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19 pages, 3592 KiB

Open AccessArticle

Development and Characterization of Quercetin-Loaded Delivery Systems for Increasing Its Bioavailability in Cervical Cancer Cells

by Miguel Ferreira, Diana Gomes, Miguel Neto, Luís A. Passarinha, Diana Costa and Ângela Sousa

Pharmaceutics 2023, 15(3), 936; https://doi.org/10.3390/pharmaceutics15030936 - 14 Mar 2023

Cited by 7 | Viewed by 2091

Abstract

Quercetin is a natural flavonoid with high anticancer activity, especially for related-HPV cancers such as cervical cancer. However, quercetin exhibits a reduced aqueous solubility and stability, resulting in a low bioavailability that limits its therapeutic use. In this study, chitosan/sulfonyl-ether-β-cyclodextrin (SBE-β-CD)-conjugated delivery systems [...] Read more.

Quercetin is a natural flavonoid with high anticancer activity, especially for related-HPV cancers such as cervical cancer. However, quercetin exhibits a reduced aqueous solubility and stability, resulting in a low bioavailability that limits its therapeutic use. In this study, chitosan/sulfonyl-ether-β-cyclodextrin (SBE-β-CD)-conjugated delivery systems have been explored in order to increase quercetin loading capacity, carriage, solubility and consequently bioavailability in cervical cancer cells. SBE-β-CD/quercetin inclusion complexes were tested as well as chitosan/SBE-β-CD/quercetin-conjugated delivery systems, using two types of chitosan differing in molecular weight. Regarding characterization studies, HMW chitosan/SBE-β-CD/quercetin formulations have demonstrated the best results, which are obtaining nanoparticle sizes of 272.07 ± 2.87 nm, a polydispersity index (PdI) of 0.287 ± 0.011, a zeta potential of +38.0 ± 1.34 mV and an encapsulation efficiency of approximately 99.9%. In vitro release studies were also performed for 5 kDa chitosan formulations, indicating a quercetin release of 9.6% and 57.53% at pH 7.4 and 5.8, respectively. IC₅₀ values on HeLa cells indicated an increased cytotoxic effect with HMW chitosan/SBE-β-CD/quercetin delivery systems (43.55 μM), suggesting a remarkable improvement of quercetin bioavailability. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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16 pages, 3535 KiB

Open AccessArticle

Microbiological Screening of 5-Functionalized Pyrazoles for the Future Development of Optimized Pyrazole-Based Delivery Systems

by Chiara Brullo, Debora Caviglia, Andrea Spallarossa, Silvana Alfei, Scott G. Franzblau, Bruno Tasso and Anna Maria Schito

Pharmaceutics 2022, 14(9), 1770; https://doi.org/10.3390/pharmaceutics14091770 - 24 Aug 2022

Cited by 4 | Viewed by 1407

Abstract

The pyrazole ring represents a widely applied chemical scaffold in medicinal chemistry research and we have observed that the physicochemical and biological features of highly substituted pyrazoles can be successfully improved by their encapsulation in dendrimer nanoparticles (NPs). For the future development of [...] Read more.

The pyrazole ring represents a widely applied chemical scaffold in medicinal chemistry research and we have observed that the physicochemical and biological features of highly substituted pyrazoles can be successfully improved by their encapsulation in dendrimer nanoparticles (NPs). For the future development of new optimized antibacterial delivery systems, we report the synthesis and biological evaluation of 5-amino functionalized pyrazole library (compounds 2–7). In detail, new derivatives 2–7 were differently decorated in C3, C4 and C5 positions. An in silico study predicted pyrazoles 2–7 to exert good drug-like and pharmacokinetic properties. Compounds 3c and 4b were endowed with moderate, but nanotechnologically improvable activity against multidrug-resistant (MDR) clinical isolates of Gram-positive species, especially of the Staphylococcus genus (MICs = 32–64 µg/mL). In addition, derivatives 3c and 4a showed moderate activities against Mycobacterium tuberculosis and 4a evidenced activity also against MDR strains. Overall, the collected evidence supported that, upon nano-formulation with proper polymer matrices, the new synthesized compounds could provide new pyrazole-based drug delivery systems with an enhanced and enlarged-spectrum of antibacterial activity. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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18 pages, 3256 KiB

