations of conventional viral vectors. In this review, we assess the efficiency of various nanoparticles, including lipid-based, polymer-based, inorganic, and extracellular vesicle-based systems, as non-viral vectors for CRISPR/Cas9 delivery. We discuss their advantages, limitations, and current challenges. By summarizing recent advancements and highlighting key strategies, this review aims to provide a comprehensive overview of the role of non-viral delivery systems in advancing CRISPR/Cas9 technology for clinical applications and gene therapy. Full article

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

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37 pages, 5256 KB

Open AccessEditor’s ChoiceReview

Emerging Trends in Dissolving-Microneedle Technology for Antimicrobial Skin-Infection Therapies

by Rui Luo, Huihui Xu, Qiaoni Lin, Jiaying Chi, Tingzhi Liu, Bingrui Jin, Jiayu Ou, Zejun Xu, Tingting Peng, Guilan Quan and Chao Lu

Pharmaceutics 2024, 16(9), 1188; https://doi.org/10.3390/pharmaceutics16091188 - 8 Sep 2024

Cited by 9 | Viewed by 4248

Abstract

Skin and soft-tissue infections require significant consideration because of their prolonged treatment duration and propensity to rapidly progress, resulting in severe complications. The primary challenge in their treatment stems from the involvement of drug-resistant microorganisms that can form impermeable biofilms, as well as [...] Read more.

Skin and soft-tissue infections require significant consideration because of their prolonged treatment duration and propensity to rapidly progress, resulting in severe complications. The primary challenge in their treatment stems from the involvement of drug-resistant microorganisms that can form impermeable biofilms, as well as the possibility of infection extending deep into tissues, thereby complicating drug delivery. Dissolving microneedle patches are an innovative transdermal drug-delivery system that effectively enhances drug penetration through the stratum corneum barrier, thereby increasing drug concentration at the site of infection. They offer highly efficient, safe, and patient-friendly alternatives to conventional topical formulations. This comprehensive review focuses on recent advances and emerging trends in dissolving-microneedle technology for antimicrobial skin-infection therapy. Conventional antibiotic microneedles are compared with those based on emerging antimicrobial agents, such as quorum-sensing inhibitors, antimicrobial peptides, and antimicrobial-matrix materials. The review also highlights the potential of innovative microneedles incorporating chemodynamic, nanoenzyme antimicrobial, photodynamic, and photothermal antibacterial therapies. This review explores the advantages of various antimicrobial therapies and emphasizes the potential of their combined application to improve the efficacy of microneedles. Finally, this review analyzes the druggability of different antimicrobial microneedles and discusses possible future developments. Full article

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

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33 pages, 2551 KB

Open AccessEditor’s ChoiceReview

Alternative Strategies for Delivering Immunotherapeutics Targeting the PD-1/PD-L1 Immune Checkpoint in Cancer

by Ryunosuke Hoshi, Kristyna A. Gorospe, Hagar I. Labouta, Taha Azad, Warren L. Lee and Kelsie L. Thu

Pharmaceutics 2024, 16(9), 1181; https://doi.org/10.3390/pharmaceutics16091181 - 7 Sep 2024

Cited by 7 | Viewed by 3713

Abstract

The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)⁺ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8⁺ T cells activates downstream signaling pathways [...] Read more.

The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)⁺ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8⁺ T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them. Full article

(This article belongs to the Special Issue Drug Repurposing and Delivery Systems for Immunotherapy)

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25 pages, 5468 KB

Open AccessEditor’s ChoiceReview

A Descriptive Review on the Potential Use of Diatom Biosilica as a Powerful Functional Biomaterial: A Natural Drug Delivery System

by Sunggu Kang, Yeeun Woo, Yoseph Seo, Daehyeon Yoo, Daeryul Kwon, Hyunjun Park, Sang Deuk Lee, Hah Young Yoo and Taek Lee

Pharmaceutics 2024, 16(9), 1171; https://doi.org/10.3390/pharmaceutics16091171 - 5 Sep 2024

Cited by 11 | Viewed by 2893

Abstract

Although various chemically synthesized materials are essential in medicine, food, and agriculture, they can exert unexpected side effects on the environment and human health by releasing certain toxic chemicals. Therefore, eco-friendly and biocompatible biomaterials based on natural resources are being actively explored. Recently, [...] Read more.

Although various chemically synthesized materials are essential in medicine, food, and agriculture, they can exert unexpected side effects on the environment and human health by releasing certain toxic chemicals. Therefore, eco-friendly and biocompatible biomaterials based on natural resources are being actively explored. Recently, biosilica derived from diatoms has attracted attention in various biomedical fields, including drug delivery systems (DDS), due to its uniform porous nano-pattern, hierarchical structure, and abundant silanol functional groups. Importantly, the structural characteristics of diatom biosilica improve the solubility of poorly soluble substances and enable sustained release of loaded drugs. Additionally, diatom biosilica predominantly comprises SiO₂, has high biocompatibility, and can easily hybridize with other DDS platforms, including hydrogels and cationic DDS, owing to its strong negative charge and abundant silanol groups. This review explores the potential applications of various diatom biosilica-based DDS in various biomedical fields, with a particular focus on hybrid DDS utilizing them. Full article

(This article belongs to the Special Issue Lipid-Based Nanoparticulate Drug Delivery Systems: Preparation, Biomedical Applications, and Evaluation)

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28 pages, 2664 KB

Open AccessEditor’s ChoiceReview

Exploring Protein-Based Carriers in Drug Delivery: A Review

by Claudia Ferraro, Marco Dattilo, Francesco Patitucci, Sabrina Prete, Giuseppe Scopelliti, Ortensia Ilaria Parisi and Francesco Puoci

Pharmaceutics 2024, 16(9), 1172; https://doi.org/10.3390/pharmaceutics16091172 - 5 Sep 2024

Cited by 18 | Viewed by 4445

Abstract

Drug delivery systems (DDSs) represent an emerging focus for many researchers and they are becoming progressively crucial in the development of new treatments. Great attention is given to all the challenges that a drug has to overcome during its journey across barriers and [...] Read more.

Drug delivery systems (DDSs) represent an emerging focus for many researchers and they are becoming progressively crucial in the development of new treatments. Great attention is given to all the challenges that a drug has to overcome during its journey across barriers and tissues and all the pharmacokinetics modulations that are needed in order to reach the targeting sites. The goal of these pathways is the delivery of drugs in a controlled way, optimizing their bioavailability and minimizing side effects. Recent innovations in DDSs include various nanotechnology-based approaches, such as nanoparticles, nanofibers and micelles, which provide effective targeted delivery and sustained release of therapeutics. In this context, protein-based drug delivery systems are gaining significant attention in the pharmaceutical field due to their potential to revolutionize targeted and efficient drug delivery. As natural biomolecules, proteins offer distinct advantages, including safety, biocompatibility and biodegradability, making them a fascinating alternative to synthetic polymers. Moreover, protein-based carriers, including those derived from gelatin, albumin, collagen, gliadin and silk proteins, demonstrate exceptional stability under physiological conditions, and they allow for controlled and sustained drug release, enhancing therapeutic efficacy. This review provides a comprehensive overview of the current trends, challenges, and future perspectives in protein-based drug delivery, focusing on the types of proteins adopted and the techniques that are being developed to enhance their functionality in terms of drug affinity and targeting capabilities, underscoring their potential to significantly impact modern therapeutics. Full article

(This article belongs to the Special Issue The 15th Anniversary of Pharmaceutics—Advances and Future Trends in Drug Delivery)

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14 pages, 2411 KB

Open AccessEditor’s ChoiceArticle

Reactive Oxygen Species-Regulated Conjugates Based on Poly(jasmine) Lactone for Simultaneous Delivery of Doxorubicin and Docetaxel

by Jyoti Verma, Vishal Kumar, Carl-Eric Wilen, Jessica M. Rosenholm and Kuldeep K. Bansal

Pharmaceutics 2024, 16(9), 1164; https://doi.org/10.3390/pharmaceutics16091164 - 3 Sep 2024

Viewed by 1898

Abstract

In cancer therapy, it is essential to selectively release cytotoxic agents into the tumor to prevent the adverse effects associated with anticancer drugs. Thus, in this study, a stimuli-sensitive polymer–drug conjugate was synthesized for selective drug release. Doxorubicin (DOX) and docetaxel (DTX) were [...] Read more.

In cancer therapy, it is essential to selectively release cytotoxic agents into the tumor to prevent the adverse effects associated with anticancer drugs. Thus, in this study, a stimuli-sensitive polymer–drug conjugate was synthesized for selective drug release. Doxorubicin (DOX) and docetaxel (DTX) were conjugated onto novel poly(jasmine lactone) based copolymer via a thioketal (TK) linker. In addition, a photosensitizer (chlorin e6) was attached to the polymer, which served as a reactive oxygen species generator to cleave the TK linker. The conjugate is readily self-assembled into micelles less than 100 nm in size. Micelles demonstrate a notable increase in their ability to cause cell death when exposed to near-infrared (NIR) light on MDA-MB-231 breast cancer cells. The increase in cytotoxicity is higher than that observed with the combination of free DOX and DTX. The accumulation of DOX in the nucleus after release from the micelles (laser irradiation) was also confirmed by confocal microscopy. In the absence of light, micelles did not show any toxicity while the free drugs were found toxic irrespective of the light exposure. The obtained results suggest the targeted drug delivery potential of micelles regulated by the external stimuli, i.e., NIR light. Full article

(This article belongs to the Special Issue Functional Nanomaterials for Drug Delivery in Photodynamic Therapy)

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32 pages, 4110 KB

Open AccessEditor’s ChoiceReview

Platinum Group Metals Nanoparticles in Breast Cancer Therapy

by Sibusiso Alven, Sendibitiyosi Gandidzanwa, Basabele Ngalo, Olwethu Poswayo, Tatenda Madanhire, Blessing A. Aderibigbe and Zenixole Tshentu

Pharmaceutics 2024, 16(9), 1162; https://doi.org/10.3390/pharmaceutics16091162 - 3 Sep 2024

Cited by 4 | Viewed by 3466

Abstract

Despite various methods currently used in cancer therapy, breast cancer remains the leading cause of morbidity and mortality worldwide. Current therapeutics face limitations such as multidrug resistance, drug toxicity and off-target effects, poor drug bioavailability and biocompatibility, and inefficient drug delivery. Nanotechnology has [...] Read more.

Despite various methods currently used in cancer therapy, breast cancer remains the leading cause of morbidity and mortality worldwide. Current therapeutics face limitations such as multidrug resistance, drug toxicity and off-target effects, poor drug bioavailability and biocompatibility, and inefficient drug delivery. Nanotechnology has emerged as a promising approach to cancer diagnosis, imaging, and therapy. Several preclinical studies have demonstrated that compounds and nanoparticles formulated from platinum group metals (PGMs) effectively treat breast cancer. PGMs are chemically stable, easy to functionalise, versatile, and tunable. They can target hypoxic microenvironments, catalyse the production of reactive oxygen species, and offer the potential for combination therapy. PGM nanoparticles can be incorporated with anticancer drugs to improve efficacy and can be attached to targeting moieties to enhance tumour-targeting efficiency. This review focuses on the therapeutic outcomes of platinum group metal nanoparticles (PGMNs) against various breast cancer cells and briefly discusses clinical trials of these nanoparticles in breast cancer treatment. It further illustrates the potential applications of PGMNs in breast cancer and presents opportunities for future PGM-based nanomaterial applications in combatting breast cancer. Full article

(This article belongs to the Special Issue Nanomedicines in Cancer Therapy)

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22 pages, 728 KB

Open AccessEditor’s ChoiceReview

Lipid-Based Nanocarriers: Bridging Diagnosis and Cancer Therapy

by Alessandra Giordano, Anna Chiara Provenza, Giorgio Reverchon, Lucia Baldino and Ernesto Reverchon

Pharmaceutics 2024, 16(9), 1158; https://doi.org/10.3390/pharmaceutics16091158 - 1 Sep 2024

Cited by 19 | Viewed by 4846

Abstract

Theranostics is a growing field that matches diagnostics and therapeutics. In this approach, drugs and techniques are uniquely coupled to diagnose and treat medical conditions synergically or sequentially. By integrating diagnostic and treatment functions in a single platform, the aim of theranostics is [...] Read more.

