Pharmaceutics

37 pages, 10326 KiB

Open AccessReview

Application of Natural Products in Neurodegenerative Diseases by Intranasal Administration: A Review

by Yu Jin, Xinyu Ma, Shuo Liu, Shiyu Zong, Yunlong Cheng, Hong Zhang, Chunliu Wang and Ye Li

Pharmaceutics 2025, 17(5), 675; https://doi.org/10.3390/pharmaceutics17050675 - 20 May 2025

Abstract

Natural products derived from traditional Chinese medicine have received significant attention as potential treatments for neurodegenerative disorders due to their wide availability, demonstrated efficacy, and favorable safety profiles. Intranasal delivery provides distinct advantages for targeting the central nervous system (CNS), enabling direct therapeutic [...] Read more.

Natural products derived from traditional Chinese medicine have received significant attention as potential treatments for neurodegenerative disorders due to their wide availability, demonstrated efficacy, and favorable safety profiles. Intranasal delivery provides distinct advantages for targeting the central nervous system (CNS), enabling direct therapeutic agent delivery to the brain by bypassing the blood-brain barrier (BBB). This review evaluates natural products administered intranasally for neurodegenerative diseases (NDs), highlighting their therapeutic potential and addressing formulation challenges related to physicochemical properties. Strategic optimization approaches are proposed, including novel carrier systems, molecular modifications, and combination therapies. By discussing current difficulties and offering practical recommendations, this review aims to encourage further scholarly research and clinical application. Full article

(This article belongs to the Special Issue Advanced Drug Delivery across the Blood–Brain Barrier)

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14 pages, 4392 KiB

Open AccessArticle

Evaluation of Indigo Naturalis Prepared Using a Novel Method: Therapeutic Effects on Experimental Ulcerative Colitis in Mice

by Xianxiang Xu, Lin Lin, Wenjie Ning, Xinyi Zhou, Aftab Ullah, Huiyong Yang, Xunxun Wu and Yong Diao

Pharmaceutics 2025, 17(5), 674; https://doi.org/10.3390/pharmaceutics17050674 - 20 May 2025

Abstract

Background/Objectives: Indigo naturalis (IN) is a traditional Chinese medicine concocted from medicinal plants such as Baphicacanthus cusia (Nees) Bremek. IN has multifaceted pharmacological activities. Recent research highlights the remarkable efficacy of IN in treating ulcerative colitis (UC). This study investigates the efficacy [...] Read more.

Background/Objectives: Indigo naturalis (IN) is a traditional Chinese medicine concocted from medicinal plants such as Baphicacanthus cusia (Nees) Bremek. IN has multifaceted pharmacological activities. Recent research highlights the remarkable efficacy of IN in treating ulcerative colitis (UC). This study investigates the efficacy of Indigo Naturalis prepared using a novel method (NIN) in ameliorating UC. Methods: We have developed a new IN processing technology without the use of lime. Correspondingly, the content of active ingredients has relatively increased in NIN. In this study, dextran sulfate sodium salt (DSS) induced UC models among male KM mice, and the protective effects of NIN on UC were verified. Results: NIN could significantly improve weight loss, diarrhea and prolapse, bloody stools, elevated Disease Activity Index (DAI) and alleviate the colitis symptoms of mice; it could also improve the shortening of colon, disappearance of intestinal crypts, epithelial cell destruction and inflammatory infiltration caused by UC; and it could also significantly reduce the Histological Index (HI). In addition, NIN relieved the inflammatory response by decreasing the content of pro-inflammatory cytokines TNF-α and IL-1β and elevating the content of anti-inflammatory cytokines IL-10 and IL-22. It also restored the intestinal mucosal barrier by increasing the level of MUC2 protein expression at the site of colonic injury. Conclusions: The significant effects of NIN on UC were verified for the first time, suggesting that NIN was worth further developing into a novel therapeutic drug and, necessarily, further safety evaluations and comparisons with traditional IN will help in the application of NIN. Full article

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29 pages, 1604 KiB

Open AccessReview

Herbal Medicine: Enhancing the Anticancer Potential of Natural Products in Hepatocellular Carcinoma Therapy Through Advanced Drug Delivery Systems

by Ghazala Muteeb, Manar T. El-Morsy, Mustafa Ali Abo-Taleb, Salma K. Mohamed and Doaa S. R. Khafaga

Pharmaceutics 2025, 17(5), 673; https://doi.org/10.3390/pharmaceutics17050673 - 20 May 2025

Abstract

Hepatocellular carcinoma (HCC) is an aggressive and prevalent liver cancer with a poor prognosis. Nanotechnology combined with natural products has emerged as a promising strategy to enhance HCC treatment efficacy. This review assesses the current literature on the application of nanotechnology in delivering [...] Read more.

Hepatocellular carcinoma (HCC) is an aggressive and prevalent liver cancer with a poor prognosis. Nanotechnology combined with natural products has emerged as a promising strategy to enhance HCC treatment efficacy. This review assesses the current literature on the application of nanotechnology in delivering natural products for HCC therapy. A comprehensive search was conducted in PubMed, Science Direct, Web of Science, and Google Scholar to identify relevant studies published up to the present articles focusing on nanotechnology-based drug delivery systems using natural products for HCC therapy, including different nanoparticle (NP) formulations and therapeutic interventions, were included. Natural products with anticancer properties have been encapsulated using various nanocarriers such as liposomes, polymeric nanoparticles, and quantum dots, which have improved drug stability, prolonged circulation time, and enhanced targeted delivery to HCC cells. These advancements have led to increased therapeutic efficacy and reduced side effects. Additionally, combining multiple natural products or integrating them with conventional therapies via nanocarriers enables personalized treatment approaches based on patient characteristics and molecular profiles. The integration of nanotechnology with natural products shows great potential for improving HCC treatment outcomes, representing a significant advancement in precision medicine for liver cancer and paving the way for more effective and personalized therapeutic strategies. Full article

(This article belongs to the Special Issue Application of Phytochemicals in Innovative Drug Delivery Systems and Formulations)

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24 pages, 2554 KiB

Open AccessArticle

Phytosynthesis and Characterization of Silver Nanoparticles from Antigonon leptopus: Assessment of Antibacterial and Cytotoxic Properties

by Marisol Gastelum-Cabrera, Pablo Mendez-Pfeiffer, Manuel G. Ballesteros-Monrreal, Brenda Velasco-Rodríguez, Patricia D. Martínez-Flores, Sergio Silva-Bea, Vicente Domínguez-Arca, Gerardo Prieto, Silvia Barbosa, Ana Otero, Pablo Taboada and Josué Juárez

Pharmaceutics 2025, 17(5), 672; https://doi.org/10.3390/pharmaceutics17050672 - 20 May 2025

Abstract

Background: Silver nanoparticles (AgNPs) show promises as antimicrobial biomaterials with use for combating multidrug-resistant microorganisms, and they are widely used in healthcare, medicine, and food industries. However, traditional physicochemical synthesis methods often require harsh conditions and toxic reagents, generating harmful waste. The synthesis [...] Read more.

Background: Silver nanoparticles (AgNPs) show promises as antimicrobial biomaterials with use for combating multidrug-resistant microorganisms, and they are widely used in healthcare, medicine, and food industries. However, traditional physicochemical synthesis methods often require harsh conditions and toxic reagents, generating harmful waste. The synthesis of AgNPs using plant-derived bioactive compounds offers an eco-friendly alternative to conventional methods. Methods: In this study, a bio-green approach was employed to synthesize AgNPs using ethanolic extracts from Antigonon leptopus leaves (EXT-AL). The synthesis was optimized under different pH conditions (5.5, 8.0, 10.0) and EXT-AL concentrations (10–200 μg/mL). Antibacterial activity was evaluated against Escherichia coli and Staphylococcus aureus, and cytotoxicity was assessed in HeLa, CaCo-2, T731-GFP, and HaCaT cell lines. Results: UV-Vis spectroscopy confirmed nanoparticle formation, with a surface plasmon resonance peak at 410 nm. Alkaline conditions (pH 10.0) favored the formation of smaller, spherical AgNPs. Characterization by DLS, TEM, and AFM revealed uniform nanoparticles with a hydrodynamic diameter of 93.48 ± 1.88 nm and a zeta potential of −37.80 ± 1.28 mV. The AgNPs remained stable in Milli-Q water but tended to aggregate in PBS, DMEM, and MHB media. Antibacterial assays demonstrated significant bactericidal activity against Escherichia coli and Staphylococcus aureus at 3.9 μg/mL (Ag⁺ equivalent). Cytotoxicity tests showed no toxicity to HeLa, T731-GFP, CaCo-2, or HaCaT cells at concentrations ≥ 7.8 μg/mL after 24 h. Conclusions: These findings highlight Antigonon leptopus extract as a sustainable and cost-effective resource for AgNPs synthesis, with strong antimicrobial properties and potential biomedical applications. Full article

