Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi, 110016, India; Biomedical Engineering Unit, All India Institute of Medical Sciences, New Delhi, 110029, India.
Bio-Nano Electronics Research Centre, Toyo University, 2100, Kujirai, Saitama, Japan.
Biomaterials. 2017 Jul;133:94-106. doi: 10.1016/j.biomaterials.2017.04.022. Epub 2017 Apr 17.
Design of safe and efficient vehicles for the combinatorial delivery of drugs and genetic agents is an emerging requisite for achieving enhanced therapeutic effect in cancer. Even though several nanoplatforms have been explored for the co-delivery of drugs and genetic materials the translation of these systems to clinical phase is still a challenge, mainly due to tedious synthesis procedures, lack of serum stability, inefficient scalability etc. Here in, we report development of reduction and pH sensitive polymeric graft of low molecular weight poly (styrene -alt -maleic anhydride) and evaluation of its efficacy in co-delivering drug and siRNA. The polymer was modified with suitable components, which could help in overcoming various systemic and cellular barriers for successful co-delivery of drugs and nucleic acids to cancer cells, using simple chemical reactions. The polymeric derivative could easily self assemble in water to form smooth, spherical micellar structures, indicating their scalability. Doxorubicin and PLK-1 siRNA were selected as model drug and nucleic acid, respectively. Doxorubicin could be loaded in the self assembling micelles with an optimum loading content of ∼8.6% w/w and efficient siRNA complexation was achieved with polymer/siRNA weight ratios >40. The polyplexes were stabilized in physiological saline by coating with bovine serum albumin (BSA). Stable drug loaded nanoplexes, for clinical administration, could be easily formulated by gently dispersing them in physiological saline containing appropriate amount of albumin. Drug release from the nanoplexes was significantly enhanced at low pH (5) and in the presence of 10 mM glutathione (GSH) showing their dual stimuli sensitive nature. In vitro cell proliferation assay and in vivo tumor regression study have shown synergistic effect of the drug loaded nanoplexes in inhibiting cancer cell proliferation. Facile synthesis steps, scalability and ease of formulation depict excellent clinical translation potential of the proposed nanosystem.
设计安全有效的药物和基因传递载体，实现癌症治疗效果的增强，是当前的一个新兴需求。尽管已经有几种纳米平台被探索用于药物和遗传物质的共递药，但这些系统向临床阶段的转化仍然是一个挑战，主要是由于繁琐的合成程序、缺乏血清稳定性、效率低下的可扩展性等。在这里，我们报告了低分子量聚（苯乙烯-共-马来酸酐）的还原和 pH 敏感聚合物接枝的开发，并评估了其在共递药和 siRNA 中的功效。该聚合物用合适的成分进行了修饰，这些成分可以通过简单的化学反应帮助克服药物和核酸成功递送到癌细胞的各种系统和细胞障碍。聚合物衍生物可以很容易地在水中自组装形成光滑的球形胶束结构，表明其可扩展性。阿霉素和 PLK-1 siRNA 分别被选为模型药物和核酸。阿霉素可以以最佳负载量约 8.6%（w/w）载入自组装胶束中，并通过聚合物/siRNA 重量比大于 40 实现了有效的 siRNA 复合。通过用牛血清白蛋白（BSA）包被，使聚合物形成的纳米胶束在生理盐水中稳定。通过将它们轻轻分散在含有适量白蛋白的生理盐水中，就可以很容易地制备出用于临床给药的稳定的载药纳米复合物。纳米复合物在低 pH（5）和 10 mM 谷胱甘肽（GSH）存在下，药物释放明显增强，表现出双重刺激敏感性。体外细胞增殖试验和体内肿瘤消退研究表明，载药纳米复合物在抑制癌细胞增殖方面具有协同作用。简便的合成步骤、可扩展性和易于制剂化描绘了所提出的纳米系统具有优异的临床转化潜力。
