Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus , Jawahar Nagar, Shameerpet, Hyderabad 500078, Telangana, India.
Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University , Boston, Massachusetts 02115, United States.
ACS Appl Mater Interfaces. 2017 May 24;9(20):16778-16792. doi: 10.1021/acsami.7b01087. Epub 2017 May 15.
Nanomedicines have emerged as a promising treatment strategy for cancer. Multiple drug resistance due to overexpression of various drug efflux transporters and upregulation of apoptotic inhibitory pathways in cancer cells are major barriers that limit the success of chemotherapy. Here, we developed a d-α-tocopherol (α-TOS)/lipid-based copolymeric nanomicellar system (VPM) by conjugating phosphatidyl ethanolamine (PE) and α-TOS with poly(ethylene glycol) (PEG) via an amino acid linkage. The synthesized polymers were characterized by Fourier transform IR, gas-phase chromatography, and H and C NMR spectroscopy. VPM exhibited mean hydrodynamic diameter of 141.0 ± 0.94 nm with low critical micelles concentrations (CMC) of 15 μM compared to plain PEG-PE micelles (PPM) with size of 23.9 ± 0.34 nm and CMC 20 μM. The bigger hydrophobic compartment in VPM resulted in improved loading of a potent chemotherapeutic drug, curcumin (Cur), and increased encapsulation efficiency (EE) (% drug loading 98.3 ± 1.92, and 85.3 ± 3.29; EE 14.8 ± 0.16 and 12.8 ± 0.09 for VPM and PPM, respectively). Curcumin loaded Vitamin E based micelles exhibited higher cytotoxicity compared to Curcumin loaded PEG-PE micelles in tested cancer cell lines. C-VPM demonstrated ∼3.2 and ∼2.7-fold higher ability to reverse multiple drug resistance compared to PPM and verapamil (concentration used 30 μM), respectively. In the in vivo study by using B16F10 implanted C57Bl6/J mice, C-VPM reduced the tumor volume and weight more efficiently than C-PPM by inducing apoptosis as analyzed by TUNEL assay on tumor cryosections. The newly developed polymeric micelles, VPM with improved drug loadability and ability to reverse the drug resistance could successfully be utilized as a nanocarrier system for hydrophobic chemotherapeutic agents for the treatment of drug-resistant solid tumors.
纳米药物已成为癌症治疗的一种有前途的策略。由于癌细胞中各种药物外排转运蛋白的过度表达和凋亡抑制途径的上调，导致多药耐药性是限制化疗成功的主要障碍。在这里，我们通过氨基酸键将磷脂酰乙醇胺 (PE) 和 α-TOS 与聚乙二醇 (PEG) 缀合，开发了一种 d-α-生育酚 (α-TOS)/基于脂质的共聚胶束系统 (VPM)。通过傅里叶变换红外光谱、气相色谱和 H 和 C NMR 光谱对合成的聚合物进行了表征。与尺寸为 23.9 ± 0.34nm 和 CMC 20μM 的普通 PEG-PE 胶束 (PPM) 相比，VPM 表现出较低的临界胶束浓度 (CMC)15μM 和平均水动力直径 141.0 ± 0.94nm。VPM 中较大的疏水区导致载药量增加，同时提高了封装效率 (EE) (%药物负载 98.3 ± 1.92，85.3 ± 3.29；EE 分别为 14.8 ± 0.16 和 12.8 ± 0.09)。与载有姜黄素的 PEG-PE 胶束相比，载有姜黄素的维生素 E 基胶束在测试的癌细胞系中表现出更高的细胞毒性。与 PPM 和维拉帕米（使用浓度 30μM）相比，C-VPM 显示出逆转多药耐药性的能力分别提高了约 3.2 倍和 2.7 倍。在使用 B16F10 植入 C57Bl6/J 小鼠的体内研究中，C-VPM 通过在肿瘤冷冻切片上进行 TUNEL 分析诱导细胞凋亡，比 C-PPM 更有效地减少肿瘤体积和重量。新开发的载药能力提高且能够逆转耐药性的聚合物胶束 VPM 可成功用作疏水性化疗药物的纳米载体系统，用于治疗耐药性实体瘤。