(This article belongs to the Special Issue Functional Bionanomaterials: Perspectives in Respiratory Disease Applications)

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25 pages, 4044 KiB

Open AccessArticle

Preparation and Characterization of Ternary Complexes to Improve the Solubility and Dissolution Performance of a Proteolysis-Targeting Chimera Drug

by Heng Zhang, Hengqian Wu, Lili Wang, Laura Machín Galarza, Chuanyu Wu, Mingzhong Li, Zhengping Wang, Erpeng Zhou and Jun Han

Pharmaceutics 2025, 17(5), 671; https://doi.org/10.3390/pharmaceutics17050671 - 20 May 2025

Abstract

Background/Objectives: Proteolysis-targeting chimeras (PROTACs) have shown significant potential in the treatment of intractable diseases. However, their clinical applications are limited by poor water solubility and permeability. In this study, the cyclodextrin inclusion method was employed for the first time to prepare the PROTAC-CD [...] Read more.

Background/Objectives: Proteolysis-targeting chimeras (PROTACs) have shown significant potential in the treatment of intractable diseases. However, their clinical applications are limited by poor water solubility and permeability. In this study, the cyclodextrin inclusion method was employed for the first time to prepare the PROTAC-CD complex with the aim of improving the dissolution of a PROTAC drug (LC001). Methods: Initially, sulfobutyl ether-β-cyclodextrin (SBE-β-CD) was selected to improve the solubility of LC001. The polymer TPGS was screened based on the phase solubility method to enhance the efficiency of complexation and solubilization capacity, and its ratio with SBE-β-CD was optimized. The ternary complex was prepared by lyophilization with an SBE-β-CD/TPGS molar ratio of 1:0.03. Differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy results confirmed the formation of an amorphous complex. Fourier-transform infrared and molecular docking simulations indicated the formation of hydrogen bond interactions between components. Results: The results showed that the ternary complexes significantly improved the dissolution rate and release amount of LC001 in PBS (pH 6.8) and were unaffected by changes in gastric pH compared to the binary complexes and physical mixtures. The lack of crystal structure in the lyophilized particles and the formation of nano aggregates in solution may be the reasons for the improved dissolution of the ternary complex. Conclusions: In conclusion, the addition of TPGS to the LC001-SBE-β-CD binary system has a synergistic effect on improving the solubility and dissolution of LC001. This ternary complex is a promising formulation for enhancing the dissolution of LC001. Full article

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

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17 pages, 5406 KiB

Open AccessArticle

Developing the Oxalate, Fumarate and Succinate Salts of Tetrabenazine: Solid-State Characterization and Solubility

by Marieta Muresan-Pop, Viorica Simon, Gheorghe Borodi and Alexandru Turza

Pharmaceutics 2025, 17(5), 670; https://doi.org/10.3390/pharmaceutics17050670 - 20 May 2025

Abstract

Background: Tetrabenazine (brand name Nitoman and Xenazine) is a compound used to treat neurological and psychiatric disorders. Due to its low solubility, this drug is administered to patients in high doses, which produces side effects. Methods: To overcome these deficiencies, we [...] Read more.

Background: Tetrabenazine (brand name Nitoman and Xenazine) is a compound used to treat neurological and psychiatric disorders. Due to its low solubility, this drug is administered to patients in high doses, which produces side effects. Methods: To overcome these deficiencies, we prepared, using the mechanochemical method, three salts of tetrabenazine with three coformers: oxalic, fumaric, and succinic acid. The new solid forms were identified by X-ray powder diffraction (XRPD). Results: Full structural characterization was performed by single-crystal X-ray diffraction (SC-XRD), which revealed that the supramolecular interactions in the new solid forms were achieved by proton transfer between the coformer and the nitrogen of the tetrabenazine molecule. The salts formation was also evidenced by thermal analyses (DSC) and infrared spectroscopy (FTIR). Furthermore, the physical stability of the salts was evaluated under extreme temperature and humidity conditions. Conclusions: From a pharmaceutical perspective, UV-VIS tests of the new salts dissolved in water revealed a significant improvement in their solubility, which could improve their bioavailability in therapeutic applications. Full article

(This article belongs to the Special Issue Pharmaceutical Polymorphs and Cocrystals and Their In Vitro and In Vivo Evaluation)

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23 pages, 2553 KiB

Open AccessArticle

A Green Integrated Approach to Multifunctional Silver Nanoparticles Derived from Aronia melanocarpa

by Andreia Corciova, Cornelia Mircea, Adrian Fifere, Ioana-Andreea Turin Moleavin, Ana Flavia Burlec, Bianca Ivanescu, Ana-Maria Vlase, Monica Hancianu and Irina Macovei

Pharmaceutics 2025, 17(5), 669; https://doi.org/10.3390/pharmaceutics17050669 - 20 May 2025

Abstract

Background/Objectives: This study reports the green synthesis, optimization, characterization, and multifunctional evaluation of silver nanoparticles (AgNPs) using an ethanolic Aronia melanocarpa berry extract. The objective was to establish optimal synthesis conditions; assess the in vitro stability; and evaluate the antioxidant, photocatalytic, and photoprotective [...] Read more.

Background/Objectives: This study reports the green synthesis, optimization, characterization, and multifunctional evaluation of silver nanoparticles (AgNPs) using an ethanolic Aronia melanocarpa berry extract. The objective was to establish optimal synthesis conditions; assess the in vitro stability; and evaluate the antioxidant, photocatalytic, and photoprotective activities. Methods: The cytogenotoxic effects of the AgNPs were evaluated on Triticum aestivum roots. The AgNPs were synthesized via bioreduction using an ethanolic extract of A. melanocarpa under varied pH, AgNO₃ concentration, extract/AgNO₃ ratio, temperature, and stirring time, with optimization guided by UV–Vis spectral analysis. The AgNPs were further characterized by FTIR, DLS, TEM, and EDX. In vitro stability was evaluated over six months in different dispersion media (ultrapure water; 5% NaCl; and PBS at pH 6, 7, and 8). Biological assessments included antioxidant assays (lipoxygenase inhibition, DPPH radical scavenging, metal chelation, and hydroxyl radical scavenging), photocatalytic dye degradation, and SPF determination. Results: Optimal synthesis was achieved at pH 8, 3 mM AgNO₃, extract/AgNO₃ ratio of 1:9, 40 °C, and 240 min stirring. The AgNPs were spherical (TEM), well dispersed (PDI = 0.32), and highly stable (zeta potential = −40.71 mV). PBS pH 6 and 7 ensured the best long-term colloidal stability. The AgNPs displayed strong dose-dependent antioxidant activity, with superior lipoxygenase inhibition (EC₅₀ = 18.29 µg/mL) and the effective photocatalytic degradation of dyes under sunlight. Photoprotective properties were confirmed through UV absorption analysis. The AgNPs showed a strong antimitotic effect on wheat root cells. Conclusions: The study demonstrates that A. melanocarpa-mediated AgNPs are stable, biologically active, and suitable for potential biomedical, cosmetic, and environmental applications, reinforcing the relevance of plant-based nanotechnology. Full article

(This article belongs to the Special Issue Advances in Bioactive Compounds and Nanotechnology: Sustainable Approaches for Pharmaceutical Applications)

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15 pages, 1485 KiB

Open AccessArticle

Novel Delivery of Cyclic-Diguanylate Monophosphate Utilizing Amyloid Depots

by Maytham Ismail, Benjamin Beluzo, Sergei Chuikov, Venkateshwar G. Keshamouni and Mathumai Kanapathipillai

Pharmaceutics 2025, 17(5), 668; https://doi.org/10.3390/pharmaceutics17050668 - 19 May 2025

Abstract

Background: Recently, cyclic diguanylate monophosphate (c-di-GMP) drug delivery has garnered interest due to its potential in cancer immune modulation. In this pilot study, we developed a novel c-di-GMP formulation based on peptide amyloids. The amyloid depots were formed by combining an amyloidogenic prone [...] Read more.