Theranostics is a growing field that matches diagnostics and therapeutics. In this approach, drugs and techniques are uniquely coupled to diagnose and treat medical conditions synergically or sequentially. By integrating diagnostic and treatment functions in a single platform, the aim of theranostics is to improve precision medicine by tailoring treatments based on real-time information. In this context, lipid-based nanocarriers have attracted great scientific attention due to their biodegradability, biocompatibility, and targeting capabilities. The present review highlights the latest research advances in the field of lipid-based nanocarriers for cancer theranostics, exploring several ways of improving in vivo performance and addressing associated challenges. These nanocarriers have significant potential to create new perspectives in the field of nanomedicine and offer promise for a significant step towards more personalized and precise medicine, reducing side effects and improving clinical outcomes for patients. This review also presents the actual barriers to and the possible challenges in the use of nanoparticles in the theranostic field, such as regulatory hurdles, high costs, and technological integration. Addressing these issues through a multidisciplinary and collaborative approach among institutions could be essential for advancing lipid nanocarriers in the theranostic field. Such collaborations can leverage diverse expertise and resources, fostering innovation and overcoming the complex challenges associated with clinical translation. This approach will be crucial for realizing the full potential of lipid-based nanocarriers in precision medicine. Full article

(This article belongs to the Topic Challenges and Opportunities in Drug Delivery Research)

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16 pages, 3069 KB

Open AccessEditor’s ChoiceArticle

An Antibacterial-Loaded PLA 3D-Printed Model for Temporary Prosthesis in Arthroplasty Infections: Evaluation of the Impact of Layer Thickness on the Mechanical Strength of a Construct and Drug Release

by Carlos Tamarit-Martínez, Lucía Bernat-Just, Carlos Bueno-López, Adrián M. Alambiaga-Caravaca, Virginia Merino, Alicia López-Castellano and Vicent Rodilla

Pharmaceutics 2024, 16(9), 1151; https://doi.org/10.3390/pharmaceutics16091151 - 30 Aug 2024

Viewed by 1282

Abstract

Infections are one of the main complications in arthroplasties. These infections are difficult to treat because the bacteria responsible for them settle in the prosthesis and form a biofilm that does not allow antimicrobials to reach the infected area. This study is part [...] Read more.

Infections are one of the main complications in arthroplasties. These infections are difficult to treat because the bacteria responsible for them settle in the prosthesis and form a biofilm that does not allow antimicrobials to reach the infected area. This study is part of a research project aimed at developing 3D-printed spacers (temporary prostheses) capable of incorporating antibacterials for the personalized treatment of arthroplasty infections. The main objective of this research was to analyze the impact of the layer thickness of 3D-printed constructs based on polylactic acid (PLA) for improved treatment of infections in arthroplasty. The focus is on the following parameters: resistance, morphology, drug release, and the effect of antibacterials incorporated in the printed temporary prostheses. The resistance studies revealed that the design and layer thickness of a printed spacer have an influence on its resistance properties. The thickness of the layer used in printing affects the amount of methylene blue (used as a model drug) that is released. Increasing layer thickness leads to a greater release of the drug from the spacer, probably as a result of higher porosity. To evaluate antibacterial release, cloxacillin and vancomycin were incorporated into the constructs. When incorporated into the 3D construct, both antibacterials were released, as evidenced by the growth inhibition of Staphylococcus aureus. In conclusion, preliminary results indicate that the layer thickness during the three-dimensional (3D) printing process of the spacer plays a significant role in drug release. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of 3D Printing)

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27 pages, 9145 KB

Open AccessEditor’s ChoiceArticle

Application of Hydrophilic Polymers to the Preparation of Prolonged-Release Minitablets with Bromhexine Hydrochloride and Bisoprolol Fumarate

by Agata Grzejdziak, Witold Brniak, Olaf Lengier, Justyna Anna Żarek, Dziyana Hliabovich and Aleksander Mendyk

Pharmaceutics 2024, 16(9), 1153; https://doi.org/10.3390/pharmaceutics16091153 - 30 Aug 2024

Cited by 2 | Viewed by 1888

Abstract

Minitablets have been extensively studied in recent years as a convenient pediatric form because they allow successful administration even in very young children. Their advantages include easy dose adjustment by multiplication of single units as well as the possibility of drug release modification [...] Read more.

Minitablets have been extensively studied in recent years as a convenient pediatric form because they allow successful administration even in very young children. Their advantages include easy dose adjustment by multiplication of single units as well as the possibility of drug release modification by coating or forming matrix systems. The aim of this study was to demonstrate the possibility of the formulation of prolonged-release minitablets with bromhexine hydrochloride (BHX) and bisoprolol fumarate (BFM) dedicated to pediatric patients. Minitablets with 3 mm diameter and 15 mg mass, containing 1 mg of active substance in 1 unit, were prepared by direct compression with hydroxypropyl methylcellulose (HPMC) of different grades, methylcellulose, sodium alginate, or polyvinyl alcohol (PVA) as a sustained-release polymer. Different amounts of polymers and different compression forces were evaluated. Analysis of minitablets included their uniformity, hardness, and dissolution tests. The kinetics of drug substance release were analyzed with dedicated software. The prepared minitablets met the pharmacopeial requirements with respect to the uniformity of mass and content. The compressibility of BFM was significantly better than that of BHX, yet all minitablets had good mechanical properties. Dissolution studies showed a strong relationship between the type of polymer and its amount in the mass of a tablet and the dissolution rate. Prolonged release of up to 8 h was achieved when HPMC of 4000 cP viscosity was used in the amount of 30% to 80%. Sodium alginate in the amount of 50% was also effective in prolonging dissolution, but PVA was much less effective. Studies on the release kinetics showed that dissolution from prolonged-release minitablets with BHX fit the best to Hopfenberg or Hixson–Crowell models, while in the case of BFM, the best fit was found for Hopfenberg or Korsmeyer–Peppas models. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Excipients Used in Solid Dosage Forms)

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16 pages, 6332 KB

Open AccessEditor’s ChoiceReview

Recent Advances in Drug Delivery Strategies for High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer: A Brief Review from 2018 to 2024

by Feng Qu, Saloni Darji and David H. Thompson

Pharmaceutics 2024, 16(9), 1154; https://doi.org/10.3390/pharmaceutics16091154 - 30 Aug 2024

Cited by 12 | Viewed by 5244

Abstract

High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is a condition that is typically treated with Bacillus Calmette–Guérin (BCG) therapy. Unfortunately, NMIBC is characterized by high recurrence, with a significant percentage of BCG patients ultimately requiring radical cystectomy. As a consequence, the development of [...] Read more.

High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is a condition that is typically treated with Bacillus Calmette–Guérin (BCG) therapy. Unfortunately, NMIBC is characterized by high recurrence, with a significant percentage of BCG patients ultimately requiring radical cystectomy. As a consequence, the development of effective new therapies to avoid RC has become a rapidly evolving field to address this unmet clinical need. To date, three biologics—Keytruda, Adstiladrin, and Anktiva—have been approved by the FDA, and multiple drug modalities, particularly gene therapies, have shown promising results in clinical trials. Advances in drug delivery strategies, such as targeted delivery, sustained release, and permeabilization of protective layers, are critical in overcoming the challenges posed by therapeutic intervention in bladder cancer. This review focuses on high-risk BCG-unresponsive NMIBC therapies that have been or are currently being investigated in clinical trials, offering a broad overview of the delivery system designs and up-to-date clinical outcomes that have been reported as of July 2024. It aims to inform the development of future drug delivery systems for second-line therapies in high-risk BCG-unresponsive NMIBC. Full article

(This article belongs to the Special Issue Nanotechnology Applied in Prevention, Diagnosis and Treatment of Cancer)

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17 pages, 3399 KB

Open AccessEditor’s ChoiceArticle

Lipid-Based Nanoparticles Fused with Natural Killer Cell Plasma Membrane Proteins for Triple-Negative Breast Cancer Therapy

by Eun-Jeong Won, Myungchul Lee, Eui-Kyung Lee, Seung-Hoon Baek and Tae-Jong Yoon

Pharmaceutics 2024, 16(9), 1142; https://doi.org/10.3390/pharmaceutics16091142 - 29 Aug 2024

Cited by 3 | Viewed by 2441

Abstract

Immunotherapy combined with chemicals and genetic engineering tools is emerging as a promising strategy to treat triple-negative breast cancer (TNBC), which is more aggressive with poorer progress than other breast cancer subtypes. In this study, lipid-based nanoparticles (LNPs) possessed an NK cell-like function [...] Read more.

Immunotherapy combined with chemicals and genetic engineering tools is emerging as a promising strategy to treat triple-negative breast cancer (TNBC), which is more aggressive with poorer progress than other breast cancer subtypes. In this study, lipid-based nanoparticles (LNPs) possessed an NK cell-like function that could deliver tumor-specific therapeutics and inhibit tumor growth. LNPs fused with an NK cell membrane protein system (NK-LNP) have three main features: (i) hydrophilic plasmid DNA can inhibit TNBC metastasis when encapsulated within LNPs and delivered to cells; (ii) the lipid composition of LNPs, including C18 ceramide, exhibits anticancer effects; (iii) NK cell membrane proteins are immobilized on the LNP surface, enabling targeted delivery to TNBC cells. These particles facilitate the targeted delivery of HIC1 plasmid DNA and the modulation of immune cell functions. Delivered therapeutic genes can inhibit metastasis of TNBC and then induce apoptotic cell death while targeting macrophages to promote cytokine release. The anticancer effect is expected to be applied in treating various difficult-to-treat cancers with LNP fused with NK cell plasma membrane proteins, which can simultaneously deliver therapeutic chemicals and genes. Full article

(This article belongs to the Special Issue Recent Advances in Polymeric Nanoparticle-Based Drug Delivery System for Cancer Therapy)

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21 pages, 1480 KB

Open AccessEditor’s ChoiceReview

Drug Nanocrystals in Oral Absorption: Factors That Influence Pharmacokinetics

by Luiza de Oliveira Macedo, Jéssica Fagionato Masiero and Nádia Araci Bou-Chacra

Pharmaceutics 2024, 16(9), 1141; https://doi.org/10.3390/pharmaceutics16091141 - 29 Aug 2024

Cited by 7 | Viewed by 3437

Abstract

Despite the safety and convenience of oral administration, poorly water-soluble drugs compromise absorption and bioavailability. These drugs can exhibit low dissolution rates, variability between fed and fasted states, difficulty permeating the mucus layer, and P-glycoprotein efflux. Drug nanocrystals offer a promising strategy to [...] Read more.

Despite the safety and convenience of oral administration, poorly water-soluble drugs compromise absorption and bioavailability. These drugs can exhibit low dissolution rates, variability between fed and fasted states, difficulty permeating the mucus layer, and P-glycoprotein efflux. Drug nanocrystals offer a promising strategy to address these challenges. This review focuses on the opportunities to develop orally administered nanocrystals based on pharmacokinetic outcomes. The impacts of the drug particle size, morphology, dissolution rate, crystalline state on oral bioavailability are discussed. The potential of the improved dissolution rate to eliminate food effects during absorption is also addressed. This review also explores whether permeation or dissolution drives nanocrystal absorption. Additionally, it addresses the functional roles of stabilizers. Drug nanocrystals may result in prolonged concentrations in the bloodstream in some cases. Therefore, nanocrystals represent a promising strategy to overcome the challenges of poorly water-soluble drugs, thus encouraging further investigation into unclear mechanisms during oral administration. Full article

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

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22 pages, 3650 KB

Open AccessEditor’s ChoiceArticle

An Innovative Bio-Vehicle for Resveratrol and Tocopherol Based on Quinoa 11S Globulin—Nanocomplex Design and Characterization

by Alejandra J. Rubinstein, Guadalupe Garcia Liñares, Valeria Boeris and Oscar E. Pérez

Pharmaceutics 2024, 16(9), 1118; https://doi.org/10.3390/pharmaceutics16091118 - 24 Aug 2024

Cited by 3 | Viewed by 1937

Abstract

Nanocomplexes, which possess immense potential to function as nanovehicles, can link diverse ligand compounds. The objective of the present study was to design and characterize resveratrol (RSV)- and tocopherol (TOC)-loaded 11S quinoa seed protein nanocomplexes. Firstly, molecular docking was performed to describe the [...] Read more.

