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12 pages, 1490 KiB

Open AccessArticle

Therapeutic Potential of Naringenin Nanosuspension: In Vitro and In Vivo Anti-Osteoporotic Studies

by Sonia Gera, Sunitha Sampathi, Sravya Maddukuri, Sujatha Dodoala, Vijayabhaskarreddy Junnuthula and Sathish Dyawanapelly

Pharmaceutics 2022, 14(7), 1449; https://doi.org/10.3390/pharmaceutics14071449 - 11 Jul 2022

Cited by 19 | Viewed by 3180

Abstract

Naringenin (NRG) is a flavonoid and has been reported as an anti-osteoporotic agent. However, poor bioavailability may limit the anti-osteoporotic potential of the drug. The purpose of the study was to compare the anti-osteoporotic activity of naringenin nanosuspension (NRG-NS) with the NRG and [...] Read more.

Naringenin (NRG) is a flavonoid and has been reported as an anti-osteoporotic agent. However, poor bioavailability may limit the anti-osteoporotic potential of the drug. The purpose of the study was to compare the anti-osteoporotic activity of naringenin nanosuspension (NRG-NS) with the NRG and standard therapeutic drug, raloxifene hydrochloride (RLX). Here, NRG-NS showed anti-osteoporotic activity in MG-63 cells by upregulating the osteocalcin levels. The in vivo anti-osteoporotic activity of NRG-NS was further investigated in an osteoporotic rat model to mimic the post-menopausal condition. The animals were randomized and separated into six groups. The animals were treated with RLX (p.o., 5.4 mg/kg), NRG (p.o., 20 mg/kg), NRG-NS (p.o., 20 mg/kg), and blank-NS for 60 days after completion of a 30-day post-surgery period and compared with control and ovariectomized (OVX) groups. After the treatment, body and uterine weights, biochemical estimation in serum (calcium, phosphorus, acid phosphatase, alkaline phosphatase, osteocalcin), bone parameters (length, diameter, dry weight, density, ash weight, bone mineral content) and bone microarchitecture by histopathology were determined. The results showed the protective effects of NRG-NS on osteoblast-like MG-63 cells. The biochemical estimations confirmed the normalization of parameters viz., alkaline phosphatase, calcium concentrations, and bone density with a decrease in levels of acid phosphatase and inorganic phosphorus with NRG-NS as compared to plain NRG. The results indicated that the oral administration of NRG-NS could be a potential therapeutic formulation for the treatment of osteoporosis. Full article

(This article belongs to the Special Issue Drug Discovery and Drug Delivery System for Biological Application)

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16 pages, 4405 KiB

Open AccessArticle

Dexamethasone-Loaded Ureasil Hydrophobic Membrane for Bone Guided Regeneration

by Rafaella Moreno Barros, Camila Garcia Da Silva, Kammila Martins Nicolau Costa, Arnóbio A. Da Silva-Junior, Cássio Rocha Scardueli, Rosemary Adriana Chiérici Marcantonio, Leila Aparecida Chiavacci and João Augusto Oshiro-Junior

Pharmaceutics 2022, 14(5), 1027; https://doi.org/10.3390/pharmaceutics14051027 - 10 May 2022

Cited by 3 | Viewed by 1945

Abstract

Physical barrier membranes have been used to release active substances to treat critical bone defects; however, hydrophilic membranes do not present a prolonged release capacity. In this sense, hydrophobic membranes have been tested. Thus, this study aimed to develop hydrophobic membranes based on [...] Read more.

Physical barrier membranes have been used to release active substances to treat critical bone defects; however, hydrophilic membranes do not present a prolonged release capacity. In this sense, hydrophobic membranes have been tested. Thus, this study aimed to develop hydrophobic membranes based on mixtures of ureasil–polyether-type materials containing incorporated dexamethasone (DMA) for the application in guided bone regeneration. The physicochemical characterization and biological assays were carried out using small-angle X-ray scattering (SAXS), an in vitro DMA release study, atomic force microscopy (AFM), a hemolysis test, and in vivo bone formation. The swelling degree, SAXS, and release results revealed that the u-PPO400/2000 membrane in the proportion of 70:30 showed swelling (4.69% ± 0.22) similar to the proportions 90:10 and 80:20, and lower than the proportion 60:40 (6.38% ± 0.49); however, an equal release percentage after 134 h was observed between the proportions 70:30 and 60:40. All u-PPO materials presented hemocompatibility (hemolysis ≤2.8%). AFM results showed that the treatments with or without DMA did not present significant differences, revealing a flat/smooth surface, with no pores and/or crystalline precipitates. Finally, in vivo results revealed that for both the commercial hydrophilic membrane and u-PPO400/2000 (70:30) after 60 days, the bone formation volume was 21%. In conclusion, hybrid membranes present unique characteristics for treating critical bone defects, considering the delayed and prolonged release results associated with the physical barrier capacity. Full article