Background: Recently, cyclic diguanylate monophosphate (c-di-GMP) drug delivery has garnered interest due to its potential in cancer immune modulation. In this pilot study, we developed a novel c-di-GMP formulation based on peptide amyloids. The amyloid depots were formed by combining an amyloidogenic prone 12 amino acid peptide sequence of receptor-interacting protein kinase 3 (RIP3) with cationic lipid ALC-0315, or using lysozyme proteins. Both RIP3 and lysozyme proteins have intrinsic physiological functions. This is the first time intrinsic peptides/protein-based amyloids have been explored for c-di-GMP delivery. The main goal was to evaluate how these amyloid depots could enhance c-di-GMP drug delivery and modulate responses in RAW 264.7 macrophage-like cells. Methods: Physicochemical characterization and cellular assays were utilized to characterize the amyloid structures and assess the efficacy. Results: Our results show that amyloid aggregates significantly improve the therapeutic efficacy of c-di-GMP. When RAW 264.7 cells were treated with c-di-GMP amyloids, we observed at least a 1.5-fold change in IL-6 expression, nitric oxide (NO) production, and reactive oxygen species (ROS) production compared to treatment with 5x free c-di-GMP treatment, which suggests that this system holds promise for enhanced therapeutic effects. Conclusions: Overall, these findings emphasize the potential of amyloid-based delivery systems as a promising approach for c-di-GMP delivery, warranting further investigations into their potential in therapeutic applications. Full article

(This article belongs to the Special Issue Advances in Delivery of Peptides and Proteins)

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14 pages, 1409 KiB

Open AccessArticle

Production, Validation, and Exposure Dose Measurement of [¹³N]Ammonia Under Academic Good Manufacturing Practice Environments

by Katsumi Tomiyoshi, Yuta Namiki, David J. Yang and Tomio Inoue

Pharmaceutics 2025, 17(5), 667; https://doi.org/10.3390/pharmaceutics17050667 - 19 May 2025

Abstract

Objective: Current good manufacturing practice (cGMP) guidance for positron emission tomography (PET) drugs has been established in Europe and the United States. In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) approved the use of radiosynthesizers as medical devices for the in-house manufacturing [...] Read more.

Objective: Current good manufacturing practice (cGMP) guidance for positron emission tomography (PET) drugs has been established in Europe and the United States. In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) approved the use of radiosynthesizers as medical devices for the in-house manufacturing of PET drugs in hospitals and clinics, regardless of the cGMP environment. Without adequate facilities, equipment, and personnel required by cGMP regulations, the quality assurance (QA) and clinical effectiveness of PET drugs largely depend on the radiosynthesizers themselves. To bridge the gap between radiochemistry standardization and site qualification, the Japanese Society of Nuclear Medicine (JSNM) has issued guidance for the in-house manufacturing of small-scale PET drugs under academic GMP (a-GMP) environments. The goals of cGMP and a-GMP are different: cGMP focuses on process optimization, certification, and commercialization, while a-GMP facilitates the small-scale, in-house production of PET drugs for clinical trials and patient-specific standard of care. Among PET isotopes, N-13 has a short half-life (10 min) and must be synthesized on site. [¹³N]Ammonia ([¹³N]NH₃) is used for myocardial perfusion imaging under the Japan Health Insurance System (JHIS) and was thus selected as a working example for the manufacturing of PET drugs in an a-GMP environment. Methods: A [¹³N]NH₃-radiosynthesizer was installed in a hot cell within an a-GMP-compliant radiopharmacy unit. To comply with a-GMP regulations, the air flow was adjusted through HEPA filters. All cabinets and cells were disinfected to ensure sterility once a month. Standard operating procedures (SOPs) were applied, including analytical methods. Batch records, QA data, and radiation exposure to staff in the synthesis of [¹³N]NH₃ were measured and documented. Results: 2.52 GBq of [¹³N]NH₃ end-of-synthesis (EOS) was obtained in an average of 13.5 min in 15 production runs. The radiochemical purity was more than 99%. Exposure doses were 11 µSv for one production run and 22 µSv for two production runs. The pre-irradiation background dose rate was 0.12 µSv/h. After irradiation, the exposed dosage in the front of the hot cell was 0.15 µSv/h. The leakage dosage measured at the bench was 0.16 µSv/h. The exposure and leakage dosages in the manufacturing of [¹³N]NH₃ were similar to the background level as measured by radiation monitoring systems in an a-GMP environments. All QAs, environmental data, bacteria assays, and particulates met a-GMP compliance standards. Conclusions: In-house a-GMP environments require dedicated radiosynthesizers, documentation for batch records, validation schedules, radiation protection monitoring, air and particulate systems, and accountable personnel. In this study, the in-house manufacturing of [¹³N]NH₃ under a-GMP conditions was successfully demonstrated. These findings support the international harmonization of small-scale PET drug manufacturing in hospitals and clinics for future multi-center clinical trials and the development of a standard of care. Full article

(This article belongs to the Special Issue Applications of Stable Nuclide and Radionuclides in the Area of Pharmacokinetic Process Control and Targeted Drug Therapy)

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17 pages, 957 KiB

Open AccessReview

Exploring the Analgesic Potential of L-Lysine: Molecular Mechanisms, Preclinical Evidence, and Implications for Pharmaceutical Pain Therapy

by Walaa Alibrahem, Nihad Kharrat Helu, Gréta Törős, Csaba Oláh and József Prokisch

Pharmaceutics 2025, 17(5), 666; https://doi.org/10.3390/pharmaceutics17050666 - 19 May 2025

Abstract

Pain is a complex, multifaceted sensory–emotional state. It still poses a significant challenge in clinical treatment, especially in cases of chronic pain. Concerns associated with the use of opioids as analgesics have led to the search for new and safer pain relievers. This [...] Read more.

Pain is a complex, multifaceted sensory–emotional state. It still poses a significant challenge in clinical treatment, especially in cases of chronic pain. Concerns associated with the use of opioids as analgesics have led to the search for new and safer pain relievers. This review examines the potential of lysine in pain control by exploring its molecular mechanisms and the preclinical evidence and clinical implications. Lysine has demonstrated analgesic effects by inhibiting NMDA receptors, modulating dopamine and serotonin pathways, and interfering with neuroimmune signaling cascades. Studies in animal models have shown that the administration of lysine reduces pain responses without altering motor function. Despite the favorable profile of lysine in terms of minor side effects and its promising effectiveness as a nutritional supplement, more research is needed to optimize its efficacy, adjust its dosage, and ensure its safety for long-term use. Full article

(This article belongs to the Section Biopharmaceutics)

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17 pages, 4503 KiB

Open AccessSystematic Review

Evaluation of the Effectiveness of Chitosan-Modified Bone Regeneration Materials: A Systematic Review

by Tsvetalina Gerova-Vatsova, Stefan Peev, Ralitsa Yotsova and Varvara-Velika Rogova

Pharmaceutics 2025, 17(5), 665; https://doi.org/10.3390/pharmaceutics17050665 - 18 May 2025

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Abstract

Background/Objectives: Today, regenerative therapy is routinely utilized in both medical and dental practices. Its outstanding results are due to the continuous development of technology and the invention of modern, more advanced biomaterials. The overarching idea in current regenerative therapy has shifted in [...] Read more.

Background/Objectives: Today, regenerative therapy is routinely utilized in both medical and dental practices. Its outstanding results are due to the continuous development of technology and the invention of modern, more advanced biomaterials. The overarching idea in current regenerative therapy has shifted in the direction of the materials applied being osseointegrative, bioactive, responsive to stimuli from the body and actively promoting the overall regeneration of natural bone tissue. The aim is to determine whether chitosan is a material capable of improving the biological properties of different types of bone regeneration materials and, if so, which biological properties are affected. Methods: After going through the eligibility criteria, twenty articles, with a total of seventeen in vitro studies and six in vivo studies (some articles consisting of both), were included in this study. Results: The results presented colorimetric assays as the most commonly used methods investigating biological properties in in vitro studies, while in in vivo studies, researchers mainly rely on radiological and histological evaluation. After analyzing the data in this systematic review, it is clear that in vitro studies found a clear advantage of the results of chitosan-modified bone grafts in terms of bioactivity, osteogenic potential, biomineralization potential, biodegradability and antibacterial activity. In in vivo studies, chitosan-modified bone grafts stood out with better results in biocompatibility, osteogenic ability and biodegradability. Conclusions: In conclusion, it can be noted that chitosan-modified bone grafts have proven efficacy and the influence of chitosan is evidently favorable in terms of biological properties. Full article

(This article belongs to the Special Issue Biomedical Applications: Advances in Bioengineering and Drug Delivery)

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13 pages, 1919 KiB

Open AccessArticle

Development of a Liposome Nanoformulation for the Delivery of Lipoic Acid as a Potential Neuroprotective Therapy in Glaucoma

by Pablo Edmundo Antezana, Ailen Gala Hvozda Arana, Sofia Municoy, Martín Federico Desimone, Pablo Evelson and Sandra Ferreira

Pharmaceutics 2025, 17(5), 664; https://doi.org/10.3390/pharmaceutics17050664 - 18 May 2025

Viewed by 51

Abstract

Background/Objectives: Glaucoma is the leading cause of irreversible blindness worldwide and oxidative stress is considered to play a key role in its development. While antioxidants offer a promising approach to mitigating oxidative stress, their clinical application is often hindered by bioavailability and [...] Read more.