Nanocomplexes, which possess immense potential to function as nanovehicles, can link diverse ligand compounds. The objective of the present study was to design and characterize resveratrol (RSV)- and tocopherol (TOC)-loaded 11S quinoa seed protein nanocomplexes. Firstly, molecular docking was performed to describe the probable binding sites between protein and ligands, and binding energies of −5.6 and −6.2 kcal/mol were found for RSV and TOC, respectively. Isothermal titration calorimetry allowed us to obtain the thermodynamic parameters that described the molecular interactions between RSV or TOC with the protein, finding the complexation process to be exothermic and spontaneous. 11S globulin intrinsic fluorescence spectra showed quenching effects exerted by RSV and TOC, demonstrating protein–bioactive compound interactions. The application of Stern–Volmer, Scatchard, and Förster resonance energy transfer models confirmed static quenching and allowed us to obtain parameters that described the 11S-RSV and 11S-TOC complexation processes. RSV has a higher tendency to bind 11S globulin according to ITC and fluorescence analysis. Secondly, the protein aggregation induced by bioactive compound interactions was confirmed by dynamic light scattering and atomic force microscopy, with diameters <150 nm detected by both techniques. Finally, it was found that the antioxidant capacity of a single 11S globulin did not decrease; meanwhile, it was additive for 11S-RSV. These nanocomplexes could constitute a real platform for the design of nutraceutical products. Full article

(This article belongs to the Topic Applications of Polymers and Polymer Nanomaterials in Drug Delivery and Nanomedicine)

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18 pages, 2899 KB

Open AccessEditor’s ChoiceArticle

The Development of a Chocolate-Based Chewable Tablet of Prednisolone—Enhancing the Palatability of Steroids for Pediatric Use

by Okhee Yoo, Edith Tang, Md Lokman Hossain, Britta S. von Ungern-Sternberg, David Sommerfield, Chloe Heath, Neil Hauser, R. Nazim Khan, Cornelia Locher, Minh Nguyen and Lee Yong Lim

Pharmaceutics 2024, 16(8), 1099; https://doi.org/10.3390/pharmaceutics16081099 - 21 Aug 2024

Cited by 2 | Viewed by 2996

Abstract

Oral liquid prednisolone medications have poor acceptance among paediatric patients due to ineffective masking of the bitterness taste of prednisolone. This study aimed to develop a child-friendly prednisolone tablet using a patented chewable chocolate-based delivery system (CDS) previously applied successfully to mask the [...] Read more.

Oral liquid prednisolone medications have poor acceptance among paediatric patients due to ineffective masking of the bitterness taste of prednisolone. This study aimed to develop a child-friendly prednisolone tablet using a patented chewable chocolate-based delivery system (CDS) previously applied successfully to mask the bitterness tastes of midazolam and tramadol. Prednisolone sodium phosphate (PSP) and prednisolone base (PB) CDS tablets were prepared, and the manufacturing process was optimised using a design of experiments (DoE) approach. Stability was assessed by quantifying residual drug content via a validated HPLC assay. A pilot randomised crossover taste study involving 25 young adult volunteers evaluated taste-masking effectiveness against Redipred™, a commercial oral PSP liquid medicine. The results showed that the PSP CDS tablet was chemically stable following storage for three months at ambient temperature, while the PB CDS tablet was unstable. The optimised PSP CDS tablet, manufactured at 50 °C with a stirring time of 26 h, was found to release over 80% of its drug load within 20 min in 0.1 M HCl and had a significantly better mean taste score compared to Redipred™ (7.08 ± 2.40 vs. 5.60 ± 2.33, p = 0.03). Fifty six percent of the participants preferred the PSP CDS tablet. In conclusion, compared to Redipred™, the CDS technology provided a more effective taste masking of PSP, potentially offering a child-friendly prednisolone formulation with improved compliance, dosing accuracy, and storage stability. Full article

(This article belongs to the Special Issue Advanced Pediatric Drug Formulation Strategies)

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12 pages, 1413 KB

Open AccessEditor’s ChoiceArticle

Synthesis, Characterization, and Cytotoxicity Evaluation of Chlorambucil-Functionalized Mesoporous Silica Nanoparticles

by Juliana Camila Fischer Karnopp, Juliana Jorge, Jaqueline Rodrigues da Silva, Diego Boldo, Kristiane Fanti Del Pino Santos, Adriana Pereira Duarte, Gustavo Rocha de Castro, Ricardo Bentes de Azevedo, Ariadna Lafourcade Prada, Jesús Rafael Rodríguez Amado and Marco Antonio Utrera Martines

Pharmaceutics 2024, 16(8), 1086; https://doi.org/10.3390/pharmaceutics16081086 - 19 Aug 2024

Cited by 1 | Viewed by 2254

Abstract

This study describes the synthesis and characterization of chlorambucil (CLB)-functionalized mesoporous silica nanoparticles (MSNs) for potential application in cancer therapy. The nanoparticles were designed with a diameter between 20 and 50 nm to optimize cellular uptake and avoid rapid clearance from the bloodstream. [...] Read more.

This study describes the synthesis and characterization of chlorambucil (CLB)-functionalized mesoporous silica nanoparticles (MSNs) for potential application in cancer therapy. The nanoparticles were designed with a diameter between 20 and 50 nm to optimize cellular uptake and avoid rapid clearance from the bloodstream. The synthesis method involved modifying a previously reported technique to reduce particle size. Successful functionalization with CLB was confirmed through various techniques, including Fourier transform infrared spectroscopy (FTIR) and elemental analysis. The cytotoxicity of the CLB-functionalized nanoparticles (MSN@NH₂-CLB) was evaluated against human lung adenocarcinoma cells (A549) and colon carcinoma cells (CT26WT). The results suggest significantly higher cytotoxicity of MSN@NH₂-CLB compared to unbound CLB, with improved selectivity towards cancer cells over normal cells. This suggests that MSN@NH₂-CLB holds promise as a drug delivery system for targeted cancer therapy. Full article

(This article belongs to the Special Issue Advances in Nanotechnology-Based Drug Delivery Systems)

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24 pages, 4412 KB

Open AccessEditor’s ChoiceArticle

Unlocking the Potential of Camel Milk-Derived Exosomes as Novel Delivery Systems: Enhanced Bioavailability of ARV-825 PROTAC for Cancer Therapy

by Aakash Nathani, Mounika Aare, Li Sun, Arvind Bagde, Yan Li, Arun Rishi and Mandip Singh

Pharmaceutics 2024, 16(8), 1070; https://doi.org/10.3390/pharmaceutics16081070 - 15 Aug 2024

Cited by 11 | Viewed by 3582

Abstract

This study investigates the use of camel milk-derived exosomes (CMEs) as carriers for ARV-825, an anticancer agent targeting bromodomain-containing protein 4 (BRD4), in oral chemotherapy. CMEs were isolated and characterized, and ARV-825-loaded CME formulations were prepared and evaluated through various in vitro and [...] Read more.

This study investigates the use of camel milk-derived exosomes (CMEs) as carriers for ARV-825, an anticancer agent targeting bromodomain-containing protein 4 (BRD4), in oral chemotherapy. CMEs were isolated and characterized, and ARV-825-loaded CME formulations were prepared and evaluated through various in vitro and in vivo tests. The ARV-825-CME formulation exhibited an entrapment efficiency of 42.75 ± 5.05%, a particle size of 136.8 ± 1.94 nm, and a zeta potential of −32.75 ± 0.70 mV, ensuring stability and sustained drug release. In vitro studies showed a 5.4-fold enhancement in drug release kinetics compared to the free ARV-825 solution. Permeability studies indicated a 3.2-fold increase in apparent permeability, suggesting improved cellular uptake. Cytotoxicity assays demonstrated potent anticancer activity, with IC50 values decreasing by 1.5 to 2-fold in cancer cell lines SF8628 DIPG and H1975R (resistant to Osimertinib). In vivo pharmacokinetic studies in Sprague-Dawley rats revealed superior systemic absorption and bioavailability of ARV-825 from CMEs, with a 2.55-fold increase in plasma concentration and a 5.56-fold increase in AUC. Distribution studies confirmed absorption through the ileum. This research highlights the potential of CMEs as a promising delivery platform for ARV-825, enhancing its therapeutic efficacy and offering a novel approach to cancer treatment. Full article

(This article belongs to the Special Issue Exosomes as Drug Carriers for Cancer Therapy)

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22 pages, 4036 KB

Open AccessEditor’s ChoiceArticle

Development and Evaluation of Different Electrospun Cysteamine-Loaded Nanofibrous Webs: A Promising Option for Treating a Rare Lysosomal Storage Disorder

by Safaa Omer, Nándor Nagy, Balázs Pinke, László Mészáros, Adrienn Kazsoki and Romána Zelkó

Pharmaceutics 2024, 16(8), 1052; https://doi.org/10.3390/pharmaceutics16081052 - 9 Aug 2024

Cited by 3 | Viewed by 2161

Abstract

Nanofibers can be utilized to overcome the challenges faced by conventional ophthalmic formulations. This study aimed to develop and characterize cysteamine (Cys)-loaded nanofiber-based ophthalmic inserts (OIs) as a potential candidate for the treatment of ophthalmic cystinosis using water-soluble polyvinyl alcohol (PVA)/poloxamer 407 (PO-407) [...] Read more.

Nanofibers can be utilized to overcome the challenges faced by conventional ophthalmic formulations. This study aimed to develop and characterize cysteamine (Cys)-loaded nanofiber-based ophthalmic inserts (OIs) as a potential candidate for the treatment of ophthalmic cystinosis using water-soluble polyvinyl alcohol (PVA)/poloxamer 407 (PO-407) and water-insoluble tetraethoxysilane (TEOS)/PVA nanofibers. Plain and Cys-loaded fibers in different proportions were prepared by the electrospinning method and studied for their morphological, physicochemical, release study, cytocompatibility effects, and stability study. The fiber formation was confirmed by scanning electron microscopy, while Fourier transform infrared spectra showed the most critical peaks for the Cys and the excipients. The release of the Cys was fast from the two polymeric matrices (≤20 min). The release from TEOS/PVA nanofibers is characterized by Case II transport (0.75 < β < 1), while the release from PVA/PO-407 nanofibers follows Fickian diffusion (β < 0.75). The cytocompatibility of compositions was confirmed by hen eggs tested on the chorioallantoic membrane (HET-CAM) of chick embryos. All formulations remained stable under stress conditions (40 ± 2 °C, 75 ± 5% relative humidity) regarding morphology and physicochemical characteristics. The developed nanofibrous mats could be an excellent alternative to available Cys drops, with better stability and convenience of self-administration as OIs. Full article

(This article belongs to the Topic Applications of Polymers and Polymer Nanomaterials in Drug Delivery and Nanomedicine)

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20 pages, 2134 KB

Open AccessEditor’s ChoiceArticle

Dopamine and Citicoline-Co-Loaded Solid Lipid Nanoparticles as Multifunctional Nanomedicines for Parkinson’s Disease Treatment by Intranasal Administration

by Stefano Castellani, Giorgia Natalia Iaconisi, Francesca Tripaldi, Vito Porcelli, Adriana Trapani, Eugenia Messina, Lorenzo Guerra, Cinzia Di Franco, Giuseppe Maruccio, Anna Grazia Monteduro, Filomena Corbo, Sante Di Gioia, Giuseppe Trapani and Massimo Conese

Pharmaceutics 2024, 16(8), 1048; https://doi.org/10.3390/pharmaceutics16081048 - 7 Aug 2024

Cited by 8 | Viewed by 3470

Abstract

This work aimed to evaluate the potential of the nanosystems constituted by dopamine (DA) and the antioxidant Citicoline (CIT) co-loaded in solid lipid nanoparticles (SLNs) for intranasal administration in the treatment of Parkinson disease (PD). Such nanosystems, denoted as DA-CIT-SLNs, were designed according [...] Read more.