Open AccessArticle

Investigations on Cellular Uptake Mechanisms and Immunogenicity Profile of Novel Bio-Hybrid Nanovesicles

by Yi-Hsuan Ou, Jeremy Liang, Wei Heng Chng, Ram Pravin Kumar Muthuramalingam, Zi Xiu Ng, Choon Keong Lee, Yub Raj Neupane, Jia Ning Nicolette Yau, Sitong Zhang, Charles Kang Liang Lou, Chenyuan Huang, Jiong-Wei Wang and Giorgia Pastorin

Pharmaceutics 2022, 14(8), 1738; https://doi.org/10.3390/pharmaceutics14081738 - 20 Aug 2022

Cited by 9 | Viewed by 2382

Abstract

In drug delivery, the development of nanovesicles that combine both synthetic and cellular components provides added biocompatibility and targeting specificity in comparison to conventional synthetic carriers such as liposomes. Produced through the fusion of U937 monocytes’ membranes and synthetic lipids, our nano-cell vesicle [...] Read more.

In drug delivery, the development of nanovesicles that combine both synthetic and cellular components provides added biocompatibility and targeting specificity in comparison to conventional synthetic carriers such as liposomes. Produced through the fusion of U937 monocytes’ membranes and synthetic lipids, our nano-cell vesicle technology systems (nCVTs) showed promising results as targeted cancer treatment. However, no investigation has been conducted yet on the immunogenic profile and the uptake mechanisms of nCVTs. Hence, this study was aimed at exploring the potential cytotoxicity and immune cells’ activation by nCVTs, as well as the routes through which cells internalize these biohybrid systems. The endocytic pathways were selectively inhibited to establish if the presence of cellular components in nCVTs affected the internalization route in comparison to both liposomes (made up of synthetic lipids only) and nano-cellular membranes (made up of biological material only). As a result, nCVTs showed an 8-to-40-fold higher cellular internalization than liposomes within the first hour, mainly through receptor-mediated processes (i.e., clathrin- and caveolae-mediated endocytosis), and low immunostimulatory potential (as indicated by the level of IL-1α, IL-6, and TNF-α cytokines) both in vitro and in vivo. These data confirmed that nCVTs preserved surface cues from their parent U937 cells and can be rationally engineered to incorporate ligands that enhance the selective uptake and delivery toward target cells and tissues. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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19 pages, 3431 KiB

Open AccessArticle

Phyto-Phospholipid Conjugated Scorpion Venom Nanovesicles as Promising Carrier That Improves Efficacy of Thymoquinone against Adenocarcinoma Human Alveolar Basal Epithelial Cells

by Hani Z. Asfour, Usama A. Fahmy, Waleed S. Alharbi, Alshaimaa M. Almehmady, Abdulmohsin J. Alamoudi, Singkome Tima, Rasha A. Mansouri, Ulfat M. Omar, Osama A. A. Ahmed, Shadi A. Zakai, Ahmed A. Aldarmahi, Alaa Bagalagel, Reem Diri and Nabil A. Alhakamy

Pharmaceutics 2021, 13(12), 2144; https://doi.org/10.3390/pharmaceutics13122144 - 13 Dec 2021

Cited by 6 | Viewed by 2355

Abstract

Lung cancer is a dangerous type of cancer in men and the third leading cause of cancer-related death in women, behind breast and colorectal cancers. Thymoquinone (THQ), a main compound in black seed essential oils, has a variety of beneficial effects, including antiproliferative, [...] Read more.