Background/Objectives: Glaucoma is the leading cause of irreversible blindness worldwide and oxidative stress is considered to play a key role in its development. While antioxidants offer a promising approach to mitigating oxidative stress, their clinical application is often hindered by bioavailability and absorption challenges. Entrapment antioxidants within liposomes may overcome these issues, enhancing their stability and delivery. The aim of this study was to develop a novel composite liposomal formulation for glaucoma treatment, designed to enhance lipoic acid bioavailability and administration through its incorporation into the lipid bilayer. Methods: Liposomes were prepared via lipid film hydration and extrusion. To characterize them, the following analyses were performed: FTIR spectroscopy, liposomal bilayer melting temperature (Tm), TEM, DLS, Z-potential, antioxidant activity, and cytotoxicity assays. Results: The efficient incorporation of lipoic acid into the liposomes’ lipid bilayer was confirmed by FTIR. This incorporation resulted in an increase in the Tm, from 37.0 °C for liposomes to 40.0 °C for liposomes with lipoic acid (L-LA). TEM images confirmed that the spherical morphology of the lipid vesicles remained unchanged following LA incorporation. Dynamic Light Scattering analysis revealed effective diameters of 423 ± 36 nm for L liposomes and 404 ± 62 nm for L-LA liposomes. Notably, the Z-potential shifted from +4.7 ± 0.4 mV (L) to −0.4 ± 0.3 mV (L-LA). Furthermore, L-LA exhibited significant antioxidant activity (31.6 ± 0.4%) compared with L (5.3 ± 0.3%) and biocompatibility, suggesting its potential for therapeutic applications. Conclusions: In summary, biocompatible composite liposomes with antioxidant capacity were successfully developed, resulting in promising candidates for neuroprotective glaucoma therapy. Full article

(This article belongs to the Special Issue Biopolymer Materials for Wound Healing, 3rd Edition)

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22 pages, 6198 KiB

Open AccessArticle

Engineering a Dual-Function Starch–Cellulose Composite for Colon-Targeted Probiotic Delivery and Synergistic Gut Microbiota Regulation in Type 2 Diabetes Therapeutics

by Ruixiang Liu, Yikang Ding, Yujing Xu, Qifeng Wu, Yanan Chen, Guiming Yan, Dengke Yin and Ye Yang

Pharmaceutics 2025, 17(5), 663; https://doi.org/10.3390/pharmaceutics17050663 - 17 May 2025

Viewed by 200

Abstract

Objectives: This study engineered a colon-targeted drug delivery system (CTDS) using the dual pharmaceutical and edible properties of Pueraria lobata to encapsulate Lactobacillus paracasei for Type 2 diabetes mellitus (T2DM) therapy. Methods: The CTDS was designed as a core–shell composite through microwave–hydrothermal engineering, [...] Read more.

Objectives: This study engineered a colon-targeted drug delivery system (CTDS) using the dual pharmaceutical and edible properties of Pueraria lobata to encapsulate Lactobacillus paracasei for Type 2 diabetes mellitus (T2DM) therapy. Methods: The CTDS was designed as a core–shell composite through microwave–hydrothermal engineering, comprising the following: (1) a retrograded starch shell with acid/enzyme-resistant crystallinity to protect probiotics from gastric degradation; (2) a porous cellulose core derived from Pueraria lobata’s natural microstructure, serving as a colonization scaffold for probiotics. Results: Structural characterization confirmed the shell’s resistance to acidic/pancreatic conditions and the core’s hierarchical porosity for bacterial encapsulation. pH/enzyme-responsive release kinetics were validated via fluorescence imaging, demonstrating targeted probiotic delivery to the colon with minimal gastric leakage. In diabetic models, the CTDS significantly reduced fasting blood glucose and improved dyslipidemia, while histopathological analysis revealed restored hepatic and pancreatic tissue architecture. Pharmacologically, the system acted as both a probiotic delivery vehicle and a microbiota modulator, selectively enriching Allobaculum and other short-chain fatty acid (SCFA)-producing bacteria to enhance SCFA biosynthesis and metabolic homeostasis. The CTDS further exhibited direct compression compatibility, enabling its translation into scalable oral dosage forms (e.g., tablets). Conclusions: By integrating natural material engineering, microbiota-targeted delivery, and tissue repair, this platform bridges the gap between pharmaceutical-grade probiotic protection and metabolic intervention in T2DM. Full article

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

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23 pages, 14789 KiB

Open AccessArticle

Feasibility of Hot Melt Extrusion in Converting Water-Based Nanosuspensions into Solid Dosage Forms

by Erasmo Ragucci, Marco Uboldi, Adam Sobczuk, Giorgio Facchetti, Alice Melocchi, Mauro Serratoni and Lucia Zema

Pharmaceutics 2025, 17(5), 662; https://doi.org/10.3390/pharmaceutics17050662 - 17 May 2025

Viewed by 104

Abstract

Aim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in [...] Read more.

Aim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in transforming a cinnarizine-based NS, selected as a case study, into granules for oral intake. Methods: Thermoplastic polymers, in principle compatible with the thermal behavior of the selected drug and characterized by different interaction mechanisms with aqueous fluids, were used as carriers to absorb the NS and were processed by HME. Results: The extruded granules pointed out good physio-technological characteristics, a drug content > 85% with coefficient of variation (CV) < 5% and tunable in vitro performance coherent with the polymeric carriers they were composed of. Particle size as well as the solid state of cinnarizine was checked using several analytical techniques in combination (e.g., DSC, SEM, FT-IR, Raman). Depending on the composition of the granules, and specifically for formulations processed below 85 °C, the drug was found to remain crystalline and in the desired nanoscale. Conclusions: HME turned out to be a versatile process to transform, in a single-step, NSs into multi-particulate solid products for oral administration showing a variety of release profiles. Full article

(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)

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28 pages, 718 KiB

Open AccessReview

Advancing Brain Targeting: Cost-Effective Surface-Modified Nanoparticles for Faster Market Entry

by Mariana Gomes, Maria João Ramalho, Joana A. Loureiro and Maria Carmo Pereira

Pharmaceutics 2025, 17(5), 661; https://doi.org/10.3390/pharmaceutics17050661 - 17 May 2025

Viewed by 111

Abstract

Abstract: Background/Objectives: The blood–brain barrier (BBB) poses a major obstacle to delivering therapeutic agents to the central nervous system (CNS), driving the need for innovative drug delivery strategies. Among these, nanoparticles (NPs) have gained attention due to their ability to enhance [...] Read more.

