Centro de Química Medicinal - Universidade do Porto (CEQUIMED-UP), Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, Portugal.
Int J Pharm. 2013 Sep 15;454(1):394-402. doi: 10.1016/j.ijpharm.2013.07.017. Epub 2013 Jul 12.
One possible approach to overcome solubility complications and enhance the biological activity of drugs is their incorporation into drug delivery systems. Within this scope, several nanosphere and nanocapsule formulations of a new inhibitor of p53-MDM2 interaction (xanthone 1) were developed and their physicochemical properties analyzed. Through the investigation of the effect of several empty nanoparticles on the growth of MCF-7 cells, it was possible to observe that four out of five formulations were cytotoxic and that some correlations between the toxic potential of these polymeric nanoparticles and their properties/composition could be extrapolated. One empty formulation of nanocapsules developed by emulsification/solvent evaporation and containing PLGA, PVA and Mygliol(®) 812 was found to be noncytotoxic to this cell line. The corresponding compound 1-loaded nanocapsules showed an incorporation efficiency of 77% and revealed to be more potent than the free drug against cell growth inhibition, which may be related to the enhancement in its intracellular delivery. In an integrative study, the intracellular uptake of nanocapsules was confirmed using fluorescent 6-coumarin and well as compound 1 release from nanocapsules. Overall, it was possible to enhance the effect of the hit inhibitor of p53-MDM2 interaction through the development of suitable noncytotoxic polymeric nanoparticles.
克服溶解度问题并提高药物生物活性的一种方法是将其纳入药物传递系统。在这一范围内，开发了几种新型 p53-MDM2 相互作用抑制剂（xanthone 1）的纳米球和纳米囊制剂，并对其理化性质进行了分析。通过研究几种空纳米粒子对 MCF-7 细胞生长的影响，观察到五种制剂中有四种具有细胞毒性，并且可以推断出这些聚合物纳米粒子的毒性潜力与其性质/组成之间存在某些相关性。通过乳化/溶剂蒸发开发的一种含有 PLGA、PVA 和 Mygliol®812 的纳米囊空制剂对该细胞系无细胞毒性。相应的载有 1 的纳米囊显示出 77%的包封效率，并且对细胞生长抑制的抑制作用比游离药物更强，这可能与细胞内传递的增强有关。在一项综合研究中，使用荧光 6-香豆素证实了纳米囊的细胞内摄取，以及纳米囊从化合物 1 的释放。总之，通过开发合适的非细胞毒性聚合物纳米粒子，可以增强 p53-MDM2 相互作用的命中抑制剂的效果。