Lung cancer is a dangerous type of cancer in men and the third leading cause of cancer-related death in women, behind breast and colorectal cancers. Thymoquinone (THQ), a main compound in black seed essential oils, has a variety of beneficial effects, including antiproliferative, anti-inflammatory, and antioxidant properties. On the other hand, scorpion venom peptides (SV) induce apoptosis in the cancer cells, making it a promising anticancer agent. THQ, SV, and Phospholipon^® 90H (PL) were incorporated in a nano-based delivery platform to assess THQ’s cellular uptake and antiproliferative efficacy against a lung cancer cell line derived from human alveolar epithelial cells (A549). Several nanovesicles were prepared and optimized using factorial experimental design. The optimized phytosome formulation contained 79.0 mg of PL and 170.0 mg of SV, with vesicle size and zeta potential of 209.9 nm and 21.1 mV, respectively. The IC50 values revealed that A549 cells were significantly more sensitive to the THQ formula than the plain formula and THQ. Cell cycle analysis revealed that THQ formula treatment resulted in significant cell cycle arrest at the S phase, increasing cell population in this phase by 22.1%. Furthermore, the THQ formula greatly increased cell apoptosis (25.17%) when compared to the untreated control (1.76%), plain formula (11.96%), or THQ alone (13.18%). The results also indicated that treatment with THQ formula significantly increased caspase-3, Bax, Bcl-2, and p53 mRNA expression compared to plain formula and THQ. In terms of the inflammatory markers, THQ formula significantly reduced the activity of TNF-α and NF-κB in comparison with the plain formula and THQ only. Overall, the findings from the study proved that a phytosome formulation of THQ could be a promising therapeutic approach for the treatment of lung adenocarcinoma. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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14 pages, 1968 KiB

Open AccessArticle

Exosome-Mediated Insulin Delivery for the Potential Treatment of Diabetes Mellitus

by Belén Rodríguez-Morales, Marilena Antunes-Ricardo and José González-Valdez

Pharmaceutics 2021, 13(11), 1870; https://doi.org/10.3390/pharmaceutics13111870 - 05 Nov 2021

Cited by 11 | Viewed by 2525

Abstract

Exosomes are extracellular nanovesicles between 30 and 150 nm that serve as essential messengers for different biological signaling and pathological processes. After their discovery, a wide range of applications have been developed, especially in therapeutic drug delivery. In this context, the aim of [...] Read more.

Exosomes are extracellular nanovesicles between 30 and 150 nm that serve as essential messengers for different biological signaling and pathological processes. After their discovery, a wide range of applications have been developed, especially in therapeutic drug delivery. In this context, the aim of this work was to test the efficiency of exosome-mediated human insulin delivery using exosomes extracted from three different cell lines: hepatocellular carcinoma (HepG2); primary dermal fibroblasts (HDFa) and pancreatic β cells (RIN-m); all are related to the production and/or the ability to sense insulin and to consequently regulate glucose levels in the extracellular medium. The obtained results revealed that the optimal insulin loading efficiency was achieved by a 200 V electroporation, in comparison with incubation at room temperature. Moreover, the maximum in vitro exosome uptake was reached after incubation for 6 h, which slightly decreased 24 h after adding the exosomes. Glucose quantification assays revealed that exosome-mediated incorporation of insulin presented significant differences in HDFa and HepG2 cells, enhancing the transport in HDFa, in comparison with free human insulin effects in the regulation of extracellular glucose levels. No significant differences were found between the treatments in RIN-m cells. Hence, the results suggest that exosomes could potentially become a valuable tool for stable and biocompatible insulin delivery in diabetes mellitus treatment alternatives. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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Review

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28 pages, 2108 KiB

Open AccessReview

Current Applications of Plant-Based Drug Delivery Nano Systems for Leishmaniasis Treatment

by Darline B. dos Santos, Janaina A. Lemos, Sued E. M. Miranda, Leonardo D. Di Filippo, Jonatas L. Duarte, Lucas A. M. Ferreira, Andre L. B. Barros and Anna E. M. F. M. Oliveira

Pharmaceutics 2022, 14(11), 2339; https://doi.org/10.3390/pharmaceutics14112339 - 29 Oct 2022

Cited by 3 | Viewed by 1800

Abstract

Leishmania is a trypanosomatid that causes leishmaniasis. It is transmitted to vertebrate hosts during the blood meal of phlebotomine sandflies. The clinical manifestations of the disease are associated with several factors, such as the Leishmania species, virulence and pathogenicity, the host–parasite relationship, and [...] Read more.