Abstract: Background/Objectives: The blood–brain barrier (BBB) poses a major obstacle to delivering therapeutic agents to the central nervous system (CNS), driving the need for innovative drug delivery strategies. Among these, nanoparticles (NPs) have gained attention due to their ability to enhance drug transport, improve bioavailability, and enable targeted delivery. Methods: This paper explores various surface modification strategies employed to optimize NP-mediated drug delivery across the BBB. Specifically, the functionalization of NPs with ligands such as transferrin (Tf), lactoferrin (Lf), protamine, and insulin is discussed, each demonstrating unique mechanisms for enhancing brain-targeting efficiency. In addition, this work provides a comprehensive overview of recent scientific advancements and market strategies aimed at accelerating the adoption of low-cost, surface-modified nanoparticles, ultimately improving patient access to effective CNS treatments. Conclusions: Preclinical and in vitro studies have demonstrated the effectiveness of these modifications in increasing drug retention and bioavailability in brain tissues. Additionally, while ligand-conjugated NPs hold significant promise for neuropharmacology, their clinical translation is often hindered by regulatory and economic constraints. Lengthy approval processes can slow market entry, but cost–benefit analyses indicate that surface-modified NPs remain financially viable, particularly as scalable manufacturing techniques and some ligands are cost-efficient. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

15 pages, 3110 KiB

Open AccessArticle

Cirsium setosum Extract-Loaded Hybrid Nanostructured Scaffolds Incorporating a Temperature-Sensitive Polymer for Mechanically Assisted Wound Healing

by Xiaojing Jiang, Shaoxuan Zhu, Jinying Song, Xingwei Li, Chengbo Li, Guige Hou and Zhongfei Gao

Pharmaceutics 2025, 17(5), 660; https://doi.org/10.3390/pharmaceutics17050660 - 17 May 2025

Viewed by 84

Abstract

Background/Objectives: Cirsium setosum (commonly known as thistle) is a traditional Chinese medicinal plant with significant therapeutic potential, exhibiting hemostatic, antioxidant, and wound-healing properties. Electrospinning offers a versatile platform for fabricating nanoscale scaffolds with tunable functionality, making them ideal for drug delivery and [...] Read more.

Background/Objectives: Cirsium setosum (commonly known as thistle) is a traditional Chinese medicinal plant with significant therapeutic potential, exhibiting hemostatic, antioxidant, and wound-healing properties. Electrospinning offers a versatile platform for fabricating nanoscale scaffolds with tunable functionality, making them ideal for drug delivery and tissue engineering. Methods: In this study, a bioactive extract from thistle was obtained and incorporated into a thermosensitive triblock copolymer (PNNS) and polycaprolactone (PCL) to develop a multifunctional nanofibrous scaffold for enhanced wound healing. The prepared nanofibers were thoroughly characterized using Fourier-transform infrared spectroscopy (FTIR), contact angle measurements, thermogravimetric analysis (TGA), and tensile fracture testing to assess their physicochemical properties. Results: Notably, the inclusion of PNNS imparted temperature-responsive behavior to the scaffold, enabling controlled deformation in response to thermal stimuli—a feature that may facilitate wound contraction and improve scar remodeling. Specifically, the scaffold demonstrated rapid shrinkage at a physiological temperature (38 °C) within minutes while maintaining structural integrity at ambient conditions (20 °C). In vitro studies confirmed the thistle extract’s potent antioxidant activity, while in vivo experiments revealed their effective hemostatic performance in a liver bleeding model when delivered via the composite nanofibers. Thistle extract and skin temperature-responsive contraction reduced the inflammatory outbreak at the wound site and promoted collagen deposition, resulting in an ideal wound-healing rate of above 95% within 14 days. Conclusions: The integrated strategy that combines mechanical signals, natural extracts, and electrospinning nanotechnology offers a feasible design approach and significant technological advantages with enhanced therapeutic efficacy. Full article

(This article belongs to the Special Issue Advanced Nanomaterials and Drug Delivery Systems for Wound Healing and Antimicrobial Therapy)

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21 pages, 1541 KiB

Open AccessArticle

Advanced QbD-Based Process Optimization of Clopidogrel Tablets with Insights into Industrial Manufacturing Design

by Young Woo Bak, Mi Ran Woo, Hyuk Jun Cho, Taek Kwan Kwon, Ho Teak Im, Jung Hyun Cho and Han-Gon Choi

Pharmaceutics 2025, 17(5), 659; https://doi.org/10.3390/pharmaceutics17050659 - 17 May 2025

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Abstract

Background/Objectives: Traditional Quality by Testing (QbT) strategies rely heavily on end-product testing and offer limited insight into how critical process parameters (CPPs) influence product quality. This increases the risk of variability and inconsistent outcomes. To overcome these limitations, this study aimed to [...] Read more.

Background/Objectives: Traditional Quality by Testing (QbT) strategies rely heavily on end-product testing and offer limited insight into how critical process parameters (CPPs) influence product quality. This increases the risk of variability and inconsistent outcomes. To overcome these limitations, this study aimed to implement a Quality by Design (QbD) approach to optimize the manufacturing process of clopidogrel tablets. Methods: A science- and risk-based QbD framework was applied to identify and prioritize key CPPs, intermediate critical quality attributes (iCQAs), and final product CQAs across key unit operations—pre-blending, dry granulation, post-blending, lubrication, and compression. Risk assessment tools and statistical design of experiments (DoE) were used to define proven acceptable ranges (PARs). Results: The study revealed strong correlations between CPPs and CQAs, allowing the definition of PARs and development of a robust control strategy. This led to improved manufacturing consistency, reduced variability, and enhanced process understanding. Conclusions: The QbD approach minimized reliance on end-product testing while ensuring high-quality outcomes. This study offers a novel QbD implementation tailored to the manufacturing challenges of clopidogrel tablets, providing a validated approach that integrates dry granulation CPPs with process-specific CQAs. These results demonstrate the value of QbD in achieving robust pharmaceutical manufacturing and meeting regulatory expectations. Full article

(This article belongs to the Special Issue Pharmaceutical Solid Dosage Forms: Manufacturing, Design, Development, and Biomedical Applications)

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26 pages, 3061 KiB

Open AccessArticle

Three-Dimensional-Printed Isoniazid Chewable Gels for On-Demand Latent Tuberculosis Treatment in Children

by Amanda de O. E. Moreira, Lêda Maria S. Azevedo Neta, Márcia Pietroluongo, Ana Paula dos S. Matos, Beatriz B. Correa, Beatriz H. Ortiz, André da S. Guimarães, Marcio Nele, Carollyne M. Santos, Ana Elizabeth C. Fai, Maria Helena Gonçalves, Flávio M. Shimizu, Monique S. Dos Santos, Rosemberg B. Moure, Diogo D. Nascimento, André Luis de A. Guimarães, Saint Clair dos S. G. Junior, Alessandra L. Vicosa and Lucio M. Cabral

Pharmaceutics 2025, 17(5), 658; https://doi.org/10.3390/pharmaceutics17050658 - 17 May 2025

Viewed by 183

Abstract

Background/Objectives: Pediatric drug administration is hindered by difficulties in swallowing conventional medications and the unpalatable taste of many drugs. Among diseases highlighting the need for improved pediatric delivery, tuberculosis (TB) stands out. One form of the disease is latent TB infection (LTBI), [...] Read more.

Background/Objectives: Pediatric drug administration is hindered by difficulties in swallowing conventional medications and the unpalatable taste of many drugs. Among diseases highlighting the need for improved pediatric delivery, tuberculosis (TB) stands out. One form of the disease is latent TB infection (LTBI), which is concerning in children. Effective LTBI treatment is crucial for prevention, with isoniazid (INH) widely used for its proven efficacy and safety. This study aims to develop innovative 3D-printed chewable gels containing INH for LTBI treatment. Methods: The gels were formulated using gelatin and carrageenan gum, sugar-free sweeteners, and flavoring. Two batches were prepared, and using 3D printing (3DP) with a semi-solid extrusion (SSE) module, chewable gels were produced. Rheological properties were measured to assess the feasibility of 3DP-SSE, evaluating the structural integrity and adequate fluidity of the formulation. The 3D-printed chewable gels were evaluated by visual, mass, and dimensional characteristics. In addition, the water activity, texture profile, INH and degradation product content, in vitro release, and taste-masking were investigated. Results: The optimized formulation maintained suitable rheological properties for 3DP-SSE, demonstrating consistent weight, dimensions, and stability after the process. The texture achieved a balance between printing parameters and shape maintenance, and the INH presented an immediate-release profile (>85% within 30 min). The chewable gels showed an improvement in palatability compared to conventional INH tablets. Conclusions: This innovative approach offers a promising solution for pediatric LTBI treatment, as it improves efficacy, medication acceptability, and on-demand access. Full article

(This article belongs to the Special Issue 3D Printing in Personalized Drug Delivery)

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22 pages, 3672 KiB

Open AccessArticle

Combinatorial Effects of Free and Nanoencapsulated Forms of Cabazitaxel and RAS-Selective Lethal 3 in Breast Cancer Cells

by Remya Valsalakumari, Marek Feith, Solveig Pettersen, Andreas K. O. Åslund, Ýrr Mørch, Tore Skotland, Kirsten Sandvig, Gunhild Mari Mælandsmo and Tore-Geir Iversen

Pharmaceutics 2025, 17(5), 657; https://doi.org/10.3390/pharmaceutics17050657 - 17 May 2025

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Abstract

Background: Combination therapies for cancer have gained considerable attention due to their potential for enhancing therapeutic efficacy and decreasing drug resistance. Introducing nanodrug delivery systems in this context may further improve the therapy due to targeted delivery, improved drug stability, sustained drug release, [...] Read more.

