§Biomedical Engineering Unit, All India Institute of Medical Sciences, AIIMS, New Delhi 110029, India.
ACS Appl Mater Interfaces. 2015 May 6;7(17):9211-27. doi: 10.1021/acsami.5b01731. Epub 2015 Apr 27.
To minimize cardiotoxicity and to increase the bioavailability of doxorubicin, polymersomes based on redox sensitive amphiphilic triblock copolymer poly(polyethylene glycol methacrylate)-poly(caprolactone)-s-s-poly(caprolactone)-poly(polyethylene glycol methacrylate) (pPEGMA-PCL-ss-PCL-pPEGMA) with disulfide linkage were designed and developed. The polymers were synthesized by ring opening polymerization (ROP) of ε-caprolactone followed by atom transfer radical polymerization (ATRP) of PEGMA. The triblock copolymers demonstrated various types of nanoparticle morphologies by varying hydrophobic/hydrophilic content of polymer blocks, with PEGMA content of ∼18% in the triblock copolymer leading to the formation of polymersomes in the size range ∼150 nm. High doxorubicin loading content of ∼21% was achieved in the polymersomes. Disulfide linkages were incorporated in the polymeric backbone to facilitate degradation of the nanoparticles by the intracellular tripeptide glutathione (GSH), leading to intracellular drug release. Release studies showed ∼59% drug release in pH 5.5 in the presence of 10 mM GSH, whereas only ∼19% was released in pH 7.4. In cellular uptake studies, dual targeted polymersomes showed ∼22-fold increase in cellular uptake efficiency in breast cancer cell lines (BT474 and MCF-7) as compared to nontargeted polymersomes with higher apoptosis rates. In vivo studies on Ehrlich's ascites tumor (EAT) bearing Swiss albino mouse model showed ∼85% tumor regression as compared to free doxorubicin (∼42%) without any significant cardiotoxicity associated with doxorubicin. The results indicate enhanced antitumor efficacy of the redox sensitive biocompatible nanosystem and shows promise as a potential drug nanocarrier in cancer therapeutics.
为了最小化心脏毒性并提高阿霉素的生物利用度，设计并开发了基于氧化还原敏感两亲性三嵌段共聚物聚（聚乙二醇甲基丙烯酸酯）-聚（己内酯）-s-聚（己内酯）-聚（聚乙二醇甲基丙烯酸酯）（pPEGMA-PCL-ss-PCL-pPEGMA）的聚合物囊泡，其中含有二硫键。聚合物通过ε-己内酯的开环聚合（ROP）和聚乙二醇甲基丙烯酸酯的原子转移自由基聚合（ATRP）合成。通过改变聚合物嵌段的疏水性/亲水性含量，三嵌段共聚物表现出各种类型的纳米颗粒形态，三嵌段共聚物中的 PEGMA 含量约为 18%，导致尺寸在 150nm 左右的聚合物囊泡的形成。聚合物囊泡中实现了约 21%的高阿霉素载药含量。在聚合物主链中引入二硫键，以促进细胞内三肽谷胱甘肽（GSH）对纳米颗粒的降解，从而导致细胞内药物释放。释放研究表明，在 pH 5.5 存在 10mM GSH 的条件下，约有 59%的药物释放，而在 pH 7.4 下仅释放约 19%。在细胞摄取研究中，与非靶向聚合物囊泡相比，双靶向聚合物囊泡在乳腺癌细胞系（BT474 和 MCF-7）中的细胞摄取效率提高了约 22 倍，并且具有更高的细胞凋亡率。在荷 Ehrlich 腹水瘤（EAT）的瑞士白化病小鼠模型中的体内研究表明，与游离阿霉素（~42%）相比，肿瘤的消退率约为 85%，且没有与阿霉素相关的明显心脏毒性。结果表明，该氧化还原敏感的生物相容性纳米系统具有增强的抗肿瘤疗效，有望成为癌症治疗中的潜在药物纳米载体。