This work aimed to evaluate the potential of the nanosystems constituted by dopamine (DA) and the antioxidant Citicoline (CIT) co-loaded in solid lipid nanoparticles (SLNs) for intranasal administration in the treatment of Parkinson disease (PD). Such nanosystems, denoted as DA-CIT-SLNs, were designed according to the concept of multifunctional nanomedicine where multiple biological roles are combined into a single nanocarrier and prepared by the melt emulsification method employing the self-emulsifying Gelucire^® 50/13 as lipid matrix. The resulting DA-CIT-SLNs were characterized regarding particle size, surface charge, encapsulation efficiency, morphology, and physical stability. Differential scanning calorimetry, FT-IR, and X ray diffraction studies were carried out to gain information on solid-state features, and in vitro release tests in simulated nasal fluid (SNF) were performed. Monitoring the particle size at two temperatures (4 °C and 37 °C), the size enlargement observed over the time at 37 °C was lower than that observed at 4 °C, even though at higher temperature, color changes occurred, indicative of possible neurotransmitter decomposition. Solid-state studies indicated a reduction in the crystallinity when DA and CIT are co-encapsulated in DA-CIT-SLNs. Interestingly, in vitro release studies in SNF indicated a sustained release of DA. Furthermore, DA-CIT SLNs displayed high cytocompatibility with both human nasal RPMI 2650 and neuronal SH-SY5Y cells. Furthermore, OxyBlot assay demonstrated considerable potential to assess the protective effect of antioxidant agents against oxidative cellular damage. Thus, such protective effect was shown by DA-CIT-SLNs, which constitute a promising formulation for PD application. Full article

(This article belongs to the Special Issue Polymer- and Lipid-Based Nanostructured Drug Delivery Systems for the Treatment of CNS Diseases: Recent Advances towards Clinical Application, 2nd Edition)

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57 pages, 3841 KB

Open AccessEditor’s ChoiceReview

Functionalized Polymeric Micelles for Targeted Cancer Therapy: Steps from Conceptualization to Clinical Trials

by Ana Serras, Célia Faustino and Lídia Pinheiro

Pharmaceutics 2024, 16(8), 1047; https://doi.org/10.3390/pharmaceutics16081047 - 6 Aug 2024

Cited by 7 | Viewed by 3954

Abstract

Cancer is still ranked among the top three causes of death in the 30- to 69-year-old age group in most countries and carries considerable societal and macroeconomic costs that differ depending on the cancer type, geography, and patient gender. Despite advances in several [...] Read more.

Cancer is still ranked among the top three causes of death in the 30- to 69-year-old age group in most countries and carries considerable societal and macroeconomic costs that differ depending on the cancer type, geography, and patient gender. Despite advances in several pharmacological approaches, the lack of stability and specificity, dose-related toxicity, and limited bioavailability of chemotherapy (standard therapy) pose major obstacles in cancer treatment, with multidrug resistance being a driving factor in chemotherapy failure. The past three decades have been the stage for intense research activity on the topic of nanomedicine, which has resulted in many nanotherapeutics with reduced toxicity, increased bioavailability, and improved pharmacokinetics and therapeutic efficacy employing smart drug delivery systems (SDDSs). Polymeric micelles (PMs) have become an auspicious DDS for medicinal compounds, being used to encapsulate hydrophobic drugs that also exhibit substantial toxicity. Through preclinical animal testing, PMs improved pharmacokinetic profiles and increased efficacy, resulting in a higher safety profile for therapeutic drugs. This review focuses on PMs that are already in clinical trials, traveling the pathways from preclinical to clinical studies until introduction to the market. Full article

(This article belongs to the Special Issue Supramolecular Systems for Gene and Drug Delivery, 2nd Edition)

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13 pages, 12577 KB

Open AccessEditor’s ChoiceArticle

Melanoma Brain Metastases Patient-Derived Organoids: An In Vitro Platform for Drug Screening

by Saif-Eldin Abedellatif, Racha Hosni, Andreas Waha, Gerrit H. Gielen, Mohammed Banat, Motaz Hamed, Erdem Güresir, Anne Fröhlich, Judith Sirokay, Anna-Lena Wulf, Glen Kristiansen, Torsten Pietsch, Hartmut Vatter, Michael Hölzel, Matthias Schneider and Marieta Ioana Toma

Pharmaceutics 2024, 16(8), 1042; https://doi.org/10.3390/pharmaceutics16081042 - 5 Aug 2024

Cited by 3 | Viewed by 2800

Abstract

Background and aims: Brain metastases are prevalent in the late stages of malignant melanoma. Multimodal therapy remains challenging. Patient-derived organoids (PDOs) represent a valuable pre-clinical model, faithfully recapitulating key aspects of the original tumor, including the heterogeneity and the mutational status. This study [...] Read more.

Background and aims: Brain metastases are prevalent in the late stages of malignant melanoma. Multimodal therapy remains challenging. Patient-derived organoids (PDOs) represent a valuable pre-clinical model, faithfully recapitulating key aspects of the original tumor, including the heterogeneity and the mutational status. This study aimed to establish PDOs from melanoma brain metastases (MBM-PDOs) and to test the feasibility of using them as a model for in vitro targeted-therapy drug testing. Methods: Surgical resection samples from eight patients with melanoma brain metastases were used to establish MBM-PDOs. The samples were enzymatically dissociated followed by seeding into low-attachment plates to generate floating organoids. The MBM-PDOs were characterized genetically, histologically, and immunohistologically and compared with the parental tissue. The MBM-PDO cultures were exposed to dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) followed by a cell viability assessment. Results: Seven out of eight cases were successfully cultivated, maintaining the histological, immunohistological phenotype, and the mutational status of the parental tumors. Five out of seven cases harbored BRAF V600E mutations and were responsive to BRAF and MEK inhibitors in vitro. Two out of seven cases were BRAF wild type: one case harboring an NRAS mutation and the other harboring a KIT mutation, and both were resistant to BRAF and MEK inhibitor therapy. Conclusions: We successfully established PDOs from melanoma brain metastases surgical specimens, which exhibited a consistent histological and mutational profile with the parental tissue. Using FDA-approved BRAF and MEK inhibitors, our data demonstrate the feasibility of employing MBM-PDOs for targeted-therapy in vitro testing. Full article

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18 pages, 3175 KB

Open AccessEditor’s ChoiceArticle

Application of a Novel Dissolution Medium with Lipids for In Vitro Simulation of the Postprandial Gastric Content

by Tjaša Felicijan, Iva Rakoše, Manca Prislan, Igor Locatelli, Marija Bogataj and Jurij Trontelj

Pharmaceutics 2024, 16(8), 1040; https://doi.org/10.3390/pharmaceutics16081040 - 3 Aug 2024

Viewed by 1914

Abstract

Food can change various physiological parameters along the gastrointestinal tract, potentially impacting postprandial drug absorption. It is thus important to consider different in vivo conditions during in vitro studies. Therefore, a novel dissolution medium simulating variable postprandial pH values and lipid concentrations was [...] Read more.

Food can change various physiological parameters along the gastrointestinal tract, potentially impacting postprandial drug absorption. It is thus important to consider different in vivo conditions during in vitro studies. Therefore, a novel dissolution medium simulating variable postprandial pH values and lipid concentrations was developed and used in this study. Additionally, by establishing and validating a suitable analytical method, the effects of these parameters on the dissolution of a model drug, cinnarizine, and on its distribution between the lipid and aqueous phases of the medium were studied. Both parameters, pH value and lipid concentration, were shown to influence cinnarizine behavior in the in vitro dissolution studies. The amount of dissolved drug decreased with increasing pH due to cinnarizine’s decreasing solubility. At pH values 5 and 7, the higher concentration of lipids in the medium increased drug dissolution, and most of the dissolved drug was distributed in the lipid phase. In all media with a lower pH of 3, dissolution was fast and complete, with a significant amount of drug distributed in the lipid phase. These results are in accordance with the in vivo observed positive food effect on cinnarizine bioavailability described in the literature. The developed medium, with its ability to easily adjust the pH level and lipid concentration, thus offers a promising tool for assessing the effect of co-ingested food on the dissolution kinetics of poorly soluble drugs. Full article

(This article belongs to the Special Issue Recent Advances in Pharmaceutical Dosage Forms)

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23 pages, 4946 KB

Open AccessEditor’s ChoiceArticle

Next-Generation Contraceptive Intravaginal Ring: Comparison of Etonogestrel and Ethinyl Estradiol In Vitro and In Vivo Release from 3D-Printed Intravaginal Ring and NuvaRing

by Isabella C. Young, Allison L. Thorson, Mackenzie L. Cottrell, Craig Sykes, Amanda P. Schauer, Rani S. Sellers, Rima Janusziewicz, Kathleen L. Vincent and Soumya Rahima Benhabbour

Pharmaceutics 2024, 16(8), 1030; https://doi.org/10.3390/pharmaceutics16081030 - 2 Aug 2024

Viewed by 3726

Abstract

Intravaginal rings (IVRs) represent a well-established, woman-controlled and sustained vaginal drug delivery system suitable for a wide range of applications. Here, we sought to investigate the differences in etonogestrel (ENG) and ethinyl estradiol (EE) release from a 3D-printed IVR utilizing continuous liquid interface [...] Read more.

Intravaginal rings (IVRs) represent a well-established, woman-controlled and sustained vaginal drug delivery system suitable for a wide range of applications. Here, we sought to investigate the differences in etonogestrel (ENG) and ethinyl estradiol (EE) release from a 3D-printed IVR utilizing continuous liquid interface production (CLIP™) (referred to as CLIP_LOW for low drug loading and CLIP_HIGH IVRs for high drug loading) and NuvaRing, a commercially available injection molded IVR. We conducted in vitro release studies in simulated vaginal fluid to compare the release of ENG and EE from CLIP_LOW IVRs and NuvaRing. CLIP_LOW IVRs had a similar hormone dose to NuvaRing and exhibited slightly slower ENG release and greater EE release in vitro compared to NuvaRing. When administered to female sheep, NuvaRing demonstrated greater ENG/EE levels in plasma, vaginal tissue and vaginal fluids compared to CLIP_LOW IVR despite similar drug loadings. Leveraging observed hormones levels in sheep from NuvaRing as an effective contraceptive benchmark, we developed a long-acting CLIP_HIGH IVR with increased ENG and EE doses that demonstrated systemic and local hormone levels greater than the NuvaRing for 90 days in sheep. No signs of toxicity were noted regarding general health, colposcopy, or histological analysis in sheep after CLIP_HIGH IVR administration. Our results provided (1) a comparison of ENG and EE release between a 3D-printed IVR and NuvaRing in vitro and in vivo, (2) a preclinical pharmacokinetic benchmark for vaginally delivered ENG and EE and (3) the generation of a 90-day CLIP IVR that will be utilized in future work to support the development of a long-acting ENG/EE IVR combined with an antiretroviral for the prevention of HIV and unplanned pregnancy. Full article

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

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13 pages, 3288 KB

Open AccessEditor’s ChoiceArticle

Identification of the Biotransformation Pathways of a Potential Oral Male Contraceptive, 11β-Methyl-19-Nortestosterone (11β-MNT) and Its Prodrugs: An In Vitro Study Highlights the Contribution of Polymorphic Intestinal UGT2B17

by Namrata Bachhav, Dilip Kumar Singh, Diana L. Blithe, Min S. Lee and Bhagwat Prasad

Pharmaceutics 2024, 16(8), 1032; https://doi.org/10.3390/pharmaceutics16081032 - 2 Aug 2024

Cited by 1 | Viewed by 1972

Abstract

11β-Methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) is a prodrug of 11β-MNT and is being considered as a promising male oral contraceptive candidate in clinical development. However, the oral administration of 11β-MNTDC exhibits an ~200-fold lower serum concentration of 11β-MNT compared to 11β-MNTDC, resulting in the poor [...] Read more.