Background: Combination therapies for cancer have gained considerable attention due to their potential for enhancing therapeutic efficacy and decreasing drug resistance. Introducing nanodrug delivery systems in this context may further improve the therapy due to targeted delivery, improved drug stability, sustained drug release, and prevention of rapid clearance from circulation. This study evaluates the combinatorial effects of two cytotoxic drugs, cabazitaxel (CBZ) and RSL3 (RAS-selective lethal 3), in free form as well as encapsulated within poly(2-ethyl butyl cyanoacrylate) (PEBCA) nanoparticles (NPs) in breast cancer cell lines. Methods: Cell proliferation was assessed using IncuCyte technology, and synergistic drug effects were determined with SynergyFinder Plus. Cell viability was measured with the MTT assay. Additionally, we investigated whether the combinatorial effects were reflected in alterations of metabolic activity or reactive oxygen species (ROS) production using Seahorse technology and the CM-H₂DCFDA assay, respectively. Results: The data presented reveal, for the first time, that CBZ and RSL3 exhibit synergistically or additively combinatorial effects on various breast cancer cell lines. The pattern of cytotoxic effects was consistent, whether the drugs were in free form or encapsulated in NPs. Moreover, the combinatorial effects were not observed to be associated with early changes in metabolic activity or ROS production. Conclusion: This study highlights the potential of CBZ and RSL3 in combinatorial nanomedicine as they may act synergistically. Further studies are warranted to better understand the mechanisms behind these combinatorial effects. Full article

(This article belongs to the Special Issue Nanoparticle-Mediated Targeted Drug Delivery Systems)

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15 pages, 2746 KiB

Open AccessArticle

Newborn Intravenous Injection of Liposomal CRISPR/Cas9 Complex Has No Incidence of Off-Targets or Tumors in Mice

by Vinícius Monteagudo, Larissa Cristina Barbosa Flores, Melaine Lopes, Flavia Nathiely Silveira Fachel, Giselle Martins, Marina Siebert, Willian da Silva Carniel, Tuane Nerissa Alves Garcez, Helder Ferreira Teixeira, Ursula Matte, Roberto Giugliani, Guilherme Baldo, Édina Poletto and Roselena Silvestri Schuh

Pharmaceutics 2025, 17(5), 656; https://doi.org/10.3390/pharmaceutics17050656 - 17 May 2025

Viewed by 161

Abstract

Background: Genome editing at specific loci is an innovative therapeutic approach; however, it faces many challenges, so optimizing delivery vectors is essential to enhance the safety and efficacy of the CRISPR/Cas9 system. This study investigated whether the hydrodynamic administration of liposomal CRISPR/Cas9 [...] Read more.

Background: Genome editing at specific loci is an innovative therapeutic approach; however, it faces many challenges, so optimizing delivery vectors is essential to enhance the safety and efficacy of the CRISPR/Cas9 system. This study investigated whether the hydrodynamic administration of liposomal CRISPR/Cas9 complexes (LCs) in newborn mice induces off-target events or tumors. Methods: Liposomes were obtained through microfluidization. The CRISPR/Cas9 plasmid and a donor plasmid containing the Idua cDNA (alpha-L-iduronidase enzyme) were incorporated by adsorption, and complexes (LCs) were characterized regarding physicochemical properties. C57BL/6 newborn mice were divided in two groups, one received the complexes through hydrodynamic intravenous injection (n = 15) and the other was used as control (n = 15). After 21 months, mice were euthanized and organs were analyzed regarding histological characteristics. Lungs and liver were analyzed by qPCR searching for potential off-target sites in chromosomes 2, 5, 11, and 17 and on-target site in chromosome 6, identified by COSMID. Sequences were analyzed using an ICE tool for indels detection. Results: LCs exhibited 136 nm mean vesicle diameter with PDI below 0.15 and a zeta potential around +43 mV. Immediate biodistribution was predominant in the lungs and liver. There was no significant increase in tumor induction (20% in LCs vs. 33% in control). Molecular analyses indicated 0% off-target effects and around 3% on-target events. Conclusions: We conclude that this set of experiments demonstrates the potential of the chosen gRNA sequence to perform safe gene editing at the murine ROSA26 locus, corroborating the safety of the CRISPR/Cas9 gene editing platform. Full article

(This article belongs to the Special Issue Nanoparticle-Based Gene Delivery)

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62 pages, 12088 KiB

Open AccessReview

Nanoparticles and Nanomaterials: A Review from the Standpoint of Pharmacy and Medicine

by Gleb V. Petrov, Alena M. Koldina, Oleg V. Ledenev, Vladimir N. Tumasov, Aleksandr A. Nazarov and Anton V. Syroeshkin

Pharmaceutics 2025, 17(5), 655; https://doi.org/10.3390/pharmaceutics17050655 - 16 May 2025

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Abstract

Nanoparticles (NPs) represent a unique class of structures in the modern world. In comparison to macro- and microparticles, NPs exhibit advantages due to their physicochemical properties. This has resulted in their extensive application not only in technical and engineering sciences, but also in [...] Read more.

Nanoparticles (NPs) represent a unique class of structures in the modern world. In comparison to macro- and microparticles, NPs exhibit advantages due to their physicochemical properties. This has resulted in their extensive application not only in technical and engineering sciences, but also in pharmacy and medicine. A recent analysis of the scientific literature revealed that the number of articles related to the search term “nanoparticle drugs” has exceeded 65,000 in the last decade alone, according to PubMed. The growth of scientific publications on NPs and nanomaterials (NMs) in pharmacy demonstrates the rapidly developing interest of scientists in exploring alternative ways to deliver drugs, thereby improving their pharmacokinetic and pharmacodynamic properties, and the increased biocompatibility of many nanopharmaceuticals is a unique key to two mandatory pharmaceutical requirements—drug efficacy and safety. A comprehensive review of the literature indicates that the modern pharmaceutical industry is increasingly employing nanostructures. The exploration of their physicochemical properties with a subsequent modern approach to quality control remains the main task of modern pharmaceutical chemistry. The primary objective of this review is to provide a comprehensive overview of data on NPs, their physicochemical properties, and modern approaches to their synthesis, modification of their surface, and application in pharmacy. Full article

(This article belongs to the Special Issue Hybrid Nanoparticles for Cancer Therapy)

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18 pages, 2419 KiB

Open AccessArticle

Characterization and Specific Detection of Lactobacillus paracasei-Derived Extracellular Vesicles Using Anti-p40-Modified Au Thin Film

by Kyeongmin Lee, Eun-Gyung Cho, Youngbo Choi, Yunsik Kim, Jin Hee Lee and Surin Hong

Pharmaceutics 2025, 17(5), 654; https://doi.org/10.3390/pharmaceutics17050654 - 16 May 2025

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Abstract

Background/Objectives: Extracellular vesicles (EVs) are nanoscale, membrane-enclosed structures that play key roles in intercellular communication and biological regulation. Among them, Lactobacillus paracasei-derived EVs (Lp-EVs) have attracted attention for their anti-inflammatory and anti-aging properties, making them promising candidates for therapeutic and cosmetic [...] Read more.

