Liu Yujie, Yang Yiliang, Qi Xianrong
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
College of Biochemical Engineering, Beijing Union University, Beijing 100023, China.
Pharmaceutics. 2025 Apr 26;17(5):572. doi: 10.3390/pharmaceutics17050572.
The ineffective delivery of drugs into tumors and the existence of multidrug resistance (MDR) are the primary causes of chemotherapy failure. Downregulation of the Sonic Hedgehog (Shh) pathway has been shown to reduce P-glycoprotein (P-gp) expression on cell membranes and to resist MDR. In this study, we combine cyclopamine (CYP, a potent Shh antagonist) with paclitaxel (PTX, an antitumor drug that can produce MDR) in a nano-drug delivery system (CYP NP and PTX NP) for the treatment of drug-resistant breast cancer. Nanoparticles were characterized for size, zeta potential, and encapsulation efficiency. P-gp expression, nanoparticle accumulation, cytotoxicity, and apoptosis were evaluated in MCF-7 and MCF-7/Adr cells. Penetration ability was assessed using 3D multicellular tumor spheroids. Antitumor efficacy and nanoparticle biodistribution were validated in MCF-7/Adr-bearing nude mice models. Our engineered CYP nanoparticles (200 nm) demonstrated prolonged intratumoral retention, enabling sustained Shh pathway inhibition and P-gp functional suppression. This size-optimized formulation created a favorable tumor microenvironment for the smaller PTX nanoparticles (30 nm), facilitating deeper tumor penetration and enhanced cellular uptake. Meanwhile, by down-regulating P-gp expression, CYP NPs could convert drug-resistant cells to PTX-sensitive cells in both cytotoxicity and apoptosis induction through the Shh pathway. The combination of CYP NP and PTX NP augmented the antitumor effects in MCF-7/Adr-bearing nude mice models. The CYP NP and PTX NP combination offers a new therapeutic strategy in cancer treatment.
药物向肿瘤内递送无效以及多药耐药性（MDR）的存在是化疗失败的主要原因。已有研究表明，抑制音猬因子（Shh）信号通路可降低细胞膜上P-糖蛋白（P-gp）的表达，从而抵抗多药耐药性。在本研究中，我们将环杷明（CYP，一种有效的Shh拮抗剂）与紫杉醇（PTX，一种可产生多药耐药性的抗肿瘤药物）组合于纳米药物递送系统（CYP纳米粒和PTX纳米粒）中，用于治疗耐药性乳腺癌。对纳米粒的粒径、zeta电位和包封率进行了表征。在MCF-7和MCF-7/Adr细胞中评估了P-gp表达、纳米粒蓄积、细胞毒性和细胞凋亡。使用三维多细胞肿瘤球体评估渗透能力。在携带MCF-7/Adr的裸鼠模型中验证了抗肿瘤疗效和纳米粒的生物分布。我们构建的CYP纳米粒（约200 nm）在肿瘤内的滞留时间延长，能够持续抑制Shh信号通路并抑制P-gp功能。这种经过尺寸优化的制剂为较小的PTX纳米粒（约30 nm）创造了有利的肿瘤微环境，促进了肿瘤更深层的渗透和增强的细胞摄取。同时，通过下调P-gp表达，CYP纳米粒可在细胞毒性和通过Shh信号通路诱导细胞凋亡方面将耐药细胞转化为对PTX敏感的细胞。CYP纳米粒和PTX纳米粒的组合增强了在携带MCF-7/Adr的裸鼠模型中的抗肿瘤作用。CYP纳米粒和PTX纳米粒的组合为癌症治疗提供了一种新的治疗策略。
