fabrication-ultra-sharp-polymeric-microneedles-via-computer-numerical

Fabrication of Ultra-sharp Polymeric Microneedles <em>via</em> Computer Numerical Control (CNC) Micromachining and Micromolding

Microneedles have recently gained recognition as a promising method in transdermal drug delivery owing to their minimally invasive, painless nature, and ...

International University, Ho Chi Minh City, Vietnam

Vietnam National University, Ho Chi Minh City, Vietnam

Amino acids have attracted considerable attention in drug development because they play important roles in many physiological and pathological processes. In the past several decades, various amino acid supplementations have been reported to have potential therapeutic efficacy for the treatment of many disorders in clinical trials. However, their effectiveness is controversially reported, which may be explained by poor pharmacokinetic properties of such low-molecular-weight agents. Amino acid-based self-assembled macromolecules could overcome the aforementioned drawbacks by improving the pharmacokinetic profile and accumulation of specific molecules at target sites to enhance the therapeutic effect. In this review, we have discussed the current therapeutic applications of certain amino acids, and have introduced our approach of using amino acid-based self-assembled nanostructures as novel therapeutic agents.

Design of amino acid-based self-assembled nano-drugs for therapeutic applications.

Chronic inflammatory diseases such as inflammatory bowel diseases (IBD), which are strongly related to the overproduction of reactive oxygen species (ROS), have become more threatening to health. Silymarin is an active compound with the effect of expressing anti-inflammatory activity; however, it exhibits poor bioavailability due to the rapid metabolism and secretion, low permeability across the intestinal epithelial cells, and poor water solubility. In this study, we developed silica-containing redox nanoparticles (siRNP) with 50-60 nm in diameter to improve the bioavailability of silymarin by improving its uptake into the bloodstream and delivery to the targeted tissues of the colon. Silymarin-loaded siRNP (SM@siRNP) significantly increased the antioxidant capacity and anti-inflammatory efficacy in vitro by scavenging 2,2-diphenyl-1-picrylhydrazyl free radical and suppressing nitric oxide and pro-inflammatory cytokines as compared to the other treatments such as free silymarin, siRNP, and silymarin-loaded si-nRNP (the control nanoparticle without ROS scavenging property). Orally administered SM@siRNP significantly improved the bioavailability of silymarin and its retention in the colonic mucosa. The anti-inflammatory effects of SM@siRNP were also investigated in dextran sodium sulfate (DSS)-induced colitis in mice and it was observed that SM@siRNP treatment significantly improved the damage in the colonic mucosa of DSS colitis mice as compared to the other treatments. The results in this study indicate that SM@siRNP is a promising nanomedicine for enhancing the anti-inflammatory activity of silymarin and has a high potential for the treatment of IBD.

Improving silymarin oral bioavailability using silica-installed redox nanoparticle to suppress inflammatory bowel disease.

Camptothecin (CPT) is a potent anticancer agent for the treatment of colorectal cancer; however, it exhibits some limitations, including poor solubility, low stability, and low bioavailability via oral administration, which restrict its usability in clinical treatments. In addition, overproduction of reactive oxygen species (ROS) during chemotherapy induces drug resistance and severe intestinal side effects. In this study, silica-installed ROS scavenging nanoparticles (siRNP) with 50-60 nm in diameter were employed to overcome the aforementioned drawbacks of CPT. The solubility of CPT was significantly improved by incorporating it into the core of the nanoparticle, forming CPT-loaded siRNP (CPT@siRNP). The anticancer activity of CPT@siRNP against colorectal cancer cells (C-26) in vitro was significantly improved as compared to free CPT through higher efficiency of intracellular internalization and induction of apoptosis. Owing to its antioxidant properties, CPT@siRNP reduced cytotoxicity to normal endothelial cells, which was in sharp contrast to the high toxicity of free CPT. Oral administration of CPT and CPT@siRNP to the C-26 tumor-bearing mice exhibited antitumor activity, accompanied by effective suppression of tumor growth. Although CPT treatment suppressed tumor progression, it caused severe side effects, including intestinal damage and significant bodyweight loss. Interestingly, such noticeable side effects were not observed in the mice treated with CPT@siRNP, and the effect of tumor growth inhibition tended to be similar to or higher than that of CPT treatment. The results obtained in this study indicate that CPT@siRNP is a potential therapeutic nanomedicine for the treatment of colon cancer. STATEMENT OF SIGNIFICANCE: Here we employed silica-containing antioxidant nanoparticle (siRNP) as promising oral delivery nanocarrier of campothecin (CPT) to treat colon cancer. The design of siRNP via covalent conjugation of antioxidant nitroxide radicals and the silanol groups in the polymer backbone contributes to a significant increase in the absorption of hydrophobic drug molecules inside the core and enhances the stability of nanoparticles in the gastrointestinal environment for oral drug delivery. CPT-loaded siRNP (CPT@siRNP) significantly improved solubility of CPT. As compared to free CTP, the CPT@siRNP treatment showed a significantly higher toxicity to colon cancer cell, inhibition of cancer cell migration, and induction of apopotosis. With the antioxidant feature, siRNP also significantly suppressed the intestinal side effects caused by CPT treatment in tumor-bearing mouse model.