Leishmania is a trypanosomatid that causes leishmaniasis. It is transmitted to vertebrate hosts during the blood meal of phlebotomine sandflies. The clinical manifestations of the disease are associated with several factors, such as the Leishmania species, virulence and pathogenicity, the host–parasite relationship, and the host’s immune system. Although its causative agents have been known and studied for decades, there have been few advances in the chemotherapy of leishmaniasis. The urgency of more selective and less toxic alternatives for the treatment of leishmaniasis leads to research focused on the study of new pharmaceuticals, improvement of existing drugs, and new routes of drug administration. Natural resources of plant origin are promising sources of bioactive substances, and the use of ethnopharmacology and folk medicine leads to interest in studying new medications from phytocomplexes. However, the intrinsic low water solubility of plant derivatives is an obstacle to developing a therapeutic product. Nanotechnology could help overcome these obstacles by improving the availability of common substances in water. To contribute to this scenario, this article provides a review of nanocarriers developed for delivering plant-extracted compounds to treat clinical forms of leishmaniasis and critically analyzing them and pointing out the future perspectives for their application. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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35 pages, 2229 KiB

Open AccessReview

Employ of Anthocyanins in Nanocarriers for Nano Delivery: In Vitro and In Vivo Experimental Approaches for Chronic Diseases

by Ana C. Gonçalves, Amílcar Falcão, Gilberto Alves, João A. Lopes and Luís R. Silva

Pharmaceutics 2022, 14(11), 2272; https://doi.org/10.3390/pharmaceutics14112272 - 24 Oct 2022

Cited by 12 | Viewed by 2399

Abstract

Anthocyanins are among the best-known phenolic compounds and possess remarkable biological activities, including antioxidant, anti-inflammatory, anticancer, and antidiabetic effects. Despite their therapeutic benefits, they are not widely used as health-promoting agents due to their instability, low absorption, and, thus, low bioavailability and rapid [...] Read more.

Anthocyanins are among the best-known phenolic compounds and possess remarkable biological activities, including antioxidant, anti-inflammatory, anticancer, and antidiabetic effects. Despite their therapeutic benefits, they are not widely used as health-promoting agents due to their instability, low absorption, and, thus, low bioavailability and rapid metabolism in the human body. Recent research suggests that the application of nanotechnology could increase their solubility and/or bioavailability, and thus their biological potential. Therefore, in this review, we have provided, for the first time, a comprehensive overview of in vitro and in vivo studies on nanocarriers used as delivery systems of anthocyanins, and their aglycones, i.e., anthocyanidins alone or combined with conventional drugs in the treatment or management of chronic diseases. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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26 pages, 2276 KiB

Open AccessReview

Nanofiber Systems as Herbal Bioactive Compounds Carriers: Current Applications in Healthcare

by Kathya Huesca-Urióstegui, Elsy J. García-Valderrama, Janet A. Gutierrez-Uribe, Marilena Antunes-Ricardo and Daniel Guajardo-Flores

Pharmaceutics 2022, 14(1), 191; https://doi.org/10.3390/pharmaceutics14010191 - 14 Jan 2022

Cited by 14 | Viewed by 2983

Abstract

Nanofibers have emerged as a potential novel platform due to their physicochemical properties for healthcare applications. Nanofibers’ advantages rely on their high specific surface-area-to-volume and highly porous mesh. Their peculiar assembly allows cell accommodation, nutrient infiltration, gas exchange, waste excretion, high drug release [...] Read more.