(This article belongs to the Special Issue Drug Discovery and Drug Delivery System for Biological Application)

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22 pages, 3741 KiB

Open AccessArticle

Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease

by Leonardo da Silva Lara, Guilherme Curty Lechuga, Lorraine Martins Rocha Orlando, Byanca Silva Ferreira, Bernardo Araújo Souto, Maurício Silva dos Santos and Mirian Claudia de Souza Pereira

Pharmaceutics 2022, 14(5), 995; https://doi.org/10.3390/pharmaceutics14050995 - 5 May 2022

Cited by 8 | Viewed by 2214

Abstract

Chagas disease, a century-old disease that mainly affects the impoverished population in Latin America, causes high morbidity and mortality in endemic countries. The available drugs, benznidazole (Bz) and nifurtimox, have limited effectiveness and intense side effects. Drug repurposing, and the development of new [...] Read more.

Chagas disease, a century-old disease that mainly affects the impoverished population in Latin America, causes high morbidity and mortality in endemic countries. The available drugs, benznidazole (Bz) and nifurtimox, have limited effectiveness and intense side effects. Drug repurposing, and the development of new chemical entities with potent activity against Trypanosoma cruzi, are a potential source of therapeutic options. The present study describes the biological activity of two new series of pyrazole-thiazoline derivatives, based on optimization of a hit system 5-aminopyrazole-imidazoline previously identified, using structure–activity relationship exploration, and computational and phenotype-based strategies. Promising candidates, 2c, 2e, and 2i derivatives, showed good oral bioavailability and ADMET properties, and low cytotoxicity (CC₅₀ > 100 µM) besides potent activity against trypomastigotes (0.4–2.1 µM) compared to Bz (19.6 ± 2.3 µM). Among them, 2c also stands out, with greater potency against intracellular amastigotes (pIC₅₀ = 5.85). The selected pyrazole-thiazoline derivatives showed good permeability and effectiveness in the 3D spheroids system, but did not sustain parasite clearance in a washout assay. The compounds’ mechanism of action is still unknown, since the treatment neither increased reactive oxygen species, nor reduced cysteine protease activity. This new scaffold will be targeted to optimize in order to enhance its biological activity to identify new drug candidates for Chagas disease therapy. Full article

(This article belongs to the Special Issue Drug Discovery and Drug Delivery System for Biological Application)

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15 pages, 21811 KiB

Open AccessArticle

In Vitro Validation of Antiparasitic Activity of PLA-Nanoparticles of Sodium Diethyldithiocarbamate against Trypanosoma cruzi

by Johny Wysllas de Freitas Oliveira, Mariana Farias Alves da Silva, Igor Zumba Damasceno, Hugo Alexandre Oliveira Rocha, Arnóbio Antônio da Silva Júnior and Marcelo Sousa Silva

Pharmaceutics 2022, 14(3), 497; https://doi.org/10.3390/pharmaceutics14030497 - 24 Feb 2022

Cited by 5 | Viewed by 2486

Abstract

Trypanosoma cruzi is a protozoan parasite responsible for Chagas disease, which affects millions around the world and is not treatable in its chronic stage. Sodium diethyldithiocarbamate is a compound belonging to the carbamate class and, in a previous study, demonstrated high efficacy against [...] Read more.

