title: A functional nanocarrier that copenetrates extracellular matrix and multiple layers of tumor cells for sequential and deep tumor autophagy inhibitor and chemotherapeutic delivery.
abstract: To further enhance the intensity of deep tumor drug delivery and integrate a combined therapy, we herein report on a core-shell nanocarrier that could simultaneously overcome the double barriers of the extracellular matrix (ECM) and multiple layers of tumor cells (MLTC). A pH-triggered reversible swelling-shrinking core and an MMP2 (matrix metallopeptidase 2) degradable shell were developed to encapsulate chemotherapeutics and macroautophagy/autophagy inhibitors, respectively. MMP2 degraded the shell, which was followed by the autophagy inhibitors' release. The exposed core could diffuse along the pore within the ECM to deliver chemotherapeutics into deep tumors, and it was able to swell in lysosomes and shrink back in the cytoplasm or ECM. The swelling of the core resulted in the rapid release of chemotherapeutics to kill autophagy-inhibited cells. After leaving the dead cells, the shrinking core could act on neighboring cells that were closer to the center of the tumor. The core thus could also cross MLTC layer by layer to deliver chemotherapeutics into the deep tumor.
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of education, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of education, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of education, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Yin
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of education, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of education, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors.forename: Kairong
authors.initials: K
authors.lastname: Shi
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of education, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors.forename: Huile
authors.initials: H
authors.lastname: Gao
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of education, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of education, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005780:Gelatin / Q000737:chemistry; D006801:Humans; D061986:MCF-7 Cells; D008546:Melanoma, Experimental / Q000473:pathology; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; C025946:3-methyladenine; D004317:Doxorubicin; D005780:Gelatin; D000225:Adenine
keywords: autophagy inhibition; deep tumor penetration; multidrug delivery; multilayers tumor cells crossing; multistage size changeable nanocarrier