Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, School of Therapeutics Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa.
Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Onderstepoort 0110, South Africa.
Int J Mol Sci. 2018 Oct 4;19(10):3030. doi: 10.3390/ijms19103030.
The present study aimed to design and develop a nanocomposite drug delivery system employing an antineoplastic-loaded antibody functionalized nanomicelle encapsulated within a Chitosan⁻Poly(vinylpyrrolidone)⁻Poly(N-isopropylacrylamide) (C⁻P⁻N) hydrogel to form an in situ forming implant (ISFI), responsive to temperature and pH for cancer cell-targeting following intraperitoneal implantation. The optimum nanomicelle formulation was surface-functionalized with anti-MUC 16 (antibody) for the targeted delivery of methotrexate to human ovarian carcinoma (NIH:OVCAR-5) cells in Athymic nude mice that expressed MUC16, as a preferential form of intraperitoneal ovarian cancer (OC) chemotherapy. The cross-linked interpenetrating C⁻P⁻N hydrogel was synthesized for the preparation of an in situ-forming implant (ISFI). Subsequently, the ISFI was fabricated by encapsulating a nanocomposite comprising of anti-MUC16 (antibody) functionalized methotrexate (MTX)-loaded poly(-isopropylacrylamide)-b-poly(aspartic acid) (PNIPAAm-b-PASP) nanomicelles (AF(MTX)NM's) within the cross-linked C⁻P⁻N hydrogel. This strategy enabled specificity and increased the residence time of the nanomicelles at tumor sites over a period exceeding one month, enhancing uptake of drugs and preventing recurrence and chemo-resistance. Chemotherapeutic efficacy was tested on the optimal ovarian tumor-bearing Athymic nude mouse model and the results demonstrated tumor regression including reduction in mouse weight and tumor size, as well as a significant (p < 0.05) reduction in mucin 16 levels in plasma and ascitic fluid, and improved survival of mice after treatment with the experimental anti-MUC16/CA125 antibody-bound nanotherapeutic implant drug delivery system (ISFI) (p < 0.05). The study also concluded that ISFI could potentially be considered an important immuno-chemotherapeutic agent that could be employed in human clinical trials of advanced, and/or recurring, metastatic epithelial ovarian cancer (EOC). The development of this ISFI may circumvent the treatment flaws experienced with conventional systemic therapies, effectively manage recurrent disease and ultimately prolong disease-free intervals in ovarian cancer patients.
本研究旨在设计和开发一种纳米复合药物递送系统，该系统采用载有抗肿瘤药物的抗体功能化纳米胶束，封装在壳聚糖-聚（乙烯基吡咯烷酮）-聚（N-异丙基丙烯酰胺）（C-P-N）水凝胶内，形成一种对温度和 pH 敏感的原位形成植入物（ISFI），用于腹腔内植入后的癌细胞靶向。最佳的纳米胶束配方经表面功能化，带有抗 MUC16（抗体），用于在表达 MUC16 的裸鼠中靶向递送甲氨蝶呤至人卵巢癌细胞（NIH：OVCAR-5），作为腹腔内卵巢癌（OC）化疗的首选形式。交联互穿的 C-P-N 水凝胶用于制备原位形成植入物（ISFI）。随后，通过封装包含抗 MUC16（抗体）功能化的甲氨蝶呤（MTX）负载的聚（异丙基丙烯酰胺）-b-聚（天冬氨酸）（PNIPAAm-b-PASP）纳米胶束（AF（MTX）NM's）的纳米复合体制备 ISFI。该策略提高了纳米胶束在肿瘤部位的特异性和滞留时间，超过一个月，增强了药物的摄取，并防止了复发和化疗耐药性。在最佳的卵巢荷瘤裸鼠模型上测试了化疗疗效，结果表明肿瘤消退，包括小鼠体重和肿瘤大小的减少，以及血浆和腹水中小鼠 MUC16 水平的显著降低（p <0.05），以及在用实验性抗 MUC16/CA125 抗体结合纳米治疗植入物药物递送系统（ISFI）治疗后小鼠的生存率提高（p <0.05）。该研究还得出结论，ISFI 可能被认为是一种重要的免疫化疗药物，可用于晚期和/或复发性转移性上皮性卵巢癌（EOC）的人类临床试验。ISFI 的开发可能会规避常规全身治疗中遇到的治疗缺陷，有效管理复发性疾病，并最终延长卵巢癌患者的无病间隔期。
