BACKGROUND & AIMS:
:Docetaxel (DTX), a widely prescribed anticancer agent, is now associated with increased instances of multidrug resistance. Also, being a problematic BCS class IV drug, it poses challenges for the formulators. Henceforth, it was envisioned to synthesize an analogue of DTX with a biocompatible lipid, i.e., palmitic acid. The in-silico studies (molecular docking and simulation) inferred lesser binding of docetaxel palmitate (DTX-PL) with P-gp vis-à-vis DTX and paclitaxel, indicating it to be a poor substrate for P-gp efflux. Solid lipid nanoparticles (SLNs) of the conjugate were prepared using various lipids, viz. palmitic acid, stearic acid, cetyl palmitate and glyceryl monostearate. The characterization studies for the nanocarrier were performed for the surface charge, drug payload, micromeritics, release pattern of drug and surface morphology. From the cytotoxicity assays on resistant MCF-7 cells, it was established that the new analogue offered substantially decreased IC50 to that of DTX. Further, apoptosis assay also corroborated the results obtained in IC50 determination wherein, SA-SLNs showed the highest apoptotic index than free DTX. The conjugate not only enhanced the solubility but also offered lower plasma protein binding and improved pharmacokinetic and pharmacodynamic effect for DTX loaded SA-SLNs in apt animal models, and lower affinity to P-gp efflux. The studies provide preliminary evidence and a ray of hope for a better candidate in its nano version for safer and effective cancer chemotherapy.
背景与目标:
多西紫杉醇 (DTX) 是一种广泛使用的抗癌药物,现在与多药耐药性增加有关。此外,作为一种有问题的BCS IV类药物,它给配方设计师带来了挑战。此后,设想合成具有生物相容性脂质 (即棕榈酸) 的DTX类似物。计算机研究 (分子对接和模拟) 推断多西紫杉醇棕榈酸酯 (dtx-pl) 与P-gp的结合相对于DTX和紫杉醇较小,表明它是P-gp外排的不良底物。使用各种脂质 (即棕榈酸,硬脂酸,棕榈酸十六烷基酯和单硬脂酸甘油酯) 制备缀合物的固体脂质纳米颗粒 (sln)。对纳米载体的表面电荷,药物有效载荷,微分生组织,药物的释放模式和表面形态进行了表征研究。根据对抗性MCF-7细胞的细胞毒性测定,可以确定新的类似物提供的IC50大大降低了DTX的IC50。此外,凋亡测定还证实了在IC50测定中获得的结果,其中sa-sln显示出比游离DTX最高的凋亡指数。该缀合物不仅增强了溶解度,而且还提供了较低的血浆蛋白结合,并改善了apt动物模型中DTX负载的sa-sln的药代动力学和药效学效果,并降低了对P-gp外排的亲和力。这些研究提供了初步的证据和一线希望,希望在其纳米版本中找到更安全,有效的癌症化学疗法。