Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India; Academy of Scientific and Innovation Research (AcSIR), Ghaziabad 201002, U.P., India.
Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India.
Int J Pharm. 2024 Jun 25;659:124234. doi: 10.1016/j.ijpharm.2024.124234. Epub 2024 May 17.
In this study, we have proposed a novel approach that combines hyaluronic acid (HA), folic acid (FA), and celastrol (CLS) within a polymeric micelle system (CLS-HF/MLs), offering a dual-action strategy against breast cancer. Polymeric mixed micelles were prepared through the thin-film hydration method, and comprehensive quality control parameters were established, encompassing particle size, polydispersity index, zeta potential, surface morphology, encapsulation efficiency, drug content, in vitro drug release, and storage stability assessment. The average particle size of CLS-HF/MLs micelles was found to be 120 nm and their drug loading and encapsulation efficiencies were 15.9 % and 89.52 %, respectively. The in vitro release data showed that the CLS-HF/MLs targeted mixed micelles displayed a prolonged release profile compared to the free drug. Additionally, the stability of the developed polymeric mixed micelles was maintained for up to 8 weeks of storage in terms of particle size and drug content. Furthermore, both flow cytometry and confocal laser scanning microscopy studies indicated a significant enhancement in the cellular uptake efficiency and cytotoxicity of CLS-HF/MLs mixed micelles against MCF-7 cell line. In terms of pharmacokinetic analysis, the half-life and AUC values of CLS-HF/MLs mixed micelles were found to be approximately 4.71- and 7.36-folds higher than the values of free drug (CLS), respectively. The CLS-HF/MLs micelles exhibited remarkable antitumor efficacy (almost complete ablation of the 4 T1-cell bearing tumor xenografts mouse model) due to the dual receptor (CD44 and folate) targeting effects with minimal side effects. When considering the cumulative findings of our present research, it becomes evident that mixed micelles designed for chemotherapy offer a promising and potentially effective therapeutic avenue for the treatment of breast cancer.
在这项研究中，我们提出了一种新的方法，即将透明质酸（HA）、叶酸（FA）和雷公藤红素（CLS）结合到聚合物胶束系统（CLS-HF/MLs）中，提供一种针对乳腺癌的双重作用策略。通过薄膜水化法制备聚合物混合胶束，并建立了综合质量控制参数，包括粒径、多分散指数、zeta 电位、表面形态、包封效率、药物含量、体外药物释放和储存稳定性评估。CLS-HF/MLs 胶束的平均粒径为 120nm，其载药量和包封率分别为 15.9%和 89.52%。体外释放数据表明，CLS-HF/MLs 靶向混合胶束与游离药物相比具有延长的释放曲线。此外，在长达 8 周的储存期内，开发的聚合物混合胶束的稳定性保持不变，粒径和药物含量均保持稳定。此外，流式细胞术和共聚焦激光扫描显微镜研究表明，CLS-HF/MLs 混合胶束对 MCF-7 细胞系的细胞摄取效率和细胞毒性均显著增强。在药代动力学分析方面，CLS-HF/MLs 混合胶束的半衰期和 AUC 值分别约为游离药物（CLS）的 4.71-和 7.36 倍。CLS-HF/MLs 胶束由于具有双重受体（CD44 和叶酸）靶向作用，副作用极小，表现出显著的抗肿瘤功效（几乎完全消融 4T1 细胞荷瘤小鼠模型）。综合考虑我们目前研究的结果，可以明显看出，用于化疗的混合胶束为治疗乳腺癌提供了一种有前途且可能有效的治疗途径。
