title: Hyaluronic acid functional amphipathic and redox-responsive polymer particles for the co-delivery of doxorubicin and cyclopamine to eradicate breast cancer cells and cancer stem cells.
abstract: Cancer stem cells (CSCs) have the ability to transform into bulk cancer cells, to promote tumor growth and establish tumor metastasis. To effectively inhibit tumor growth and prevent metastasis, treatments with conventional chemotherapy drugs should be combined with CSC targeted drugs. In this study, we describe the synthesis and characterization of a new amphiphilic polymer, hyaluronic acid-cystamine-polylactic-co-glycolic acid (HA-SS-PLGA), composed of a hydrophobic PLGA head and a hydrophilic HA segment linked by a bioreducible disulfide bond. With a double emulsion method, a nano delivery system was constructed to deliver doxorubicin (DOX) and cyclopamine (CYC, a primary inhibitor of the hedgehog signaling pathway of CSCs) to both a CD44-overexpressing breast CSC subpopulation and bulk breast cancer cells and allow an on-demand release. The resulting drug-loaded NPs exhibited a redox-responsive drug release profile. Dual drug-loaded particles potently diminished the number and size of tumorspheres and HA showed a targeting effect towards breast CSCs. In vivo combination therapy further demonstrated a remarkable synergistic anti-tumor effect and prolonged survival compared to mono-therapy using the orthotopic mammary fat pad tumor growth model. The co-delivery of drug and the CSC specific inhibitor towards targeted cancer chemotherapeutics provides an insight into anticancer strategy with facile control and high efficacy.
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, China. liuy@nanoctr.cn wuy@nanoctr.cn chenchy@nanoctr.cn.
authors.forename: Kelei
authors.initials: K
authors.lastname: Hu
authors.forename: Huige
authors.initials: H
authors.lastname: Zhou
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhu
authors.initials: Z
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Jinglong
authors.initials: J
authors.lastname: Tang
authors.forename: Jiayang
authors.initials: J
authors.lastname: Li
authors.forename: Jiakun
authors.initials: J
authors.lastname: Zhang
authors.forename: Wang
authors.initials: W
authors.lastname: Sheng
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Chunying
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006820:Hyaluronic Acid / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D019344:Lactic Acid / Q000737:chemistry; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010084:Oxidation-Reduction; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D016896:Treatment Outcome; D014704:Veratrum Alkaloids / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D014704:Veratrum Alkaloids; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004317:Doxorubicin; D006820:Hyaluronic Acid; C000541:cyclopamine