Nanofibers have emerged as a potential novel platform due to their physicochemical properties for healthcare applications. Nanofibers’ advantages rely on their high specific surface-area-to-volume and highly porous mesh. Their peculiar assembly allows cell accommodation, nutrient infiltration, gas exchange, waste excretion, high drug release rate, and stable structure. This review provided comprehensive information on the design and development of natural-based polymer nanofibers with the incorporation of herbal medicines for the treatment of common diseases and their in vivo studies. Natural and synthetic polymers have been widely used for the fabrication of nanofibers capable of mimicking extracellular matrix structure. Among them, natural polymers are preferred because of their biocompatibility, biodegradability, and similarity with extracellular matrix proteins. Herbal bioactive compounds from natural extracts have raised special interest due to their prominent beneficial properties in healthcare. Nanofiber properties allow these systems to serve as bioactive compound carriers to generate functional matrices with antimicrobial, anti-inflammatory, antioxidant, antiseptic, anti-viral, and other properties which have been studied in vitro and in vivo, mostly to prove their wound healing capacity and anti-inflammation properties. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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28 pages, 2544 KiB

Open AccessReview

Potential Applications and Functional Roles of Exosomes in Cardiometabolic Disease

by Sergio Ayala-Mar, Belén Rodríguez-Morales, Pedro Chacón-Ponce and José González-Valdez

Pharmaceutics 2021, 13(12), 2056; https://doi.org/10.3390/pharmaceutics13122056 - 02 Dec 2021

Cited by 4 | Viewed by 3334

Abstract

Despite diagnostic and therapeutic advances, cardiometabolic disease remains the leading cause of death worldwide. Extracellular vesicles (EVs), which include exosomes and microvesicles, have gained particular interest because of their role in metabolic homeostasis and cardiovascular physiology. Indeed, EVs are recognized as critical mediators [...] Read more.

Despite diagnostic and therapeutic advances, cardiometabolic disease remains the leading cause of death worldwide. Extracellular vesicles (EVs), which include exosomes and microvesicles, have gained particular interest because of their role in metabolic homeostasis and cardiovascular physiology. Indeed, EVs are recognized as critical mediators of intercellular communication in the cardiovascular system. Exosomes are naturally occurring nanocarriers that transfer biological information in the setting of metabolic abnormalities and cardiac dysfunction. The study of these EVs can increase our knowledge on the pathophysiological mechanisms of metabolic disorders and their cardiovascular complications. Because of their inherent properties and composition, exosomes have been proposed as diagnostic and prognostic biomarkers and therapeutics for specific targeting and drug delivery. Emerging fields of study explore the use exosomes as tools for gene therapy and as a cell-free alternative for regenerative medicine. Furthermore, innovative biomaterials can incorporate exosomes to enhance tissue regeneration and engineering. In this work, we summarize the most recent knowledge on the role of exosomes in cardiometabolic pathophysiology while highlighting their potential therapeutic applications. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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24 pages, 1600 KiB

Open AccessReview

Non-Viral Gene Delivery Systems for Treatment of Myocardial Infarction: Targeting Strategies and Cardiac Cell Modulation

by Jieting Wang, Luying Yu, Ao Zhou, Jie Liu, Kai Wang, Ying Luo and Fang Wang

Pharmaceutics 2021, 13(9), 1520; https://doi.org/10.3390/pharmaceutics13091520 - 19 Sep 2021

Cited by 4 | Viewed by 3026

Abstract

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide. Conventional therapies involving surgery or pharmacological strategies have shown limited therapeutic effects due to a lack of cardiac tissue repair. Gene therapy has opened an avenue for the treatment of cardiac [...] Read more.

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide. Conventional therapies involving surgery or pharmacological strategies have shown limited therapeutic effects due to a lack of cardiac tissue repair. Gene therapy has opened an avenue for the treatment of cardiac diseases through manipulating the underlying gene mechanics. Several gene therapies for cardiac diseases have been assessed in clinical trials, while the clinical translation greatly depends on the delivery technologies. Non-viral vectors are attracting much attention due to their safety and facile production compared to viral vectors. In this review, we discuss the recent progress of non-viral gene therapies for the treatment of cardiovascular diseases, with a particular focus on myocardial infarction (MI). Through a summary of delivery strategies with which to target cardiac tissue and different cardiac cells for MI treatment, this review aims to inspire new insights into the design/exploitation of non-viral delivery systems for gene cargos to promote cardiac repair/regeneration. Full article

(This article belongs to the Special Issue Novel Insights in Delivery Systems: Phytochemicals and Biopharmaceuticals)

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