Targeted delivery of cisplatin by LHRH-peptide conjugated dextran nanoparticles suppresses breast cancer growth and metastasis.
The metastasis of breast cancer is the leading cause of cancer death in women. In this work, an attempt to simultaneously inhibit the primary tumor growth and organ-specific metastasis by the cisplatin-loaded LHRH-modified dextran nanoparticles (Dex-SA-CDDP-LHRH) was performed in the 4T1 orthotopic mammary tumor metastasis model. With the rationally designed conjugation site of the LHRH ligand, the Dex-SA-CDDP-LHRH nanoparticles maintained the targeting function of LHRH and specifically bound to the LHRH-receptors overexpressed on the surface of 4T1 breast cancer cells. Therefore, the Dex-SA-CDDP-LHRH nanoparticles exhibited improved cellular uptake and promoted cytotoxicity, when compared with the non-targeted Dex-SA-CDDP nanoparticles. Moreover, both the non-targeted and targeted nanoparticles significantly decreased the systemic toxicity of CDDP and increased the maximum tolerated dose of CDDP from 4 to 30mgkg(-1). Importantly, Dex-SA-CDDP-LHRH markedly enhanced the accumulation of CDDP in the injected primary tumor and metastasis-containing organs, and meanwhile significantly reduced the nephrotoxicity of CDDP. Dose-dependent therapeutic effects further demonstrated that the CDDP-loaded LHRH-decorated polysaccharide nanoparticles significantly enhanced the antitumor and antimetastasis efficacy, as compared to the non-targeted nanoparticles. These results suggest that Dex-SA-CDDP-LHRH nanoparticles show great potential for targeted chemotherapy of metastatic breast cancer.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
Mingqiang
M
Li
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
Zhaohui
Z
Tang
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
Yu
Y
Zhang
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
Shixian
S
Lv
Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130012, PR China.
Quanshun
Q
Li
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China. Electronic address: xschen@ciac.ac.cn.
Xuesi
X
Chen
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D003911:Dextrans / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009362:Neoplasm Metastasis; D016019:Survival Analysis; D014018:Tissue Distribution / Q000187:drug effects
D000970:Antineoplastic Agents; D003911:Dextrans; D007987:Gonadotropin-Releasing Hormone; D002945:Cisplatin
Breast cancer; Chemotherapy; Cisplatin; Metastasis; Targeted drug delivery