Trypanosoma cruzi is a protozoan parasite responsible for Chagas disease, which affects millions around the world and is not treatable in its chronic stage. Sodium diethyldithiocarbamate is a compound belonging to the carbamate class and, in a previous study, demonstrated high efficacy against T. cruzi, showing itself to be a promising compound for the treatment of Chagas disease. This study investigates the encapsulation of sodium diethyldithiocarbamate by poly-lactic acid in nanoparticles, a system of biodegradable nanoparticles that is capable of reducing the toxicity caused by free DETC against cells and maintaining the antiparasitic activity. The nanosystem PLA-DETC was fabricated using nanoprecipitation, and its physical characterization was measured via DLS, SEM, and AFM, demonstrating a small size around 168 nm and a zeta potential of around −19 mv. Furthermore, the toxicity was determined by MTT reduction against three cell lines (VERO, 3T3, and RAW), and when compared to free DETC, we observed a reduction in cell mortality, demonstrating the importance of DETC nanoencapsulation. In addition, the nanoparticles were stained with FITC and put in contact with cells for 24 h, followed by confirmation of whether the nanosystem was inside the cells. Lastly, the antiparasitic activity against different strains of T. cruzi in trypomastigote forms was determined by resazurin reduction and ROS production, which demonstrated high efficacy towards T. cruzi equal to that of free DETC. Full article

(This article belongs to the Special Issue Drug Discovery and Drug Delivery System for Biological Application)

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21 pages, 34622 KiB

Open AccessArticle

The Compound (E)-2-Cyano-N,3-diphenylacrylamide (JMPR-01): A Potential Drug for Treatment of Inflammatory Diseases

by Pablo Rayff da Silva, Renan Fernandes do Espírito Santo, Camila de Oliveira Melo, Fábio Emanuel Pachú Cavalcante, Thássia Borges Costa, Yasmim Vilarim Barbosa, Yvnni M. S. de Medeiros e Silva, Natália Ferreira de Sousa, Cristiane Flora Villarreal, Ricardo Olímpio de Moura and Vanda Lucia dos Santos

Pharmaceutics 2022, 14(1), 188; https://doi.org/10.3390/pharmaceutics14010188 - 13 Jan 2022

Cited by 6 | Viewed by 2493

Abstract

The compound (E)-2-cyano-N,3-diphenylacrylamide (JMPR-01) was structurally developed using bioisosteric modifications of a hybrid prototype as formed from fragments of indomethacin and paracetamol. Initially, in vitro assays were performed to determine cell viability (in macrophage cultures), and its ability to modulate [...] Read more.

The compound (E)-2-cyano-N,3-diphenylacrylamide (JMPR-01) was structurally developed using bioisosteric modifications of a hybrid prototype as formed from fragments of indomethacin and paracetamol. Initially, in vitro assays were performed to determine cell viability (in macrophage cultures), and its ability to modulate the synthesis of nitrite and cytokines (IL-1β and TNFα) in non-cytotoxic concentrations. In vivo, anti-inflammatory activity was explored using the CFA-induced paw edema and zymosan-induced peritonitis models. To investigate possible molecular targets, molecular docking was performed with the following crystallographic structures: LT-A4-H, PDE4B, COX-2, 5-LOX, and iNOS. As results, we observed a significant reduction in the production of nitrite and IL-1β at all concentrations used, and also for TNFα with JMPR-01 at 50 and 25 μM. The anti-edematogenic activity of JMPR-01 (100 mg/kg) was significant, reducing edema at 2–6 h, similar to the dexamethasone control. In induced peritonitis, JMPR-01 reduced leukocyte migration by 61.8, 68.5, and 90.5% at respective doses of 5, 10, and 50 mg/kg. In silico, JMPR-01 presented satisfactory coupling; mainly with LT-A4-H, PDE4B, and iNOS. These preliminary results demonstrate the strong potential of JMPR-01 to become a drug for the treatment of inflammatory diseases. Full article

(This article belongs to the Special Issue Drug Discovery and Drug Delivery System for Biological Application)

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Review

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45 pages, 25291 KiB

Open AccessReview

Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications

by Sharma Arvind Virendra, Ankur Kumar, Pooja A. Chawla and Narsimha Mamidi

Pharmaceutics 2022, 14(10), 2139; https://doi.org/10.3390/pharmaceutics14102139 - 8 Oct 2022

Cited by 7 | Viewed by 2782

Abstract

The family of nuclear peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) is a set of ligand-activated transcription factors that regulate different functions in the body. Whereas activation of PPARα is known to reduce the levels of circulating triglycerides and regulate energy homeostasis, the [...] Read more.

