本研究的目的是开发和评估噻嗪肽联合紫杉醇（PTX）和精氨酰温曲达（ELA）加载的聚乙二醇修饰的pH敏感脂质体（TPPLs），用于靶向传递抗癌药物。本研究中，紫杉醇作为一种抗癌药物，促进微管聚合并阻止细胞周期在有丝分裂阶段进行，从而导致细胞死亡。单独使用PTX会导致多药耐药（MDR）并导致疗效失败。因此，将PTX与P-糖蛋白抑制剂（ELA）结合使用以达到PTX的最大治疗效果。此外，单克隆抗体（噻唑胺）被用作靶向药物负载载体到乳腺癌细胞上。因此，噻唑胺锚定的pH敏感脂质体携带PTX和ELA是使用薄膜水合法和Box-Behnken Design（BBD）开发的，以优化各种制剂变量。优化后的脂质体进行了诸如囊泡大小、PDI和ζ电位的表征，观察到聚乙二醇修饰的pH敏感脂质体（PEG-Ls）的尺寸为122±2.14nm，PDI为0.224，ζ电位为-15.5mV，TPPLs的尺寸为134±1.88nm，PDI为0.238，ζ电位为-13.98mV。PEG-Ls和TPPLs的体外药物释放研究结果表明，在酸性pH 5条件下，药物释放率较生理pH 7.4明显增强。此外，进行了SK-BR-3和MDA-MB-231细胞系的体外细胞毒性研究。 FITC加载的TPPLs在SK-BR-3细胞中的细胞摄取研究显示比FITC加载的PEG-Ls有更高的摄取率，而在MDA-MB-231细胞中，FITC加载的TPPLs和FITC加载的PEG-Ls之间的细胞摄取没有显著差异。因此，可以得出结论，HER-2过表达乳腺癌细胞系(SK-BR-3)表现出比低水平表达HER2的细胞（MDA-MB-231）更好的TPPLs细胞毒性和细胞摄取。体内肿瘤回归研究结果显示，TPPLs在28天后显著减少肿瘤负担，相比其他脂质体减少了约74%。此外，TPPLs的体内研究显示出最小的毒性剖面、最小的溶血、更高的肿瘤组织分布和优越的抗肿瘤效果，与其他制剂相比。这些研究结果证实了TPPLs是一种安全有效的乳腺癌治疗方法。

The object of the current study was to develop and evaluate trastuzumab-conjugated Paclitaxel (PTX) and Elacridar (ELA)-loaded PEGylated pH-sensitive liposomes (TPPLs) for site-specific delivery of an anticancer drug. In this study, paclitaxel is used as an anticancer drug which promotes microtubules polymerization and arrest cell cycle progression at mitosis and subsequently leading to cell death. The single use of PTX causes multiple drug resistance (MDR) and results failure of the therapy. Hence, the combination of PTX and P-glycoprotein inhibitor (ELA) are used to achieve maximum therapeutic effects of PTX. Moreover, monoclonal antibody (trastuzumab) is used as ligand for the targeting the drug bearing carriers to BC. Thus, trastuzumab anchored pH-sensitive liposomes bearing PTX and ELA were developed using thin film hydration method and Box-Behnken Design (BBD) for optimizing various formulation variables. The optimized liposomes undergo characterization such as vesicle size, PDI, and zeta potential, which were observed to be 122 ± 2.14 nm, 0.224, and -15.5 mV for PEGylated pH-sensitive liposomes (PEG-Ls) and 134 ± 1.88 nm, 0.238, and -13.98 mV for TPPLs, respectively. The results of the in vitro drug release study of both formulations (PEG-Ls and TPPLs) showed enhanced percentage drug release at an acidic pH 5 as compared to drug release at a physiological pH 7.4. Further, the in vitro cytotoxicity studies were performed in the SK-BR-3 and MDA-MB-231 cell lines. The cellular uptake study of FITC-loaded TPPLs in SK-BR-3 cells showed greater uptake than FITC-loaded PEG-Ls, while in MDA-MB-231 cells there was no significant difference in cell uptake between FITC-loaded TPPLs and FITC-loaded PEG-Ls. Hence, it can be concluded that the HER-2 overexpressing cancer cell line (SK-BR-3) was showing better cytotoxicity and cell uptake of TPPLs than the cells that expressed low levels of HER2 (MDA-MB-231). The in vivo tumor regression study, TPPLs showed significantly more tumor burden reduction i.e. up ∼74% as compared to other liposomes after 28 days. Furthermore, the in vivo studies of TPPLs showed a minimal toxicity profile, minimal hemolysis, higher tumor tissue distribution, and superior antitumor efficacy as compared to other formulations. These studies confirmed that TPPLs are a safe and efficacious treatment for breast cancer.