载姜黄素和紫杉醇的“核壳”靶向两亲性共聚物逆转卵巢癌细胞耐药性的治疗作用

BACKGROUND: Ovarian cancer is a common malignancy in the female reproductive system with a high mortality rate. The most important reason is multidrug resistance (MDR) of cancer chemotherapy. To reduce side effects, reverse resistance and improve efficacy for the treatment of ovarian cancer, a "core-shell" polymeric nanoparticle-mediated curcumin and paclitaxel co-delivery platform was designed. METHODS: Nuclear magnetic resonance confirmed the successful grafting of polyethylenimine (PEI) and stearic acid (SA) (PEI-SA), which is designed as a mother core for transport carrier. Then, PEI-SA was modified with hyaluronic acid (HA) and physicochemical properties were examined. To understand the regulatory mechanism of resistance and measure the anti-tumor efficacy of the treatments, cytotoxicity assay, cellular uptake, P-glycoprotein (P-gp) expression and migration experiment of ovarian cancer cells were performed. In addition, adverse reactions of nanoformulation to the reproductive system were examined. RESULTS: HA-modified drug-loaded PEI-SA had a narrow size of about 189 nm in diameters, and the particle size was suitable for endocytosis. The nanocarrier could target specifically to CD44 receptor on the ovarian cancer cell membrane. Co-delivery of curcumin and paclitaxel by the nanocarriers exerts synergistic anti-ovarian cancer effects on chemosensitive human ovarian cancer cells (SKOV3) and multi-drug resistant variant (SKOV3-TR30) in vitro, and it also shows a good anti-tumor effect in ovarian tumor-bearing nude mice. The mechanism of reversing drug resistance may be that the nanoparticles inhibit the efflux of P-gp, inhibit the migration of tumor cells, and curcumin synergistically reverses the resistance of PTX to increase antitumor activity. It is worth noting that the treatment did not cause significant toxicity to the uterus and ovaries with the observation of macroscopic and microscopic. CONCLUSION: This special structure of targeting nanoparticles co-delivery with the curcumin and paclitaxel can increase the anti-tumor efficacy without increasing the adverse reactions as a promising strategy for therapy ovarian cancer.

背景：卵巢癌是女性生殖系统常见的恶性肿瘤，死亡率很高。最重要的原因是癌症化疗的多药耐药（MDR）。为了降低副作用、逆转耐药性并提高卵巢癌的疗效，设计了一种“核-壳”聚合物纳米颗粒介导的姜黄素和紫杉醇共递药平台。

方法：核磁共振证实了成功接枝聚乙二烯亚胺（PEI）和硬脂酸（SA）（PEI-SA），其被设计为运输载体的母核。然后，对 PEI-SA 进行透明质酸（HA）修饰，并对其理化性质进行了研究。为了了解耐药的调节机制并衡量治疗的抗肿瘤功效，对卵巢癌细胞进行了细胞毒性测定、细胞摄取、P-糖蛋白（P-gp）表达和迁移实验。此外，还研究了纳米制剂对生殖系统的不良反应。

结果：HA 修饰的载药 PEI-SA 的粒径约为 189nm，粒径适合内吞作用。纳米载体可以特异性地靶向卵巢癌细胞膜上的 CD44 受体。纳米载体共递姜黄素和紫杉醇对体外敏感人卵巢癌细胞（SKOV3）和多药耐药变异体（SKOV3-TR30）具有协同的抗卵巢癌作用，并且在卵巢荷瘤裸鼠中也表现出良好的抗肿瘤作用。逆转耐药的机制可能是纳米粒子抑制 P-gp 的外排，抑制肿瘤细胞的迁移，姜黄素协同逆转 PTX 的耐药性，增加抗肿瘤活性。值得注意的是，在观察到的宏观和微观层面，该治疗方法对子宫和卵巢没有引起明显毒性。

结论：这种靶向纳米粒子共递姜黄素和紫杉醇的特殊结构可以在不增加不良反应的情况下提高抗肿瘤疗效，是治疗卵巢癌的一种很有前途的策略。