The family of nuclear peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) is a set of ligand-activated transcription factors that regulate different functions in the body. Whereas activation of PPARα is known to reduce the levels of circulating triglycerides and regulate energy homeostasis, the activation of PPARγ brings about insulin sensitization and increases the metabolism of glucose. On the other hand, PPARβ when activated increases the metabolism of fatty acids. Further, these PPARs have been claimed to be utilized in various metabolic, neurological, and inflammatory diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity. A series of different heterocyclic scaffolds have been synthesized and evaluated for their ability to act as PPAR agonists. This review is a compilation of efforts on the part of medicinal chemists around the world to find novel compounds that may act as PPAR ligands along with patents in regards to PPAR ligands. The structure–activity relationship, as well as docking studies, have been documented to better understand the mechanistic investigations of various compounds, which will eventually aid in the design and development of new PPAR ligands. From the results of the structural activity relationship through the pharmacological and in silico evaluation the potency of heterocycles as PPAR ligands can be described in terms of their hydrogen bonding, hydrophobic interactions, and other interactions with PPAR. Full article

(This article belongs to the Special Issue Drug Discovery and Drug Delivery System for Biological Application)

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35 pages, 4090 KiB

Open AccessReview

Nanomedicines for Overcoming Cancer Drug Resistance

by Tingting Hu, Hanlin Gong, Jiayue Xu, Yuan Huang, Fengbo Wu and Zhiyao He

Pharmaceutics 2022, 14(8), 1606; https://doi.org/10.3390/pharmaceutics14081606 - 1 Aug 2022

Cited by 17 | Viewed by 3638

Abstract

Clinically, cancer drug resistance to chemotherapy, targeted therapy or immunotherapy remains the main impediment towards curative cancer therapy, which leads directly to treatment failure along with extended hospital stays, increased medical costs and high mortality. Therefore, increasing attention has been paid to nanotechnology-based [...] Read more.

Clinically, cancer drug resistance to chemotherapy, targeted therapy or immunotherapy remains the main impediment towards curative cancer therapy, which leads directly to treatment failure along with extended hospital stays, increased medical costs and high mortality. Therefore, increasing attention has been paid to nanotechnology-based delivery systems for overcoming drug resistance in cancer. In this respect, novel tumor-targeting nanomedicines offer fairly effective therapeutic strategies for surmounting the various limitations of chemotherapy, targeted therapy and immunotherapy, enabling more precise cancer treatment, more convenient monitoring of treatment agents, as well as surmounting cancer drug resistance, including multidrug resistance (MDR). Nanotechnology-based delivery systems, including liposomes, polymer micelles, nanoparticles (NPs), and DNA nanostructures, enable a large number of properly designed therapeutic nanomedicines. In this paper, we review the different mechanisms of cancer drug resistance to chemotherapy, targeted therapy and immunotherapy, and discuss the latest developments in nanomedicines for overcoming cancer drug resistance. Full article

(This article belongs to the Special Issue Drug Discovery and Drug Delivery System for Biological Application)

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38 pages, 3693 KiB

Open AccessEditor’s ChoiceReview

Redesigning of Cell-Penetrating Peptides to Improve Their Efficacy as a Drug Delivery System

by Ildikó Szabó, Mo’ath Yousef, Dóra Soltész, Csaba Bató, Gábor Mező and Zoltán Bánóczi

Pharmaceutics 2022, 14(5), 907; https://doi.org/10.3390/pharmaceutics14050907 - 21 Apr 2022

Cited by 38 | Viewed by 6272

Abstract

Cell-penetrating peptides (CPP) are promising tools for the transport of a broad range of compounds into cells. Since the discovery of the first members of this peptide family, many other peptides have been identified; nowadays, dozens of these peptides are known. These peptides [...] Read more.

Cell-penetrating peptides (CPP) are promising tools for the transport of a broad range of compounds into cells. Since the discovery of the first members of this peptide family, many other peptides have been identified; nowadays, dozens of these peptides are known. These peptides sometimes have very different chemical–physical properties, but they have similar drawbacks; e.g., non-specific internalization, fast elimination from the body, intracellular/vesicular entrapment. Although our knowledge regarding the mechanism and structure–activity relationship of internalization is growing, the prediction and design of the cell-penetrating properties are challenging. In this review, we focus on the different modifications of well-known CPPs to avoid their drawbacks, as well as how these modifications may increase their internalization and/or change the mechanism of penetration. Full article

(This article belongs to the Special Issue Drug Discovery and Drug Delivery System for Biological Application)

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