Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, 02115, United States.
Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, 06630, Ankara, Turkey.
Pharm Res. 2020 Mar 12;37(3):65. doi: 10.1007/s11095-020-2759-4.
Since the last decade, it is established that nonspecific delivery of chemotherapeutics fails to effectively treat cancer due to systemic cytotoxicity, poor biodistribution at tumor site and most importantly the development of drug resistance (MDR). Stimuli-sensitive drug delivery systems gained significant attention in recent years for effective tumor therapy and reversal of MDR. The aim of this study was developing a redox sensitive micellar prodrug system, by taking the advantage of the significant difference in GSH levels between extracellular and intracellular environments, but more importantly in healthy and tumor tissues.
Redox sensitive PEG-S-S-PTX micelles were developed for intracellular paclitaxel delivery and characterized in vitro. In vitro release studies were carried out and followed by cytotoxicity studies in chemo-resistant ovarian and breast cancer cells in various reducing environments for different time periods to confirm their potential.
PEG-S-S-PTX, was synthesized and characterized as a redox sensitive micellar prodrug system. The reduction sensitivity and in vitro PTX release properties were confirmed in reducing environments comparatively with physiological conditions. Cytotoxicity studies suggested that ovarian (SK-OV-3) cells could be better candidates for treatment with redox-sensitive drug delivery systems than breast (MCF-7) cancer cells.
The results of this study highlights the importance of personalized therapy since no fits-for-all system can be developed for different cancer with significantly different metabolic activities. Graphical Abstract Schematic representation of self-assembly of reduction-sensitive PEG2000-S-S-PTX micelles and GSH dependent release of PTX.
过去十年以来，由于全身细胞毒性、肿瘤部位生物分布不佳以及最重要的是耐药性（MDR）的发展，非特异性化疗药物的递送未能有效治疗癌症。近年来，刺激响应性药物递送系统因其在有效肿瘤治疗和逆转 MDR 方面的优势而受到广泛关注。本研究旨在开发一种氧化还原敏感的胶束前药系统，利用细胞外和细胞内环境之间以及更重要的是在健康组织和肿瘤组织之间谷胱甘肽（GSH）水平的显著差异的优势。
为了实现细胞内紫杉醇的递送，开发了氧化还原敏感的 PEG-S-S-PTX 胶束，并对其进行了体外表征。进行了体外释放研究，并随后在不同还原环境下不同时间进行了针对耐药卵巢和乳腺癌细胞的细胞毒性研究，以确认其潜力。
PEG-S-S-PTX 被合成并表征为一种氧化还原敏感的胶束前药系统。在还原环境下，与生理条件相比，证实了其还原敏感性和体外 PTX 释放特性。细胞毒性研究表明，氧化还原敏感药物递送系统对卵巢（SK-OV-3）细胞的治疗效果可能优于乳腺癌（MCF-7）细胞。
本研究的结果强调了个性化治疗的重要性，因为对于代谢活性明显不同的不同癌症，不可能开发出一种适用于所有情况的系统。
