Xiao Kai, Liu Qiangqiang, Suby Nell, Xiao Wenwu, Agrawal Rinki, Vu Michael, Zhang Hongyong, Luo Yan, Li Yuanpei, Lam Kit S
National Chengdu Center for Safety Evaluation of Drugs and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, P. R. China.
Department of Obstetrics and Gynecology, School of Medicine, University of California, Davis, CA, 95817, USA.
Adv Healthc Mater. 2021 Feb;10(3):e2001196. doi: 10.1002/adhm.202001196. Epub 2020 Nov 16.
Systemic chemotherapy is efficacious against triple-negative breast cancer (TNBC), but it is often associated with serious side effects. Here, a luteinizing hormone-releasing hormone (LHRH) receptor-targeted and tumor microenvironment-responsive nanoparticle system to selectively deliver chemotherapeutic drugs to TNBC cells, is reported. This delivery system (termed "LHRH-DCMs") contains poly(ethylene glycol) and dendritic cholic acid as a micellar carrier, reversible intra-micellar disulfide bond as a redox-responsive crosslink, and synthetic high-affinity (D-Lys)-LHRH peptide as a targeting moiety. LHRH-DCMs exhibit high drug loading efficiency, optimal particle size, good colloidal stability, and glutathione-responsive drug release. As expected, LHRH-DCMs are more efficiently internalized into human TNBC cells through receptor-mediated endocytosis, resulting in stronger cytotoxicity against these cancer cells than the non-targeted counterpart when encapsulated with paclitaxel (PTX). Furthermore, near-infrared fluorescence and magnetic resonance imaging demonstrate that LHRH-DCMs facilitate the tumor distribution and penetration of payloads in three different animal models of breast cancer, including cell line-derived xenograft (CDX), patient-derived xenograft (PDX), and transgenic mammary carcinoma. Finally, in vivo therapeutic studies show that PTX-LHRH-DCMs outperform both the corresponding nontargeted PTX-DCMs and the current clinical formulation (Taxol) in an orthotopic TNBC model. These results provide new insights into approaches for precise drug delivery of TNBC.
全身化疗对三阴性乳腺癌（TNBC）有效，但常伴有严重副作用。在此，报道了一种靶向黄体生成素释放激素（LHRH）受体且对肿瘤微环境有响应的纳米颗粒系统，用于将化疗药物选择性地递送至TNBC细胞。该递送系统（称为“LHRH-DCMs”）包含聚乙二醇和树枝状胆酸作为胶束载体，胶束内的可逆二硫键作为氧化还原响应交联剂，以及合成的高亲和力（D-赖氨酸）-LHRH肽作为靶向部分。LHRH-DCMs表现出高载药效率、最佳粒径、良好的胶体稳定性和谷胱甘肽响应性药物释放。正如预期的那样，LHRH-DCMs通过受体介导的内吞作用更有效地内化到人类TNBC细胞中，当与紫杉醇（PTX）包封时，对这些癌细胞的细胞毒性比非靶向对应物更强。此外，近红外荧光和磁共振成像表明，LHRH-DCMs促进了在三种不同乳腺癌动物模型（包括细胞系来源的异种移植瘤（CDX）、患者来源的异种移植瘤（PDX）和转基因乳腺癌）中有效载荷的肿瘤分布和渗透。最后，体内治疗研究表明，在原位TNBC模型中，PTX-LHRH-DCMs的性能优于相应的非靶向PTX-DCMs和当前的临床制剂（紫杉醇）。这些结果为TNBC精确给药方法提供了新的见解。