Background/Objectives: Extracellular vesicles (EVs) are nanoscale, membrane-enclosed structures that play key roles in intercellular communication and biological regulation. Among them, Lactobacillus paracasei-derived EVs (Lp-EVs) have attracted attention for their anti-inflammatory and anti-aging properties, making them promising candidates for therapeutic and cosmetic use. However, methods for specific detection and quantitative evaluation of Lp-EVs are still limited. This study aims to develop a surface plasmon resonance (SPR)-based sensor system for the precise and selective detection of Lp-EVs. Methods: Anti-p40 antibodies were immobilized on gold thin films to construct an SPR sensing platform. The overexpression of the p40 protein on Lp-EVs was confirmed using flow cytometry and Western blotting. For functional evaluation, Lp-EVs were applied to an artificial skin membrane mounted on a Franz diffusion cell, followed by SPR-based quantification and fluorescence imaging to assess their skin penetration behavior. Results: The developed SPR sensor demonstrated high specificity and a detection limit of 0.12 µg/mL, with a linear response range from 0.1 to 0.375 µg/mL. It successfully discriminated Lp-EVs from other bacterial EVs. In the skin diffusion assay, Lp-EVs accumulated predominantly in the epidermal layer without penetrating into the dermis, likely due to their negative surface charge and interaction with the hydrophobic epidermal lipid matrix. Fluorescence imaging confirmed this epidermal confinement, which increased over 24 h. Conclusions: This study presents a sensitive and selective SPR-based platform for detecting Lp-EVs and demonstrates their potential for targeted epidermal delivery. These findings support the use of Lp-EVs in skin-focused therapeutic and cosmetic applications. Future studies will explore strategies such as microneedle-assisted delivery to enhance transdermal penetration and efficacy. Full article

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

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39 pages, 5856 KiB

Open AccessArticle

Dissolving Microneedles Containing Lactoferrin Nanosuspension for Enhancement of Antimicrobial and Anti-Inflammatory Effects in the Treatment of Dry Eye Disease

by Sammar Fathy Elhabal, Ahmed Mohsen Faheem, Sandra Hababeh, Jakline Nelson, Nahla A. Elzohairy, Suzan Awad AbdelGhany Morsy, Tassneim M. Ewedah, Ibrahim S. Mousa, Marwa A. Fouad and Ahmed Mohsen Elsaid Hamdan

Pharmaceutics 2025, 17(5), 653; https://doi.org/10.3390/pharmaceutics17050653 - 16 May 2025

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Abstract

Background/Objectives: Dry eye disease (DED), also known as “keratoconjunctivitis sicca”, is a common chronic ocular surface disease accompanied by inflammation and diminished tear production. Bovine Lactoferrin (BLF), a multi-functional iron-binding glycoprotein found in tears, decreased significantly in patients with DED, used for the [...] Read more.

Background/Objectives: Dry eye disease (DED), also known as “keratoconjunctivitis sicca”, is a common chronic ocular surface disease accompanied by inflammation and diminished tear production. Bovine Lactoferrin (BLF), a multi-functional iron-binding glycoprotein found in tears, decreased significantly in patients with DED, used for the treatment of dry eye, conjunctivitis, and ocular inflammation. BLF has limited therapeutic efficacy due to poor ocular bioavailability. Methods: This study developed and optimized a BLF-loaded nanosuspension (BLF-NS) using the Box–Behnken Design (BBD). Optimized BLF-NS was then incorporated with polyvinyl pyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) dissolving microneedles (MNs). The formulations were characterized by Scanning and transmission microscopy, DSC, FTIR, ex vivo studies in corneal tissue from sheep and tested for its antibacterial and antifungal efficacy against Methicillin-Resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, and Aspergillus niger, respectively. Moreover, they were tested for their Benzalkonium chloride (BCL) dry eye in a rabbit model. Results: The optimized nanosuspension showed a vesicle size of (215 ± 0.45) nm, a Z.P (zeta potential) of (−28 ± 0.34) mV, and an Entrapment Efficiency (EE%) of (90 ± 0.66) %. The MNs were fabricated using a ratio of biodegradable polymers, PVP/HPMC. The resulting BLF-NS-MNs exhibited sharp pyramidal geometry with high mechanical strength, ensuring ocular insertion. In vitro release showed 95% lactoferrin release over 24 h, while ex vivo permeation achieved 93% trans-corneal delivery. In vivo, BLF-NS-MNs significantly reduced pro-inflammatory cytokines (TNF-α, IL-6, MMP-9, IL-1β, MCP-1) and upregulated antioxidant and anti-inflammatory genes (PPARA, SOD 1), restoring their levels to near-normal (p < 0.001). Conclusions: The nanosuspension combined with MNs has shown higher ocular tolerance against DED ensured by the Draize and Schirmer Tear Test. Full article

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

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19 pages, 1285 KiB

Open AccessReview

From Mechanism to Therapy: The Role of MSC-EVs in Alleviating Radiation-Induced Injuries

by Chong Huang, Heng Li, Zhiyue Zhang, Ting Mou, Dandan Wang, Chenlu Li, Lei Tian and Chunlin Zong

Pharmaceutics 2025, 17(5), 652; https://doi.org/10.3390/pharmaceutics17050652 - 16 May 2025

Viewed by 22

Abstract

Radiation injury is a severe issue in both nuclear accidents and cancer radiotherapy. Ionizing radiation impairs the regenerative and repair capabilities of tissues and organs, resulting in a scarcity of effective therapeutic approaches to prevent or mitigate such injuries. Mesenchymal stem cells (MSCs) [...] Read more.

Radiation injury is a severe issue in both nuclear accidents and cancer radiotherapy. Ionizing radiation impairs the regenerative and repair capabilities of tissues and organs, resulting in a scarcity of effective therapeutic approaches to prevent or mitigate such injuries. Mesenchymal stem cells (MSCs) possess favorable biological characteristics and have emerged as ideal candidates for the treatment of radiation injury. However, the use of MSCs as therapeutic agents is associated with uncertainties in therapeutic efficacy, transient effects, and the risk of immune rejection. Recent advances in research have revealed that extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) exhibit similar beneficial properties to MSCs and represent a promising cell-free therapy for mitigating radiation injuries. MSC-EVs are enriched with microRNAs (miRNAs), proteins, and lipids, which can modulate immune responses, inflammatory reactions, cell survival, and proliferation in irradiated tissues. This review synthesizes recent studies on the application of MSC-EVs in radiation injury, focusing on the therapeutic effects and mechanisms of MSC-EVs derived from various sources in radiation-induced diseases of different organs. The therapeutic potential of MSC-EVs for radiation injury provides valuable insights for addressing ionizing radiation-induced injuries and offers a reference for future clinical applications. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics, 2nd Edition)

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19 pages, 847 KiB

Open AccessReview

Targeted Drug Delivery to the Spleen and Its Implications for the Prevention and Treatment of Cancer

by Ikramy A. Khalil, Ahmed Faheem and Mohamed El-Tanani

Pharmaceutics 2025, 17(5), 651; https://doi.org/10.3390/pharmaceutics17050651 - 15 May 2025

Viewed by 93

Abstract

The spleen, the largest secondary lymphoid organ, plays several vital roles in the body, including blood filtration, hematopoiesis, and immune regulation. Despite its importance, the spleen has not received substantial attention as a target organ for drug delivery. Most systemically administered colloidal and [...] Read more.

The spleen, the largest secondary lymphoid organ, plays several vital roles in the body, including blood filtration, hematopoiesis, and immune regulation. Despite its importance, the spleen has not received substantial attention as a target organ for drug delivery. Most systemically administered colloidal and particulate drug carriers are cleared from the blood by the liver and spleen, making these two organs potential targets for drug accumulation. While various systems have been developed to target the liver, there is an urgent need to design spleen-targeted drug delivery systems that can evade clearance and degradation while delivering drugs efficiently to their target cells in the spleen. Targeting the spleen holds great potential for the treatment of a range of diseases, including blood disorders, immune and inflammatory diseases, infectious diseases, and cancer. It is also crucial for the development of effective vaccines. In this review, we explore different approaches used to target the spleen after systemic administration, and we discuss the factors that shift the biodistribution of drug carriers from the liver to the spleen. We focus on cell-specific delivery within the spleen, strategies to avoid degradation, and methods to achieve the efficient intracellular delivery of various drugs and genes. We also highlight the therapeutic implications of spleen-targeted drug delivery systems, particularly for the prevention and treatment of cancer. Full article

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

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22 pages, 4214 KiB

Open AccessArticle

Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy

by Amy F. Geard, Giulia Massaro, Michael P. Hughes, Patrick Arbuthnot, Simon N. Waddington and Ahad A. Rahim

Pharmaceutics 2025, 17(5), 650; https://doi.org/10.3390/pharmaceutics17050650 - 15 May 2025

Viewed by 135

Abstract

Background/Objectives: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA1 gene. Type 1 Gaucher disease is characterised by substrate accumulation in the visceral organs, which occurs in combination with acute and chronic neurodegeneration that distinguish [...] Read more.