A silica-based antioxidant nanoparticle for oral delivery of Camptothecin which reduces intestinal side effects while improving drug efficacy for colon cancer treatment.

Compounds containing benzimidazole moiety occupy privileged chemical space for discovering new bioactive substances. In continuation of our recent work, 69 benzimidazole derivatives were designed and synthesized with good to excellent yields of 46-99% using efficient synthesis protocol  sodium metabisulfite catalyzed condensation of aromatic aldehydes with -phenylenediamines to form 2-arylbenzimidazole derivatives followed by -alkylation by conventional heating or microwave irradiation for diversification. Potent antibacterial compounds against MSSA and MRSA were discovered such as benzimidazole compounds 3k (2-(4-nitrophenyl), -benzyl), 3l (2-(4-chlorophenyl), -(4-chlorobenzyl)), 4c (2-(4-chlorophenyl), 6-methyl, -benzyl), 4g (2-(4-nitrophenyl), 6-methyl, -benzyl), and 4j (2-(4-nitrophenyl), 6-methyl, -(4-chlorobenzyl)) with MIC of 4-16 μg mL. In addition, compound 4c showed good antimicrobial activities (MIC = 16 μg mL) against the bacteria strains  and . Moreover, compounds 3k, 3l, 4c, 4g, and 4j have been found to kill HepG2, MDA-MB-231, MCF7, RMS, and C26 cancer cells with low μM IC (2.39-10.95). These compounds showed comparable drug-like properties as ciprofloxacin, fluconazole, and paclitaxel in computational ADMET profiling. Finally, docking studies were used to assess potential protein targets responsible for their biological activities. Especially, we found that DHFR is a promising target both  and  with compound 4c having IC of 2.35 μM.

,2,6-Trisubstituted 1-benzimidazole derivatives as a new scaffold of antimicrobial and anticancer agents: design, synthesis,  evaluation, and  studies.

Gastric ulcer is a common gastrointestinal disorder worldwide. Although its pathogenesis is unclear, the overproduction of reactive oxygen species (ROS), which results in an oxidative imbalance, has been reported as a central driving mechanism. Within the scope of this investigation, we developed two different self-assembling redox nanoparticles (RNPs) with ROS-scavenging features for the oral treatment of gastric ulcers. One of them, referred to as RNP, disintegrates in response to acidic pH, whereas the other, denoted as RNP, remains intact regardless of pH variations. Both types of RNPs showed different free radical scavenging activities in vitro. Protonation of the amino linkages in the side chains of RNP caused the micelle structure to collapse and the nitroxide radicals encapsulated in the core were exposed to the outside, resulting in a significant increase in antioxidant capacity as the pH decreases. In contrast, RNP maintained its spherical structure and consistent antioxidant reactivity irrespective of pH changes. The in vivo gastric retention of orally administered RNP was significantly improved compared to that of RNP which might be explained by the increased exposure of cationic protonating segments in RNP on the negatively charged gastric mucosal surface. Owing to its improved gastric retention and enhanced ROS scavenging capacity under acidic pH conditions, RNP exhibited superior protective effects against oxidative stress induced by aspirin in a gastric ulcer mouse model compared to RNP. In addition, neither RNP nor RNP resulted in severe lethal effects or significant changes in the morphology of zebrafish embryos, indicating their biosafety. Our results suggest that the oral administration of RNPs has a high therapeutic potential for gastric ulcer treatment.

Article	Year
Design of amino acid-based self-assembled nano-drugs for therapeutic applications. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 32562856	2020
Improving silymarin oral bioavailability using silica-installed redox nanoparticle to suppress inflammatory bowel disease. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 33616078	2021
A silica-based antioxidant nanoparticle for oral delivery of Camptothecin which reduces intestinal side effects while improving drug efficacy for colon cancer treatment. Acta biomaterialia\| PubMed ID: 35235866	2022
,2,6-Trisubstituted 1-benzimidazole derivatives as a new scaffold of antimicrobial and anticancer agents: design, synthesis, evaluation, and studies. RSC advances\| PubMed ID: 36605630	2022
Development of oral pH-sensitive redox nanotherapeutics for gastric ulcer therapy. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 39326501	2024

Long Binh Vong

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