11β-Methyl-19-nortestosterone dodecylcarbonate (11β-MNTDC) is a prodrug of 11β-MNT and is being considered as a promising male oral contraceptive candidate in clinical development. However, the oral administration of 11β-MNTDC exhibits an ~200-fold lower serum concentration of 11β-MNT compared to 11β-MNTDC, resulting in the poor bioavailability of 11β-MNT. To elucidate the role of the first-pass metabolism of 11β-MNT in its poor bioavailability, we determined the biotransformation products of 11β-MNT and its prodrugs in human in vitro models. 11β-MNT and its two prodrugs 11β-MNTDC and 11β-MNT undecanoate (11β-MNTU) were incubated in cryopreserved human hepatocytes (HHs) and subjected to liquid chromatography–high resolution tandem mass spectrometry analysis, which identified ten 11β-MNT biotransformation products with dehydrogenated and glucuronidation (11β-MNTG) metabolites being the major metabolites. However, 11β-MNTG formation is highly variable and prevalent in human intestinal S9 fractions. A reaction phenotyping study of 11β-MNT using thirteen recombinant UDP-glucuronosyltransferase (UGT) enzymes confirmed the major role of UGT2B17 in 11β-MNTG formation. This was further supported by a strong correlation (R² > 0.78) between 11β-MNTG and UGT2B17 abundance in human intestinal microsomes, human liver microsomes, and HH systems. These results suggest that 11β-MNT and its prodrugs are rapidly metabolized to 11β-MNTG by the highly polymorphic intestinal UGT2B17, which may explain the poor and variable bioavailability of the drug. Full article

(This article belongs to the Special Issue Advances in ADME for Drug Discovery)

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16 pages, 3117 KB

Open AccessEditor’s ChoiceArticle

Optimization of Sodium Iodide-Based Root Filling Material for Clinical Applications: Enhancing Physicochemical Properties

by Hye-Shin Park, Yu-Jin Kim, Soo-Jin Chang, Hae-Hyoung Lee, Mi-Ran Han, Joon-Haeng Lee, Jong-Soo Kim, Jong-Bin Kim, Ji-Sun Shin and Jung-Hwan Lee

Pharmaceutics 2024, 16(8), 1031; https://doi.org/10.3390/pharmaceutics16081031 - 2 Aug 2024

Cited by 2 | Viewed by 2468

Abstract

Premature loss of root canal-treated primary teeth has long been a concern in dentistry. To address this, researchers developed a sodium iodide-based root canal-filling material as an alternative to traditional iodoform-based materials. The goal of this study was to improve the physicochemical properties [...] Read more.

Premature loss of root canal-treated primary teeth has long been a concern in dentistry. To address this, researchers developed a sodium iodide-based root canal-filling material as an alternative to traditional iodoform-based materials. The goal of this study was to improve the physicochemical properties of the sodium iodide-based material to meet clinical use standards. To resolve high solubility issues in the initial formulation, researchers adjusted component ratios and added new ingredients, resulting in a new paste called L5. This study compared L5 with L0 (identical composition minus lanolin) and Vitapex as controls, conducting physicochemical and antibacterial tests. Results showed that L5 met all ISO 6876 standards, demonstrated easier injection and irrigation properties than Vitapex, and exhibited comparable antibacterial efficacy to Vitapex, which is currently used clinically. The researchers conclude that if biological stability is further verified, L5 could potentially be presented as a new option for root canal-filling materials in primary teeth. Full article

(This article belongs to the Special Issue Advances in Scaffolds for Dental and Periodontal Tissue Regeneration)

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10 pages, 5741 KB

Open AccessEditor’s ChoiceArticle

Quenched Zwitterionic Cyclic Arg-Gly-Asp-Containing Pentapeptide Probe for Real-Time Brain Tumor Imaging

by Hyunjin Kim, Maixian Liu and Yongdoo Choi

Pharmaceutics 2024, 16(8), 1034; https://doi.org/10.3390/pharmaceutics16081034 - 2 Aug 2024

Cited by 1 | Viewed by 1398

Abstract

The efficacy of glioblastoma treatment is closely associated with complete tumor resection. However, conventional surgical techniques often result in incomplete removal, leading to poor prognosis. A major challenge is the accurate delineation of tumor margins from healthy tissues. Imaging-guided surgery, particularly using fluorescent [...] Read more.

The efficacy of glioblastoma treatment is closely associated with complete tumor resection. However, conventional surgical techniques often result in incomplete removal, leading to poor prognosis. A major challenge is the accurate delineation of tumor margins from healthy tissues. Imaging-guided surgery, particularly using fluorescent probes, is a promising solution for intraoperative guidance. The recently developed ‘always-on’ types of targeted fluorescence probes generate signals irrespective of their presence in tumor cells or in blood circulation, hampering their effectiveness. Here, we propose a novel activatable fluorescence imaging probe, Q-cRGD, that targets glioma cells via the specific binding of the cyclic Arg-Gly Asp-containing pentapeptide (cRGD) to integrins. The Q-cRGD probe was synthesized by conjugating a near-infrared (NIR) dye to a tryptophan quencher via a disulfide linkage, including a cRGD-targeting ligand. This activatable probe remained inactive until the redox-responsive cleavage of the disulfide linkage occurred within the target cell. The zwitterionic nature of NIR dyes minimizes nonspecific interactions with serum proteins, thereby enhancing the tumor-to-background signal ratio (TBR). An in vivo fluorescence imaging study demonstrated a TBR value of 2.65 within 3 h of the intravenous injection of Q-cRGD, confirming its potential utility in imaging-guided brain cancer surgery. Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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16 pages, 3332 KB

Open AccessEditor’s ChoiceArticle

Pulmonary Inhalation of Biotherapeutics: A Systematic Approach to Understanding the Effects of Atomisation Gas Flow Rate on Particle Physiochemical Properties and Retained Bioactivity

by Laura Foley, Ahmad Ziaee, Gavin Walker and Emmet O’Reilly

Pharmaceutics 2024, 16(8), 1020; https://doi.org/10.3390/pharmaceutics16081020 - 1 Aug 2024

Cited by 2 | Viewed by 1348

Abstract

The identification of spray-drying processing parameters capable of producing particles suitable for pulmonary inhalation with retained bioactivity underpins the development of inhalable biotherapeutics. Effective delivery of biopharmaceuticals via pulmonary delivery routes such as dry powder inhalation (DPI) requires developing techniques that engineer particles [...] Read more.

The identification of spray-drying processing parameters capable of producing particles suitable for pulmonary inhalation with retained bioactivity underpins the development of inhalable biotherapeutics. Effective delivery of biopharmaceuticals via pulmonary delivery routes such as dry powder inhalation (DPI) requires developing techniques that engineer particles to well-defined target profiles while simultaneously minimising protein denaturation. This study examines the simultaneous effects of atomisation gas flow rate on particle properties and retained bioactivity for the model biopharmaceutical lysozyme. The results show that optimising the interplay between atomisation gas flow rate and excipient concentration enables the production of free-flowing powder with retained bioactivity approaching 100%, moisture content below 4%, and D₅₀ < 4 µm, at yields exceeding 50%. The developed methodologies inform the future design of protein-specific spray-drying parameters for inhalable biotherapeutics. Full article

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

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13 pages, 1924 KB

Open AccessEditor’s ChoiceArticle

Synthesis of Gelatin Methacryloyl Analogs and Their Use in the Fabrication of pH-Responsive Microspheres

by Karolina Valente, Geneviève N. Boice, Cameron Polglase, Roman G. Belli, Elaina Bourque, Afzal Suleman and Alexandre Brolo

Pharmaceutics 2024, 16(8), 1016; https://doi.org/10.3390/pharmaceutics16081016 - 31 Jul 2024

Cited by 3 | Viewed by 2966

Abstract

pH-responsive hydrogels have numerous applications in tissue engineering, drug delivery systems, and diagnostics. Gelatin methacryloyl (GelMA) is a biocompatible, semi-synthetic polymer prepared from gelatin. When combined with aqueous solvents, GelMA forms hydrogels that have extensive applications in biomedical engineering. GelMA can be produced [...] Read more.

pH-responsive hydrogels have numerous applications in tissue engineering, drug delivery systems, and diagnostics. Gelatin methacryloyl (GelMA) is a biocompatible, semi-synthetic polymer prepared from gelatin. When combined with aqueous solvents, GelMA forms hydrogels that have extensive applications in biomedical engineering. GelMA can be produced with different degrees of methacryloyl substitution; however, the synthesis of this polymer has not been tuned towards producing selectively modified materials for single-component pH-responsive hydrogels. In this work, we have explored two different synthetic routes targeting different gelatin functional groups (amine, hydroxyl, and/or carboxyl) to produce two GelMA analogs: gelatin A methacryloyl glycerylester (polymer A) and gelatin B methacrylamide (polymer B). Polymers A and B were used to fabricate pH-responsive hydrogel microspheres in a flow-focusing microfluidic device. At neutral pH, polymer A and B microspheres displayed an average diameter of ~40 µm. At pH 6, microspheres from polymer A showed a swelling ratio of 159.1 ± 11.5%, while at pH 10, a 288.6 ± 11.6% swelling ratio was recorded for polymer B particles. Full article

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19 pages, 8754 KB

Open AccessEditor’s ChoiceArticle

Unraveling Novel Strategies in Mesothelioma Treatments Using a Newly Synthetized Platinum(IV) Compound

by Cristina Favaron, Ludovica Gaiaschi, Claudio Casali, Fabrizio De Luca, Federica Gola, Margherita Cavallo, Valeria Ramundo, Elisabetta Aldieri, Gloria Milanesi, Silvia Damiana Visonà, Mauro Ravera and Maria Grazia Bottone

Pharmaceutics 2024, 16(8), 1015; https://doi.org/10.3390/pharmaceutics16081015 - 31 Jul 2024

Cited by 2 | Viewed by 1916

Abstract

Malignant mesothelioma is a rare tumor associated with asbestos exposure. Mesothelioma carcinogenesis is related to enhanced reactive oxygen species (ROS) production and iron overload. Despite the recent advances in biomedical sciences, to date the only available treatments include surgery in a small fraction [...] Read more.

Malignant mesothelioma is a rare tumor associated with asbestos exposure. Mesothelioma carcinogenesis is related to enhanced reactive oxygen species (ROS) production and iron overload. Despite the recent advances in biomedical sciences, to date the only available treatments include surgery in a small fraction of patients and platinum-based chemotherapy in combination with pemetrexed. In this view, the purpose of this study was to evaluate the therapeutic potential of the newly synthetized platinum prodrug Pt(IV)Ac-POA compared to cisplatin (CDDP) on human biphasic mesothelioma cell line MSTO-211H using different complementary techniques, such as flow-cytometry, transmission electron microscopy (TEM), and immunocytochemistry. Healthy mesothelial cell lines Met-5A were also employed to assess the cytotoxicity of the above-mentioned compounds. Our in vitro results showed that Pt(IV)Ac-POA significantly interfere with iron metabolisms and more importantly is able to trigger cell death, through different pathways, including ferroptosis, necroptosis, and apoptosis, in neoplastic cells. On the other hand, CDDP triggers mainly apoptotic and necrotic cell death. In conclusion, Pt(IV)Ac-POA may represent a new promising pharmacological agent in the treatment of malignant mesothelioma. Full article

(This article belongs to the Special Issue The State-of-the-art in Improving the Antitumor Efficacy of Platinum Drugs)

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15 pages, 5014 KB

Open AccessEditor’s ChoiceArticle

A Stereolithography-Based Modified Spin-Casting Method for Faster Laboratory-Scale Production of Dexamethasone-Containing Dissolving Microneedle Arrays

by Martin Cseh, Gábor Katona, Szilvia Berkó, Mária Budai-Szűcs and Ildikó Csóka

Pharmaceutics 2024, 16(8), 1005; https://doi.org/10.3390/pharmaceutics16081005 - 29 Jul 2024

Viewed by 1668

Abstract

Microneedle arrays (MNAs) consist of a few dozens of submillimeter needles, which tend to penetrate through the stratum corneum layer of the skin and deliver hardly penetrating drugs to the systemic circulation. The application of this smart dosage form shows several advantages, such [...] Read more.

