Sakhi Mirina, Khan Abad, Iqbal Zafar, Khan Ismail, Raza Abida, Ullah Asmat, Nasir Fazli, Khan Saeed Ahmad
Department of Pharmacy, University of Swabi, Swabi, Pakistan.
Department of Pharmacy, University of Peshawar, Peshawar, Pakistan.
Front Pharmacol. 2022 Mar 14;13:855294. doi: 10.3389/fphar.2022.855294. eCollection 2022.
The aim of the study was to design and formulate an antibody-mediated targeted, biodegradable polymeric drug delivery system releasing drug in a controlled manner to achieve a therapeutic goal for the effective treatment of breast cancer. Antibody-mediated paclitaxel-loaded PLGA polymeric nanoformulations were prepared by the solvent evaporation method using different experimental parameters and compatibility studies. The optimized formulations were selected for and evaluation and cytotoxicity studies. The drug release studies show a biphasic release pattern for the paclitaxel-loaded PLGA nanoparticles showing a burst release for 24 h followed by an extended release for 14 days; however, a more controlled and sustained release was observed for antibody-conjugated polymeric nanoparticles. The cytotoxicity of reference drug and paclitaxel-loaded PLGA nanoparticles with and without antibody was determined by performing MTT assay against MCF-7 cells. Rabbits were used as experimental animals for the assessment of various pharmacokinetic parameters of selected formulations. The pharmacokinetic parameters such as C (1.18-1.33 folds), AUC (39.38-46.55 folds), MRT (10.04-12.79 folds), t (3.06-4.6 folds), and V (6.96-8.38 folds) have been increased significantly while clearance (4.34-4.61 folds) has been decreased significantly for the selected nanoformulations as compared to commercially available paclitaxel formulation (Paclixil). The surface conjugation of nanoparticles with trastuzumab resulted in an increase in cytotoxicity as compared to plain nanoformulations and commercially available conventional brand (Paclixil). The developed PLGA-paclitaxel nanoformulations conjugated with trastuzumab have the desired physiochemical characteristics, surface morphology, sustained release kinetics, and enhanced targeting.
本研究的目的是设计并制备一种抗体介导的靶向、可生物降解的聚合物药物递送系统，该系统能够以可控方式释放药物，以实现有效治疗乳腺癌的治疗目标。采用溶剂蒸发法，通过不同的实验参数和相容性研究，制备了抗体介导的载紫杉醇聚乳酸-羟基乙酸共聚物（PLGA）纳米制剂。选择优化后的制剂进行评价和细胞毒性研究。药物释放研究表明，载紫杉醇的PLGA纳米颗粒呈现双相释放模式，24小时内出现突释，随后14天持续释放；然而，对于抗体偶联的聚合物纳米颗粒，观察到更可控和持续的释放。通过对MCF-7细胞进行MTT测定，确定了参考药物以及有无抗体的载紫杉醇PLGA纳米颗粒的细胞毒性。使用兔子作为实验动物，评估所选制剂的各种药代动力学参数。与市售紫杉醇制剂（Paclixil）相比，所选纳米制剂的药代动力学参数如C（1.18 - 1.33倍）、AUC（39.38 - 46.55倍）、MRT（10.04 - 12.79倍）、t（3.06 - 4.6倍）和V（6.96 - 8.38倍）显著增加，而清除率（4.34 - 4.61倍）显著降低。与普通纳米制剂和市售传统品牌（Paclixil）相比，纳米颗粒与曲妥珠单抗的表面偶联导致细胞毒性增加。所开发的与曲妥珠单抗偶联的PLGA-紫杉醇纳米制剂具有所需的物理化学特性、表面形态、缓释动力学和增强的靶向性。
