TY - JOUR
T1 - LHRH-Targeted Redox-Responsive Crosslinked Micelles Impart Selective Drug Delivery and Effective Chemotherapy in Triple-Negative Breast Cancer
AU - Xiao, Kai
AU - Liu, Qiangqiang
AU - Suby, Nell
AU - Xiao, Wenwu
AU - Agrawal, Rinki
AU - Vu, Michael
AU - Zhang, Hongyong
AU - Luo, Yan
AU - Li, Yuanpei
AU - Lam, Kit S.
N1 - Funding Information:
The authors are thankful for the financial support from NIH/NCI (R01CA115483), NIH/NIBIB (5R01EB012569), DoD BCRP Award (W81XWH‐10‐1‐0817), National Natural Science Foundation of China (81572617 & 81630101), and Sichuan Science and Technology Program (2019JDRC0019).
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - breast cancer
KW - disulfide crosslinkers
KW - LHRH
KW - micelles
KW - paclitaxel
KW - redox-responsive micelles
KW - targeted delivery
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U2 - 10.1002/adhm.202001196
DO - 10.1002/adhm.202001196
M3 - Article
C2 - 33200571
AN - SCOPUS:85096744362
JO - Advanced healthcare materials
JF - Advanced healthcare materials
SN - 2192-2640
ER -