J Biomed Nanotechnol. 2014 Aug;10(8):1401-15. doi: 10.1166/jbn.2014.1847.
Migratory capacity of cancer plays a critical role in the process of metastasis. Aberrant focal adhesions activated by the phosphorylation of Src kinase enables cancer cells to anchor on its micro-environment and migrate towards biochemically favorable niche, causing metastasis. Effective blocking of the migratory capacity of cancer cells by inhibiting protein kinases and subsequent application of cytotoxic stress may provide better therapeutic outcome. Here, we report a novel core-shell nanomedicine that inhibits cancer migration by nano-shell and impart reactive oxygen stress by laser assisted photosensitization of nano-core. For this, we have optimized a polymer-protein nanoconstruct where a photosensitizer (5,10,15, 20-tetrakis(meso-hydroxyphenyl)porphyrin (mTHPP) is loaded into poly(lactic-co-glycolic acid) (PLGA) nano-core and Src kinase inhibitor (dasatinib) is loaded into albumin nano-shell. The polymer-core was prepared by electrospray technique and albumin-shell was formed by alcohol coacervation. Transmission electron microscopy studies revealed the formation of - 80 nm sized nano-core decorated with - 10 nm size nano-shell. Successful incorporation of monomeric mTHPP in nano-core resulted improved photo-physical properties and singlet oxygen release under physiological conditions compared to free-mTHPP. Core-shell nanomedicine also showed dose and time dependent cellular uptake in U87MG glioma cells. Dasatinib released from nano-shell caused down regulation of phospho-Src leading to significant impairment of cancer migration and subsequent laser assisted photosensitization of nano-core resulted in the release of reactive oxygen stress leading to apoptosis of spatially confined cancer cells. In vivo studies on Wistar rats indicated the absence of any significant toxicity caused by the intravenous administration of nanomedicine. These results clearly show the advantage of core-shell nanomedicine mediated combinatorial approach for inhibiting important cancer signalling pathways togother with imparting cytotoxic stress.
癌细胞的迁移能力在转移过程中起着关键作用。Src 激酶磷酸化激活的异常黏附斑使癌细胞能够附着在其微环境上，并向生化有利的小生境迁移，从而导致转移。通过抑制蛋白激酶有效阻断癌细胞的迁移能力，随后施加细胞毒性应激，可能提供更好的治疗效果。在这里，我们报告了一种新型的核壳纳米药物，通过纳米壳抑制癌症迁移，并通过纳米核的激光辅助光致敏赋予活性氧应激。为此，我们优化了一种聚合物-蛋白质纳米结构，其中将光敏剂（5,10,15,20-四（间-羟苯基）卟啉（mTHPP）负载到聚（乳酸-共-乙醇酸）（PLGA）纳米核中，Src 激酶抑制剂（达沙替尼）负载到白蛋白纳米壳中。聚合物核通过电喷雾技术制备，白蛋白壳通过醇凝聚形成。透射电子显微镜研究表明，形成了-80nm 大小的纳米核，其表面装饰有-10nm 大小的纳米壳。与游离 mTHPP 相比，纳米核中成功掺入单体 mTHPP 导致其在生理条件下改善了光物理性质和单线态氧释放。核壳纳米药物在 U87MG 神经胶质瘤细胞中也表现出剂量和时间依赖性的细胞摄取。纳米壳中释放的达沙替尼导致磷酸化 Src 下调，从而显著损害癌细胞迁移，随后激光辅助纳米核的光致敏导致活性氧应激的释放，导致空间受限的癌细胞凋亡。在 Wistar 大鼠体内研究表明，静脉给予纳米药物不会引起任何明显的毒性。这些结果清楚地表明，核壳纳米药物介导的组合方法在抑制重要癌症信号通路的同时施加细胞毒性应激具有优势。