Microneedle arrays (MNAs) consist of a few dozens of submillimeter needles, which tend to penetrate through the stratum corneum layer of the skin and deliver hardly penetrating drugs to the systemic circulation. The application of this smart dosage form shows several advantages, such as simple use and negligible pain caused by needle punctures compared to conventional subcutaneous injections. Dissolving MNAs (DMNAs) represent a promising form of cutaneous drug delivery due to their high drug content, biocompatibility, and ease of use. Although different technologies are suitable to produce microneedle arrays (e.g., micromilling, chemical etching, laser ablation etc.), many of these are expensive or hardly accessible. Following the exponential growth of the 3D-printing industry in the last decade, high-resolution desktop printers became accessible for researchers to easily and cost-effectively design and produce microstructures, including MNAs. In this work, a low force stereolithography (LFS) 3D-printer was used to develop the dimensionally correct MNA masters for the spin-casting method. The present study aimed to develop and characterize drug-loaded DMNAs using a two-level, full factorial design for three factors focusing on the optimization of DMNA production and adequate drug content. For the preparation of DMNAs, carboxymethylcellulose and trehalose were used in certain amounts as matrices for dexamethasone sodium phosphate (DEX). Investigation of the produced DexDMNAs included mechanical analysis via texture analyzer and optical microscopy, determination of drug content and distribution with HPLC and Raman microscopy, dissolution studies via HPLC, and ex vivo qualitative permeation studies by Raman mapping. It can be concluded that a DEX-containing, mechanically stable, biodegradable DexDMNA system was successfully developed in two dosage strengths, of which both efficiently delivered the drug to the lower layers (dermis) of human skin. Moreover, the ex vivo skin penetration results support that the application of DMNAs for cutaneous drug delivery can be more effective than that of a conventional dermal gel. Full article

(This article belongs to the Special Issue Pharmaceutical Applications of 3D Printing)

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20 pages, 7014 KB

Open AccessEditor’s ChoiceArticle

Amorphous Polymer–Phospholipid Solid Dispersions for the Co-Delivery of Curcumin and Piperine Prepared via Hot-Melt Extrusion

by Kamil Wdowiak, Andrzej Miklaszewski and Judyta Cielecka-Piontek

Pharmaceutics 2024, 16(8), 999; https://doi.org/10.3390/pharmaceutics16080999 - 28 Jul 2024

Cited by 4 | Viewed by 2947

Abstract

Curcumin and piperine are plant compounds known for their health-promoting properties, but their use in the prevention or treatment of various diseases is limited by their poor solubility. To overcome this drawback, the curcumin–piperine amorphous polymer–phospholipid dispersions were prepared by hot melt extrusion [...] Read more.

Curcumin and piperine are plant compounds known for their health-promoting properties, but their use in the prevention or treatment of various diseases is limited by their poor solubility. To overcome this drawback, the curcumin–piperine amorphous polymer–phospholipid dispersions were prepared by hot melt extrusion technology. X-ray powder diffraction indicated the formation of amorphous systems. Differential scanning calorimetry confirmed amorphization and provided information on the good miscibility of the active compound–polymer–phospholipid dispersions. Owing to Fourier-transform infrared spectroscopy, the intermolecular interactions in systems were investigated. In the biopharmaceutical properties assessment, the improvement in solubility as well as the maintenance of the supersaturation state were confirmed. Moreover, PAMPA models simulating the gastrointestinal tract and blood-brain barrier showed enhanced permeability of active compounds presented in dispersions compared to the crystalline form of individual compounds. The presented paper suggests that polymer–phospholipid dispersions advantageously impact the bioaccessibility of poorly soluble active compounds. Full article

(This article belongs to the Special Issue Advanced Materials Science and Technology in Drug Delivery)

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21 pages, 3365 KB

Open AccessEditor’s ChoiceArticle

Development of Proniosome Gel Formulation for CHIKV Infection

by Ayça Altay Benetti, Ma Thinzar Thwin, Ahmad Suhaimi, Ryan Sia Tze Liang, Lisa Fong-Poh Ng, Fok-Moon Lum and Camillo Benetti

Pharmaceutics 2024, 16(8), 994; https://doi.org/10.3390/pharmaceutics16080994 - 26 Jul 2024

Cited by 3 | Viewed by 1884

Abstract

Given the increasing aging population and the rising prevalence of musculoskeletal diseases due to obesity and injury, urgent research is needed to formulate new treatment alternatives, as current options remain inadequate. Viruses can exacerbate arthritis and worsen symptoms in patients with pre-existing osteoarthritis. [...] Read more.

Given the increasing aging population and the rising prevalence of musculoskeletal diseases due to obesity and injury, urgent research is needed to formulate new treatment alternatives, as current options remain inadequate. Viruses can exacerbate arthritis and worsen symptoms in patients with pre-existing osteoarthritis. Over the past decade, the chikungunya virus (CHIKV) has emerged as a significant public health concern, especially in Asia and South America. Exploring natural products, such as berberine, has shown promise due to its anticatabolic, antioxidative, and anti-inflammatory effects. However, berberine’s low stability and bioavailability limit its efficacy. We hypothesized that encapsulating berberine into a proniosome gel, known for its ease of preparation and stability, could enhance its bioavailability and efficacy when applied topically, potentially treating CHIKV infection. Our investigation focused on how varying berberine loads and selected excipients in the proniosome gel influenced its physical properties, stability, and skin permeability. We also examined the biological half-life of berberine in plasma upon topical administration in mice to assess the potential for controlled and sustained drug release. Additionally, we analyzed the antioxidant stress activity and cell viability of HaCaT keratinocytes and developed a lipopolysaccharide-stimulated cell culture model to evaluate anti-inflammatory effects using pro-inflammatory cytokines. Overall, the research aims to transform the treatment landscape for arthritis by leveraging berberine’s therapeutic potential. Full article

(This article belongs to the Special Issue The 15th Anniversary of Pharmaceutics—Biotechnological Drugs: Innovations in Preparation and Delivery Strategies)

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12 pages, 2398 KB

Open AccessEditor’s ChoiceArticle

Mesoporous Silica-Based Membranes in Transdermal Drug Delivery: The Role of Drug Loss in the Skin

by Frank Baumann, Theresa Paul, Susann Ossmann, Dirk Enke and Achim Aigner

Pharmaceutics 2024, 16(8), 995; https://doi.org/10.3390/pharmaceutics16080995 - 26 Jul 2024

Cited by 3 | Viewed by 1451

Abstract

Compared to other forms of drug administration, the use of Transdermal Drug Delivery Systems (TDDSs) offers significant advantages, including uniform drug release profiles that contribute to lower side effects and higher tolerability, avoidance of direct exposure to the gastrointestinal tract, better patient compliance [...] Read more.

Compared to other forms of drug administration, the use of Transdermal Drug Delivery Systems (TDDSs) offers significant advantages, including uniform drug release profiles that contribute to lower side effects and higher tolerability, avoidance of direct exposure to the gastrointestinal tract, better patient compliance due to their non-invasive means of application and others. Mesoporous silica membranes are of particular interest in this regard, due to their chemical stability and their tunable porous system, with adjustable pore sizes, pore volumes and surface chemistries. While this allows for fine-tuning and, thus, the development of optimized TDDSs with high loading capacities and the desired release profile of a given drug, its systemic availability also relies on skin penetration. In this paper, using a TDDS based on mesoporous silica membranes in Franz cell experiments on porcine skin, we demonstrate surprisingly substantial drug loss during skin penetration. Drug passage through porcine skin was found to be dependent on the age and pre-treatment of the skin. pH and temperature were major determinants of drug recovery rates as well, indicating drug loss in the skin by enzymatic metabolization. Regarding the TDDS, higher loading obtained by SO₃H surface modification of the mesoporous silica membranes reduced drug loss. Still, high loss rates in the skin were determined for different drugs, including anastrozole, xylazine and imiquimod. We conclude that, beyond the fine-tuned drug release profiles from the mesoporous silica membrane TDDS, remarkably high drug loss in the skin is a major issue for achieving desired skin penetration and, thus, the systemic availability of drugs. This also poses critical requirements for defining an optimal TDDS based on mesoporous silica membranes. Full article

(This article belongs to the Special Issue Mesoporous Silica-Based Materials in Drug Delivery and Controlled Release)

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29 pages, 8084 KB

Open AccessEditor’s ChoiceArticle

Local, Sustained, and Targeted Co-Delivery of MEK Inhibitor and Doxorubicin Inhibits Tumor Progression in E-Cadherin-Positive Breast Cancer

by Paul M. Kuhn, Gabriella C. Russo, Ashleigh J. Crawford, Aditya Venkatraman, Nanlan Yang, Bartholomew A. Starich, Zachary Schneiderman, Pei-Hsun Wu, Thi Vo, Denis Wirtz and Efrosini Kokkoli

Pharmaceutics 2024, 16(8), 981; https://doi.org/10.3390/pharmaceutics16080981 - 25 Jul 2024

Cited by 2 | Viewed by 2512

Abstract

Effectively utilizing MEK inhibitors in the clinic remains challenging due to off-target toxicity and lack of predictive biomarkers. Recent findings propose E-cadherin, a breast cancer diagnostic indicator, as a predictor of MEK inhibitor success. To address MEK inhibitor toxicity, traditional methodologies have systemically [...] Read more.

Effectively utilizing MEK inhibitors in the clinic remains challenging due to off-target toxicity and lack of predictive biomarkers. Recent findings propose E-cadherin, a breast cancer diagnostic indicator, as a predictor of MEK inhibitor success. To address MEK inhibitor toxicity, traditional methodologies have systemically delivered nanoparticles, which require frequent, high-dose injections. Here, we present a different approach, employing a thermosensitive, biodegradable hydrogel with functionalized liposomes for local, sustained release of MEK inhibitor PD0325901 and doxorubicin. The poly(δ-valerolactone-co-lactide)-b-poly(ethylene-glycol)-b-poly(δ-valerolactone-co-lactide) triblock co-polymer gels at physiological temperature and has an optimal degradation time in vivo. Liposomes were functionalized with PR_b, a biomimetic peptide targeting the α₅β₁ integrin receptor, which is overexpressed in E-cadherin-positive triple negative breast cancer (TNBC). In various TNBC models, the hydrogel-liposome system delivered via local injection reduced tumor progression and improved animal survival without toxic side effects. Our work presents the first demonstration of local, sustained delivery of MEK inhibitors to E-cadherin-positive tumors alongside traditional chemotherapeutics, offering a safe and promising therapeutic strategy. Full article

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

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19 pages, 4993 KB

Open AccessEditor’s ChoiceArticle

Nanosized Complexes of the Proteolytic Enzyme Serratiopeptidase with Cationic Block Copolymer Micelles Enhance the Proliferation and Migration of Human Cells

by Katya Kamenova, Anna Prancheva, Lyubomira Radeva, Krassimira Yoncheva, Maya M. Zaharieva, Hristo M. Najdenski and Petar D. Petrov

Pharmaceutics 2024, 16(8), 988; https://doi.org/10.3390/pharmaceutics16080988 - 25 Jul 2024

Cited by 4 | Viewed by 1464

Abstract

In this study, we describe the preparation of the cationic block copolymer nanocarriers of the proteolytic enzyme serratiopeptidase (SER). Firstly, an amphiphilic poly(2-(dimethylamino)ethyl methacrylate)-b-poly(ε-caprolactone)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA₉-b-PCL₃₅-b-PDMAEMA₉) triblock copolymer was synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Then, [...] Read more.

In this study, we describe the preparation of the cationic block copolymer nanocarriers of the proteolytic enzyme serratiopeptidase (SER). Firstly, an amphiphilic poly(2-(dimethylamino)ethyl methacrylate)-b-poly(ε-caprolactone)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA₉-b-PCL₃₅-b-PDMAEMA₉) triblock copolymer was synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization. Then, cationic micellar nanocarriers consisting of a PCL hydrophobic core and a PDMAEMA hydrophilic shell were formed by the solvent evaporation method. SER was loaded into the polymeric micelles by electrostatic interaction between the positively charged micellar shell and the negatively charged enzyme molecules. The particle size, zeta potential, and colloid stability of complexes as a function of SER concentration were investigated by dynamic and electrophoretic light scattering. It was found that SER retained its proteolytic activity after immobilization in polymeric carriers. Moreover, the complexes have a concentration-dependent enhancing effect on the proliferation and migration of human keratinocyte HaCaT and gingival fibroblast HGF cells. Full article

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

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18 pages, 3072 KB

Open AccessEditor’s ChoiceArticle

Hyaluronic Acid-Based Nanoparticles Loaded with Rutin as Vasculo-Protective Tools against Anthracycline-Induced Endothelial Damages

by Carla Serri, Vincenzo Quagliariello, Iriczalli Cruz-Maya, Vincenzo Guarino, Nicola Maurea, Paolo Giunchedi, Giovanna Rassu and Elisabetta Gavini

Pharmaceutics 2024, 16(8), 985; https://doi.org/10.3390/pharmaceutics16080985 - 25 Jul 2024

Cited by 4 | Viewed by 1760

Abstract

Anthracycline-based therapies exert endothelial damages through peroxidation and the production of proinflammatory cytokines, resulting in a high risk of cardiovascular complications in cancer patients. Hyaluronic acid-based hybrid nanoparticles (LicpHA) are effective pharmacological tools that can target endothelial cells and deliver drugs or nutraceuticals. [...] Read more.

