LHRH‐Targeted Redox‐Responsive Crosslinked Micelles Impart Selective Drug Delivery and Effective Chemotherapy in Triple‐Negative Breast Cancer. Issue 3 (16th November 2020)

• Record Type: Journal Article
• Authors: Xiao, Kai; Liu, Qiangqiang; Suby, Nell; Xiao, Wenwu; Agrawal, Rinki; Vu, Michael; Zhang, Hongyong; Luo, Yan; Li, Yuanpei; Lam, Kit S.
• Is Part Of: Advanced healthcare materials. Volume 10:Issue 3(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-11-16
• Subjects: breast cancer -- disulfide crosslinkers -- LHRH -- micelles -- paclitaxel -- redox‐responsive micelles -- targeted delivery; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1002/adhm.202001196
• Languages: English
• ISSNs: 2192-2640

Abstract

Abstract: 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. Abstract : LHRH‐targeted redox‐responsive crosslinked micelles (LHRH‐DCMs) composed of 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, are developed. LHRH‐DCMs facilitate the precise delivery of chemotherapeutic drugs to breast cancer tissue/cells, resulting in enhanced anti‐tumor efficacy.