Surnar Bapurao, Sharma Kavita, Jayakannan Manickam
Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune, Dr. HomiBhabha Road, Pune 411008, Maharashtra, India.
Nanoscale. 2015 Nov 14;7(42):17964-79. doi: 10.1039/c5nr04963f.
Platinum drug delivery against the detoxification of cytoplasmic thiols is urgently required for achieving efficacy in breast cancer treatment that is over expressed by glutathione (GSH, thiol-oligopeptide). GSH-resistant polymer-cisplatin core-shell nanoparticles were custom designed based on biodegradable carboxylic functional polycaprolactone (PCL)-block-poly(ethylene glycol) diblock copolymers. The core of the nanoparticle was fixed as 100 carboxylic units and the shell part was varied using various molecular weight poly(ethylene glycol) monomethyl ethers (MW of PEGs = 100-5000 g mol(-1)) as initiator in the ring-opening polymerization. The complexation of cisplatin aquo species with the diblocks produced core-shell nanoparticles of 75 nm core with precise size control the particles up to 190 nm. The core-shell nanoparticles were found to be stable in saline solution and PBS and they exhibited enhanced stability with increase in the PEG shell thickness at the periphery. The hydrophobic PCL layer on the periphery of the cisplatin core behaved as a protecting layer against the cytoplasmic thiol residues (GSH and cysteine) and exhibited <5% of drug detoxification. In vitro drug-release studies revealed that the core-shell nanoparticles were ruptured upon exposure to lysosomal enzymes like esterase at the intracellular compartments. Cytotoxicity studies were performed both in normal wild-type mouse embryonic fibroblast cells (Wt-MEFs), and breast cancer (MCF-7) and cervical cancer (HeLa) cell lines. Free cisplatin and polymer drug core-shell nanoparticles showed similar cytotoxicity effects in the HeLa cells. In MCF-7 cells, the free cisplatin drug exhibited 50% cell death whereas complete cell death (100%) was accomplished by the polymer-cisplatin core-shell nanoparticles. Confocal microscopic images confirmed that the core-shell nanoparticles were taken up by the MCF-7 and HeLa cells and they were accumulated both at the cytoplasm as well at peri-nuclear environments. The present investigation lays a new foundation for the polymer-based core-shell nanoparticles approach for overcoming detoxification in platinum drugs for the treatment of GSH over-expressed breast cancer cells.
为了在由谷胱甘肽（GSH，硫醇寡肽）过度表达的乳腺癌治疗中实现疗效，迫切需要针对细胞质硫醇解毒的铂类药物递送。基于可生物降解的羧基官能化聚己内酯（PCL）-嵌段-聚（乙二醇）二嵌段共聚物，定制设计了抗GSH的聚合物-顺铂核壳纳米颗粒。纳米颗粒的核心固定为100个羧基单元，壳部分使用各种分子量的聚（乙二醇）单甲醚（PEGs的分子量 = 100 - 5000 g mol(-1)）作为开环聚合的引发剂进行变化。顺铂水合物种与二嵌段的络合产生了核心为75 nm的核壳纳米颗粒，精确控制颗粒尺寸可达190 nm。发现核壳纳米颗粒在盐溶液和PBS中稳定，并且随着外围PEG壳厚度的增加，它们表现出增强的稳定性。顺铂核心外围的疏水性PCL层起到了针对细胞质硫醇残基（GSH和半胱氨酸）的保护层作用，并且药物解毒率<5%。体外药物释放研究表明，核壳纳米颗粒在细胞内区室暴露于酯酶等溶酶体酶时会破裂。在正常野生型小鼠胚胎成纤维细胞（Wt-MEFs）以及乳腺癌（MCF-7）和宫颈癌（HeLa）细胞系中进行了细胞毒性研究。游离顺铂和聚合物药物核壳纳米颗粒在HeLa细胞中显示出相似的细胞毒性作用。在MCF-7细胞中，游离顺铂药物导致50%的细胞死亡，而聚合物-顺铂核壳纳米颗粒实现了完全细胞死亡（100%）。共聚焦显微镜图像证实，核壳纳米颗粒被MCF-7和HeLa细胞摄取，并且它们在细胞质以及核周环境中都有积累。本研究为基于聚合物的核壳纳米颗粒方法奠定了新基础，该方法用于克服铂类药物在治疗GSH过度表达的乳腺癌细胞中的解毒问题。
