State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
ACS Appl Mater Interfaces. 2021 Mar 31;13(12):13990-14003. doi: 10.1021/acsami.1c00852. Epub 2021 Mar 19.
Paclitaxel (PTX) is a first-line chemotherapeutic agent to treat prostate cancer (PCa), but a large number of patients acquired drug resistance after short-term treatment. To develop combinational therapeutics to overcome PTX-resistant PCa, we established PTX-resistant LNCaP (LNCaP/PTX) cells and found that the LNCaP/PTX cells exhibited epithelial-mesenchymal transition (EMT) and enhanced metastasis during the selection process. We revealed that β-tubulin III, androgen receptor, and CXCR4 expressions were significantly increased in LNCaP/PTX cells and directly contributed to PTX resistance and EMT. Therefore, we developed prostate-specific membrane antigen aptamer (Apt)-functionalized shell-core nanoparticles (PTX/siRNAs NPs-Apt); the hydrophobic DSPE encapsulating PTX formed the dense inner core and the hydrophilic Apt-PEG with calcium phosphate (CaP) absorbing siRNAs formed the outer shell to sequentially release siRNAs and PTX, where CaP could trigger lysosomal escape to ensure that pooled siRNAs efficiently released into the cytoplasm to reverse EMT and resensitize PTX, while the PTX located in the core was subsequently released to exert the killing effect of chemotherapy to achieve the best synergistic effect. PTX/siRNAs NPs-Apt showed an enhanced tumor-targeting ability and achieved superior efficacy in the subcutaneous and orthotopic PCa tumor model with minimal side effects.
紫杉醇（PTX）是治疗前列腺癌（PCa）的一线化疗药物，但大量患者在短期治疗后产生了耐药性。为了开发联合治疗方法来克服 PTX 耐药性 PCa，我们建立了 PTX 耐药性 LNCaP（LNCaP/PTX）细胞，发现 LNCaP/PTX 细胞在选择过程中表现出上皮-间充质转化（EMT）和增强的转移能力。我们揭示了β-微管蛋白 III、雄激素受体和 CXCR4 在 LNCaP/PTX 细胞中的表达显著增加，直接导致了 PTX 耐药性和 EMT。因此，我们开发了前列腺特异性膜抗原适体（Apt）功能化核壳纳米颗粒（PTX/siRNAs NPs-Apt）；疏水性 DSPE 包封的 PTX 形成致密的内核，亲水性 Apt-PEG 与磷酸钙（CaP）吸收 siRNAs 形成外壳，以顺序释放 siRNAs 和 PTX，其中 CaP 可以触发溶酶体逃逸，以确保聚集的 siRNAs 有效地释放到细胞质中，逆转 EMT 并重新敏化 PTX，而位于核心的 PTX 随后被释放以发挥化疗的杀伤作用，从而实现最佳协同效应。PTX/siRNAs NPs-Apt 表现出增强的肿瘤靶向能力，并在皮下和原位 PCa 肿瘤模型中表现出优异的疗效，副作用极小。