Background/Objectives: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA1 gene. Type 1 Gaucher disease is characterised by substrate accumulation in the visceral organs, which occurs in combination with acute and chronic neurodegeneration that distinguish type 2 and type 3 GD, respectively. We have previously shown the efficacy of neonatal AAV9 gene therapy for treating type 2 GD and aimed to investigate post-symptomatic administration into a model of type 1 disease. Current murine models of type 1 disease are limited in their recapitulation of early onset phenotypic manifestation and thus we aimed to create a novel model of type 1 in which to test the efficacy of adult gene therapy. Methods: The novel AAV-GD1 model was created through intracerebroventricular injection of AAV9 containing the human GBA1 gene under control of the neuron-specific synapsin promoter (AAV9.hSynI.hGBA1) to the pre-existing acute K14-lnl/lnl model of type 2 GD. Administration of AAV9.hSynI.hGBA1 aimed to restore glucocerebrosidase expression in the brain and extend the lifespan beyond 14 days, allowing the visceral pathology to develop further. The organ pathology was characterised by immunohistochemistry at various time points. Once visceral disease was confirmed, an intravenous injection of AAV9 containing a ubiquitously active CAG promoter driving hGBA1 (AAV9.CAG.hGBA1) was administered to post-symptomatic mice. Animals were aged for 2 and 4 months post-treatment with AAV9.CAG.hGBA1, and immunohistochemistry and enzymatic activity were assessed to investigate therapeutic efficacy. Results: The AAV-GD1 model displayed visceral pathology in the spleen, lung, and liver from 2 months of age. This allowed us to validate the efficacy of adult gene therapy; intravenous administration of AAV9.CAG.hGBA1 transiently ameliorated the lung pathology and rescued the spleen pathology up to 4 months post-administration. Conclusions: The creation of the novel AAV-GD1 model with more aggressive visceral pathology presents a unique opportunity for investigation of new therapies to treat type 1 GD. AAV9.CAG.hGBA1 represents a potential therapeutic option for all forms of Gaucher disease. Full article

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

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15 pages, 1993 KiB

Open AccessArticle

Nanostructured Lipoxin A4: Understanding Its Biological Behavior and Impact on Alzheimer’s Disease (Proof of Concept)

by Natália Cristina Gomes-da-Silva, Isabelle Xavier-de-Britto, Marilia Amável Gomes Soares, Natalia Mayumi Andrade Yoshihara, Derya Ilem Özdemir, Eduardo Ricci-Junior, Pierre Basílio Almeida Fechine, Luciana Magalhães Rebelo Alencar, Maria das Graças Muller de Oliveira Henriques, Thereza Christina Barja-Fidalgo, Cristian Follmer and Ralph Santos-Oliveira

Pharmaceutics 2025, 17(5), 649; https://doi.org/10.3390/pharmaceutics17050649 - 15 May 2025

Viewed by 204

Abstract

Background/Objectives: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed [...] Read more.

Background/Objectives: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed to develop and characterize nanomicelles encapsulating LXA4 (nano-lipoxin A4) to improve its pharmacological efficacy against Alzheimer’s disease (AD), a neurodegenerative condition marked by chronic inflammation and beta-amyloid (Aβ) accumulation. Methods: Nano-lipoxin A4 was synthesized using Pluronic F-127 as a carrier and characterized in terms of morphology, physicochemical stability, and in vitro activity against Aβ fibrils. Dissociation of Aβ fibrils was assessed via Thioflavin-T fluorescence assays and transmission electron microscopy. In vivo biodistribution and pharmacokinetic profiles were evaluated using technetium-99m-labeled nano-lipoxin A4 in rodent models. Hepatic biochemical parameters were also measured to assess potential systemic effects. Results: In vitro studies demonstrated that nano-lipoxin A4 effectively dissociated Aβ fibrils at concentrations of 50 nM and 112 nM. Electron microscopy confirmed the disruption of fibrillar structures. In vivo imaging revealed predominant accumulation in the liver and spleen, consistent with reticuloendothelial system uptake. Pharmacokinetic analysis showed a prolonged half-life (63.95 h) and low clearance rate (0.001509 L/h), indicating sustained systemic presence. Biochemical assays revealed elevated liver enzyme levels, suggestive of increased hepatic metabolism or potential hepatotoxicity. Conclusions: Nano-lipoxin A4 exhibits significant therapeutic potential for Alzheimer’s disease through effective modulation of Aβ pathology and favorable pharmacokinetic characteristics. However, the elevation in liver enzymes necessitates further investigation into systemic safety to support clinical translation. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications, 2nd Edition)

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18 pages, 2224 KiB

Open AccessReview

Combining Advanced Therapies with Alternative Treatments: A New Approach to Managing Antimicrobial Resistance?

by Greta Kaspute, Arunas Zebrauskas, Akvile Streckyte, Tatjana Ivaskiene and Urte Prentice

Pharmaceutics 2025, 17(5), 648; https://doi.org/10.3390/pharmaceutics17050648 - 15 May 2025

Viewed by 294

Abstract

Bacterial antimicrobial resistance (AMR) represents a critical public health threat, with increasing resistance compromising the effectiveness of treatments worldwide. Resistance trends, such as fluctuating benzylpenicillin resistance in Staphylococcus aureus, highlight the growing urgency, with projections indicating a rise in resistance to various [...] Read more.

Bacterial antimicrobial resistance (AMR) represents a critical public health threat, with increasing resistance compromising the effectiveness of treatments worldwide. Resistance trends, such as fluctuating benzylpenicillin resistance in Staphylococcus aureus, highlight the growing urgency, with projections indicating a rise in resistance to various antibiotics, including complete resistance to gentamicin and tetracycline by 2027. Despite substantial efforts to develop new antibiotics and drug delivery systems, these approaches must undergo rigorous clinical evaluation to ensure their safety and efficacy. In parallel, alternative therapies, such as phytotherapy and apitherapy, have garnered attention for their potential in combating infections. Natural substances like tea tree essential oils and propolis, which exhibit antimicrobial properties, are being increasingly incorporated into novel drug delivery systems. However, much of the research on these materials is not new, with several studies already exploring their effectiveness. To address the escalating AMR crisis, combining advanced therapies with alternative medicine could offer a promising solution. Advanced therapy products could target bacterial genomes and enhance the effectiveness of antibiotics and natural substances. This integrated approach remains underexplored in pre-clinical and clinical trials, presenting future research opportunities to develop more effective strategies in combating AMR. Given the rapid spread of resistant infections, there is an urgent need for innovative antimicrobial agents to overcome emerging resistance mechanisms and improve diagnoses and treatments. Full article

(This article belongs to the Special Issue Antimicrobial Resistance and Antimicrobial Activity of Bioactive Compounds in Drug Formulations)

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14 pages, 1451 KiB

Open AccessArticle

In Silico Evaluation of the Biopharmaceutical and Pharmacokinetic Behavior of Metronidazole from Coated Colonic Release Matrix Tablets

by Roberto Arévalo-Pérez, Cristina Maderuelo and José M. Lanao

Pharmaceutics 2025, 17(5), 647; https://doi.org/10.3390/pharmaceutics17050647 - 14 May 2025

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Abstract

Background: Physiologically based biopharmaceutics modeling (PBBM) models can help to predict drug release and in vivo absorption behaviors. Colon drug delivery systems have gained interest over the past few years due to the advantages they provide in treating certain diseases in a local [...] Read more.

Background: Physiologically based biopharmaceutics modeling (PBBM) models can help to predict drug release and in vivo absorption behaviors. Colon drug delivery systems have gained interest over the past few years due to the advantages they provide in treating certain diseases in a local way. The objectives of this work were to simulate the biopharmaceutical and pharmacokinetic behavior of metronidazole hydrophilic matrices coated with different enteric polymers and to highlight the factors with a significant impact on the simulated pharmacokinetic parameters. Methods: Physicochemical properties of metronidazole were introduced into Simcyp^® simulator platform, and the Advanced Dissolution Absorption Model (ADAM) was employed to simulate the in vivo intestinal absorption and colonic concentrations of metronidazole using a PBBM model. A Kruskal–Wallis test was carried out in order to determine which one of the factors studied has a statistically significant impact on the pharmacokinetic parameters (AUC, C_max, and T_max) simulated. Results: Enteric-coated matrix tablets are capable of avoiding metronidazole absorption in the small intestine and releasing it in the colonic region. The release and absorption rates of metronidazole depend largely on the percentage of weight gain of the coating and also on the coating agent. Coated tablets with a time-dependent coating show less variability. Conclusions: PBBM models can help predict the release from drug delivery systems and the pharmacokinetics in vivo of metronidazole from data obtained in vitro, although complementary in vivo studies should be needed. Full article

(This article belongs to the Topic Pharmacokinetic and Pharmacodynamic Modelling in Drug Discovery and Development)

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