Anthracycline-based therapies exert endothelial damages through peroxidation and the production of proinflammatory cytokines, resulting in a high risk of cardiovascular complications in cancer patients. Hyaluronic acid-based hybrid nanoparticles (LicpHA) are effective pharmacological tools that can target endothelial cells and deliver drugs or nutraceuticals. This study aimed to prepared and characterized a novel LicpHA loaded with Rutin (LicpHA Rutin), a flavonoid with high antioxidant and anti-inflammatory properties, to protect endothelial cells against epirubicin-mediated endothelial damages. LicpHA Rutin was prepared using phosphatidylcholine, cholesterol, poloxamers, and hyaluronic acid by a modified nanoprecipitation technique. The chemical-physical characterization of the nanoparticles was carried out (size, zeta potential, morphology, stability, thermal analysis, and encapsulation efficiency). Cytotoxicity studies were performed in human endothelial cells exposed to epirubicin alone or in combination with Free-Rutin or LicpHA Rutin. Anti-inflammatory studies were performed through the intracellular quantification of NLRP-3, MyD-88, IL-1β, IL-6, IL17-α, TNF-α, IL-10, and IL-4 using selective ELISA methods. Morphological studies via TEM and image analysis highlighted a heterogeneous population of LicpHA particles with non-spherical shapes (circularity equal to 0.78 ± 0.14), and the particle size was slightly affected by Rutin entrapment (the mean diameter varied from 179 ± 4 nm to 209 ± 4 nm). Thermal analysis and zeta potential analyses confirmed the influence of Rutin on the chemical-physical properties of LicpHA Rutin, mainly indicated by the decrease in the surface negative charge (from −35 ± 1 mV to −30 ± 0.5 mV). Cellular studies demonstrated that LicpHA Rutin significantly reduced cell death and inflammation when compared to epirubicin alone. The levels of intracellular NLRP3, Myd-88, and proinflammatory cytokines were significantly lower in epirubicin + LicpHA Rutin-exposed cells when compared to epirubicin groups (p < 0.001). Hyaluronic acid-based nanoparticles loaded with Rutin exerts significant vasculo-protective properties during exposure to anthracyclines. The overall picture of this study pushes towards preclinical and clinical studies in models of anthracycline-induced vascular damages. Full article

(This article belongs to the Special Issue Advances in Nanotechnology-Based Drug Delivery Systems)

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17 pages, 3181 KB

Open AccessEditor’s ChoiceArticle

Inulin Amphiphilic Copolymer-Based Drug Delivery: Unraveling the Structural Features of Graft Constructs

by Carla Sardo, Giulia Auriemma, Carmela Mazzacano, Claudia Conte, Virgilio Piccolo, Tania Ciaglia, Marta Denel-Bobrowska, Agnieszka B. Olejniczak, Donatella Fiore, Maria Chiara Proto, Patrizia Gazzerro and Rita Patrizia Aquino

Pharmaceutics 2024, 16(8), 971; https://doi.org/10.3390/pharmaceutics16080971 - 23 Jul 2024

Cited by 3 | Viewed by 1651

Abstract

In this study, the structural attributes of nanoparticles obtained by a renewable and non-immunogenic “inulinated” analog of the “pegylated” PLA (PEG-PLA) were examined, together with the potential of these novel nanocarriers in delivering poorly water-soluble drugs. Characterization of INU-PLA assemblies, encompassing critical aggregation [...] Read more.

In this study, the structural attributes of nanoparticles obtained by a renewable and non-immunogenic “inulinated” analog of the “pegylated” PLA (PEG-PLA) were examined, together with the potential of these novel nanocarriers in delivering poorly water-soluble drugs. Characterization of INU-PLA assemblies, encompassing critical aggregation concentration (CAC), NMR, DLS, LDE, and SEM analyses, was conducted to elucidate the core/shell architecture of the carriers and in vitro cyto- and hemo-compatibility were assayed. The entrapment and in vitro delivery of sorafenib tosylate (ST) were also studied. INU-PLA copolymers exhibit distinctive features: (1) Crew-cut aggregates are formed with coronas of 2–4 nm; (2) a threshold surface density of 1 INU/nm² triggers a configuration change; (3) INU surface density influences PLA core dynamics, with hydrophilic segment stretching affecting PLA distribution towards the interface. INU-PLA₂NPs demonstrated an outstanding loading of ST and excellent biological profile, with effective internalization and ST delivery to HepG2 cells, yielding a comparable IC₅₀. Full article

(This article belongs to the Special Issue Supernatural: Delivery of Natural and Biotechnological Actives)

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23 pages, 8493 KB

Open AccessEditor’s ChoiceArticle

Chitosan-Tricarbocyanine-Based Nanogels Were Able to Cross the Blood–Brain Barrier Showing Its Potential as a Targeted Site Delivery Agent

by Emilio Rivera López, Cecilia Samaniego López, Carla C. Spagnuolo, Bruno G. Berardino, Agustina Alaimo and Oscar E. Pérez

Pharmaceutics 2024, 16(7), 964; https://doi.org/10.3390/pharmaceutics16070964 - 21 Jul 2024

Cited by 8 | Viewed by 2211

Abstract

Targeting drugs to the central nervous system (CNS) is challenging due to the presence of the blood–brain barrier (BBB). The cutting edge in nanotechnology generates optimism to overcome the growing challenges in biomedical sciences through the effective engineering of nanogels. The primary objective [...] Read more.

Targeting drugs to the central nervous system (CNS) is challenging due to the presence of the blood–brain barrier (BBB). The cutting edge in nanotechnology generates optimism to overcome the growing challenges in biomedical sciences through the effective engineering of nanogels. The primary objective of the present report was to develop and characterize a biocompatible natural chitosan (CS)-based NG that can be tracked thanks to the tricarbocyanine (CNN) fluorescent probe addition on the biopolymer backbone. FTIR shed light on the chemical groups involved in the CS and CNN interactions and between CNN-CS and tripolyphosphate, the cross-linking agent. Both in vitro and in vivo experiments were carried out to determine if CS-NGs can be utilized as therapeutic delivery vehicles directed towards the brain. An ionic gelation method was chosen to generate cationic CNN-CS-NG. DLS and TEM confirmed that these entities’ sizes fell into the nanoscale. CNN-CS-NG was found to be non-cytotoxic, as determined in the SH-SY5Y neuroblastoma cell line through biocompatibility assays. After cellular internalization, the occurrence of an endo-lysosomal escape (a crucial event for an efficient drug delivery) of CNN-CS-NG was detected. Furthermore, CNN-CS-NG administered intraperitoneally to female CF-1 mice were detected in different brain regions after 2 h of administration, using fluorescence microscopy. To conclude, the obtained findings in the present report can be useful in the field of neuro-nanomedicine when designing drug vehicles with the purpose of delivering drugs to the CNS. Full article

(This article belongs to the Special Issue Recent Progress in Microencapsulation and Nanoencapsulation for Pharmaceutical Applications)

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22 pages, 2852 KB

Open AccessEditor’s ChoiceArticle

Upgrading Mitochondria-Targeting Peptide-Based Nanocomplexes for Zebrafish In Vivo Compatibility Assays

by Rúben Faria, Eric Vivès, Prisca Boisguérin, Simon Descamps, Ângela Sousa and Diana Costa

Pharmaceutics 2024, 16(7), 961; https://doi.org/10.3390/pharmaceutics16070961 - 20 Jul 2024

Cited by 2 | Viewed by 1959

Abstract

The lack of effective delivery systems has slowed the development of mitochondrial gene therapy. Delivery systems based on cell-penetrating peptides (CPPs) like the WRAP (tryptophan and arginine-rich peptide) family conjugated with a mitochondrial targeting sequence (MTS) have emerged as adequate carriers to mediate [...] Read more.

The lack of effective delivery systems has slowed the development of mitochondrial gene therapy. Delivery systems based on cell-penetrating peptides (CPPs) like the WRAP (tryptophan and arginine-rich peptide) family conjugated with a mitochondrial targeting sequence (MTS) have emerged as adequate carriers to mediate gene expression into the mitochondria. In this work, we performed the PEGylation of WRAP/pDNA nanocomplexes and compared them with previously analyzed nanocomplexes such as (KH)₉/pDNA and CpMTP/pDNA. All nanocomplexes exhibited nearly homogeneous sizes between 100 and 350 nm in different environments. The developed complexes were biocompatible and hemocompatible to both human astrocytes and lung smooth muscle cells, ensuring in vivo safety. The nanocomplexes displayed mitochondria targeting ability, as through transfection they preferentially accumulate into the mitochondria of astrocytes and muscle cells to the detriment of cytosol and lysosomes. Moreover, the transfection of these cells with MTS–CPP/pDNA complexes produced significant levels of mitochondrial protein ND1, highlighting their efficient role as gene delivery carriers toward mitochondria. The positive obtained data pave the way for in vivo research. Using confocal microscopy, the cellular internalization capacity of these nanocomplexes in the zebrafish embryo model was assessed. The peptide-based nanocomplexes were easily internalized into zebrafish embryos, do not cause harmful or toxic effects, and do not affect zebrafish’s normal development and growth. These promising results indicate that MTS–CPP complexes are stable nanosystems capable of internalizing in vivo models and do not present associated toxicity. This work, even at an early stage, offers good prospects for continued in vivo zebrafish research to evaluate the performance of nanocomplexes for mitochondrial gene therapy. Full article

(This article belongs to the Special Issue The 15th Anniversary of Pharmaceutics—Advances and Future Trends in Drug Delivery)

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37 pages, 40998 KB

Open AccessEditor’s ChoiceArticle

Development and Evaluation of Docetaxel-Loaded Nanostructured Lipid Carriers for Skin Cancer Therapy

by Florentina-Iuliana Cocoș, Valentina Anuța, Lăcrămioara Popa, Mihaela Violeta Ghica, Mihaela-Alexandra Nica, Mirela Mihăilă, Radu Claudiu Fierăscu, Bogdan Trică, Cristian Andi Nicolae and Cristina-Elena Dinu-Pîrvu

Pharmaceutics 2024, 16(7), 960; https://doi.org/10.3390/pharmaceutics16070960 - 19 Jul 2024

Cited by 9 | Viewed by 2881

Abstract

This study focuses on the design, characterization, and optimization of nanostructured lipid carriers (NLCs) loaded with docetaxel for the treatment of skin cancer. Employing a systematic formulation development process guided by Design of Experiments (DoE) principles, key parameters such as particle size, polydispersity [...] Read more.

This study focuses on the design, characterization, and optimization of nanostructured lipid carriers (NLCs) loaded with docetaxel for the treatment of skin cancer. Employing a systematic formulation development process guided by Design of Experiments (DoE) principles, key parameters such as particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency were optimized to ensure the stability and drug-loading efficacy of the NLCs. Combined XRD and cryo-TEM analysis were employed for NLC nanostructure evaluation, confirming the formation of well-defined nanostructures. In vitro kinetics studies demonstrated controlled and sustained docetaxel release over 48 h, emphasizing the potential for prolonged therapeutic effects. Cytotoxicity assays on human umbilical vein endothelial cells (HUVEC) and SK-MEL-24 melanoma cell line revealed enhanced efficacy against cancer cells, with significant selective cytotoxicity and minimal impact on normal cells. This multidimensional approach, encompassing formulation optimization and comprehensive characterization, positions the docetaxel-loaded NLCs as promising candidates for advanced skin cancer therapy. The findings underscore the potential translational impact of these nanocarriers, paving the way for future preclinical investigations and clinical applications in skin cancer treatment. Full article

(This article belongs to the Special Issue Nano-Based Drug Delivery System: Recent Developments and Future Prospects)

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25 pages, 3975 KB

Open AccessEditor’s ChoiceArticle

Exploring a New Generation of Pyrimidine and Pyridine Derivatives as Anti-Influenza Agents Targeting the Polymerase PA–PB1 Subunits Interaction

by Ilaria Giacchello, Annarita Cianciusi, Chiara Bertagnin, Anna Bonomini, Valeria Francesconi, Mattia Mori, Anna Carbone, Francesca Musumeci, Arianna Loregian and Silvia Schenone

Pharmaceutics 2024, 16(7), 954; https://doi.org/10.3390/pharmaceutics16070954 - 18 Jul 2024

Cited by 2 | Viewed by 2047

Abstract

The limited range of available flu treatments due to virus mutations and drug resistance have prompted the search for new therapies. RNA-dependent RNA polymerase (RdRp) is a heterotrimeric complex of three subunits, i.e., polymerase acidic protein (PA) and polymerase basic proteins 1 and [...] Read more.

The limited range of available flu treatments due to virus mutations and drug resistance have prompted the search for new therapies. RNA-dependent RNA polymerase (RdRp) is a heterotrimeric complex of three subunits, i.e., polymerase acidic protein (PA) and polymerase basic proteins 1 and 2 (PB1 and PB2). It is widely recognized as one of the most promising anti-flu targets because of its critical role in influenza infection and high amino acid conservation. In particular, the disruption of RdRp complex assembly through protein–protein interaction (PPI) inhibition has emerged as a valuable strategy for discovering a new therapy. Our group previously identified the 3-cyano-4,6-diphenyl-pyridine core as a privileged scaffold for developing PA–PB1 PPI inhibitors. Encouraged by these findings, we synthesized a small library of pyridine and pyrimidine derivatives decorated with a thio-N-(m-tolyl)acetamide side chain (compounds 2a–n) or several amino acid groups (compounds 3a–n) at the C2 position. Interestingly, derivative 2d, characterized by a pyrimidine core and a phenyl and 4-chloro phenyl ring at the C4 and C6 positions, respectively, showed an IC₅₀ value of 90.1 μM in PA–PB1 ELISA, an EC₅₀ value of 2.8 μM in PRA, and a favorable cytotoxic profile, emerging as a significant breakthrough in the pursuit of new PPI inhibitors. A molecular modeling study was also completed as part of this project, allowing us to clarify the biological profile of these compounds. Full article

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

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21 pages, 1156 KB

Open AccessEditor’s ChoiceReview

Low-Density Lipoprotein Receptor-Related Protein 1 as a Potential Therapeutic Target in Alzheimer’s Disease

by Sabrina Petralla, Maria Panayotova, Elisa Franchina, Gert Fricker and Elena Puris

Pharmaceutics 2024, 16(7), 948; https://doi.org/10.3390/pharmaceutics16070948 - 17 Jul 2024

Cited by 19 | Viewed by 5788

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease impacting the lives of millions of people worldwide. The formation of amyloid β (Aβ) plagues in the brain is the main pathological hallmark of AD. The Aβ deposits are formed due to the imbalance between [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease impacting the lives of millions of people worldwide. The formation of amyloid β (Aβ) plagues in the brain is the main pathological hallmark of AD. The Aβ deposits are formed due to the imbalance between the production and Aβ clearance in the brain and across the blood–brain barrier (BBB). In this respect, low-density lipoprotein receptor-related protein 1 (LRP1) plays a significant role by mediating both brain Aβ production and clearance. Due to its important role in AD pathogenesis, LRP1 is considered an attractive drug target for AD therapies. In the present review, we summarize the current knowledge about the role of LRP1 in AD pathogenesis as well as recent findings on changes in LRP1 expression and function in AD. Finally, we discuss the advances in utilizing LRP1 as a drug target for AD treatments as well as future perspectives on LRP1 research. Full article

(This article belongs to the Special Issue New Discoveries in Drug Targets and Delivery for Alzheimer’s Disease)

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22 pages, 7760 KB

Open AccessEditor’s ChoiceReview

Chemodynamic Therapy of Glioblastoma Multiforme and Perspectives

by Zia Ullah, Yasir Abbas, Jingsi Gu, Sai Ko Soe, Shubham Roy, Tingting Peng and Bing Guo

Pharmaceutics 2024, 16(7), 942; https://doi.org/10.3390/pharmaceutics16070942 - 15 Jul 2024

Cited by 3 | Viewed by 2833

Abstract

Glioblastoma multiforme (GBM), a potential public health issue, is a huge challenge for the advanced scientific realm to solve. Chemodynamic therapy (CDT) based on the Fenton reaction emerged as a state-of-the-art therapeutic modality to treat GBM. However, crossing the blood–brain barrier (BBB) to [...] Read more.

Glioblastoma multiforme (GBM), a potential public health issue, is a huge challenge for the advanced scientific realm to solve. Chemodynamic therapy (CDT) based on the Fenton reaction emerged as a state-of-the-art therapeutic modality to treat GBM. However, crossing the blood–brain barrier (BBB) to reach the GBM is another endless marathon. In this review, the physiology of the BBB has been elaborated to understand the mechanism of crossing these potential barriers to treat GBM. Moreover, the designing of Fenton-based nanomaterials has been discussed for the production of reactive oxygen species in the tumor area to eradicate the cancer cells. For effective tumor targeting, biological nanomaterials that can cross the BBB via neurovascular transport channels have also been explored. To overcome the neurotoxicity caused by inorganic nanomaterials, the use of smart nanoagents having both enhanced biocompatibility and effective tumor targeting ability to enhance the efficiency of CDT are systematically summarized. Finally, the advancements in intelligent Fenton-based nanosystems for a multimodal therapeutic approach in addition to CDT are demonstrated. Hopefully, this systematic review will provide a better understanding of Fenton-based CDT and insight into GBM treatment. Full article

(This article belongs to the Special Issue Recent Advances in NIR-II Fluorescence Imaging-Based Cancer Treatment)

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20 pages, 4385 KB

Open AccessEditor’s ChoiceReview

Recent Advances in Photodynamic Therapy: Metal-Based Nanoparticles as Tools to Improve Cancer Therapy

by Stefania Mariano, Elisabetta Carata, Lucio Calcagnile and Elisa Panzarini

Pharmaceutics 2024, 16(7), 932; https://doi.org/10.3390/pharmaceutics16070932 - 12 Jul 2024

Cited by 17 | Viewed by 3524

Abstract

Cancer remains a significant global health challenge, with traditional therapies like surgery, chemotherapy, and radiation often accompanied by systemic toxicity and damage to healthy tissues. Despite progress in treatment, these approaches have limitations such as non-specific targeting, systemic toxicity, and resistance development in [...] Read more.

Cancer remains a significant global health challenge, with traditional therapies like surgery, chemotherapy, and radiation often accompanied by systemic toxicity and damage to healthy tissues. Despite progress in treatment, these approaches have limitations such as non-specific targeting, systemic toxicity, and resistance development in cancer cells. In recent years, nanotechnology has emerged as a revolutionary frontier in cancer therapy, offering potential solutions to these challenges. Nanoparticles, due to their unique physical and chemical properties, can carry therapeutic payloads, navigate biological barriers, and selectively target cancer cells. Metal-based nanoparticles, in particular, offer unique properties suitable for various therapeutic applications. Recent advancements have focused on the integration of metal-based nanoparticles to enhance the efficacy and precision of photodynamic therapy. Integrating nanotechnology into cancer therapy represents a paradigm shift, enabling the development of strategies with enhanced specificity and reduced off-target effects. This review aims to provide a comprehensive understanding of the pivotal role of metal-based nanoparticles in photodynamic therapy. We explore the mechanisms, biocompatibility, and applications of metal-based nanoparticles in photodynamic therapy, highlighting the challenges and the limitations in their use, as well as the combining of metal-based nanoparticles/photodynamic therapy with other strategies as a synergistic therapeutic approach for cancer treatment. Full article

(This article belongs to the Special Issue Metal-Based Nanoparticles for Pharmaceutical Applications)

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20 pages, 2207 KB

Open AccessEditor’s ChoiceArticle

Pharmacokinetics and Enterohepatic Circulation of 2-(Quinoline-8-carboxamido)benzoic Acid (2-QBA) in Mice

by Ji-Hyeon Jeon, So-Yeon Jeon, Yeon-Ju Baek, Chan-E Park, Min-Koo Choi, Young Taek Han and Im-Sook Song

Pharmaceutics 2024, 16(7), 934; https://doi.org/10.3390/pharmaceutics16070934 - 12 Jul 2024

Cited by 2 | Viewed by 1833

Abstract

The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson’s disease. We developed an analytical method for 2-QBA using a liquid chromatography–tandem mass spectrometry [...] Read more.

The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson’s disease. We developed an analytical method for 2-QBA using a liquid chromatography–tandem mass spectrometry (LC-MS/MS) in mouse plasma, in which a protein precipitation method for the sample preparation of 2-QBA in mouse plasma was used due to its simplicity and good extraction recovery rates (80.49–97.56%). The linearity of the calibration standard sample, inter- and intraday precision and accuracy, and stability of three quality control samples were suitable based on the assessment criteria and the lower limit of quantification (LLOQ) of the 2-QBA was 1 ng/mL. A pharmacokinetic study of 2-QBA was performed in mice divided into oral (2.0, 5.0, and 15 mg/kg) and intravenous (0.5 and 1.0 mg/kg) administration groups. The absolute oral bioavailability (BA) range of 2-QBA was calculated as 68.3–83.7%. Secondary peaks were observed at approximately 4–8 h after the oral administration of 2-QBA at all doses. The elimination half-life of the orally administered 2-QBA was significantly longer than that of the intravenous 2-QBA. In addition, glucuronide metabolites of 2-QBA were identified. They were transformed into 2-QBA using the β-glucuronidase treatment. Furthermore, the 2-QBA was readily absorbed from the jejunum to lower ileum. Taken together, the secondary peaks could be explained by the enterohepatic circulation of 2-QBA. In conclusion, the reabsorption of orally administered 2-QBA could contribute to the high oral BA of 2-QBA and could be beneficial for the efficacy of 2-QBA. Moreover, the simple and validated analytical method for 2-QBA using LC-MS/MS was applied to the pharmacokinetic study and BA assessments of 2-QBA in mice and would be helpful for subsequent pharmacokinetic studies, as well as for evaluations of the toxicokinetics and pharmacokinetic–pharmacodynamic correlation of 2-QBA to assess its potential as a drug. Full article

(This article belongs to the Special Issue Bioanalysis and Metabolomics, 2nd Edition)

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19 pages, 8763 KB

Open AccessEditor’s ChoiceArticle

pH-Triggered Hydrogel Nanoparticles for Efficient Anticancer Drug Delivery and Bioimaging Applications

by Keristina Wagdi K. Amin, Ágota Deák, Miklós Csanády, Jr., Nikoletta Szemerédi, Diána Szabó, Árpád Turcsányi, Ditta Ungor, Gabriella Spengler, László Rovó and László Janovák

Pharmaceutics 2024, 16(7), 931; https://doi.org/10.3390/pharmaceutics16070931 - 11 Jul 2024

Cited by 4 | Viewed by 2051

Abstract

In this work, we developed multifunctional hydrogel nanoparticles (NPs) that can encapsulate anticancer drugs and imaging contrast agents as well. Mitomycin C (MMC) and rhodamine B (RB) were selected as models for anticancer drugs and imaging contrasting agents, respectively. Both MMC and RB [...] Read more.

In this work, we developed multifunctional hydrogel nanoparticles (NPs) that can encapsulate anticancer drugs and imaging contrast agents as well. Mitomycin C (MMC) and rhodamine B (RB) were selected as models for anticancer drugs and imaging contrasting agents, respectively. Both MMC and RB were linked to the succinated polyvinyl alcohol polymer (PVA-SA). The selected labeled hydrogel NPs ((0.5% RB)-PVA-SA NPs and (1.5% RB)-PVA-SA NPs) improved the RB quantum yield from 29.8% to a minimum of 42.7%. Moreover, they showed higher emission stability compared to free RB when they were repeatedly excited at 554 nm for 2 h. Furthermore, the dye polymeric interactions significantly increased the RB fluorescence lifetime by approximately twofold. All these optical properties pave the way for our labeled hydrogel NPs to be used in imaging-guided therapy. For the labeled MMC-loaded NPs, the MMC-binding efficiency was found to be exceedingly high in all synthesized samples: a minimum of 92% was achieved. In addition, the obtained pH-dependent drug release profiles as well as the cytotoxicity evaluation demonstrated the high potential of releasing MMC under acidic cancerous conditions. Moreover, the in vitro cellular uptake experiment confirmed the accumulation of MMC NPs throughout the cytoplasm. Full article

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

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