title: Comprehensively priming the tumor microenvironment by cancer-associated fibroblast-targeted liposomes for combined therapy with cancer cell-targeted chemotherapeutic drug delivery system.
abstract: Cancer-associated fibroblasts (CAFs) not only support tumorigenesis and tumor metastasis by reciprocal cellular cross-talk with cancer cells, but also remodel the extracellular matrix (ECM) and architecture of tumor microenvironment. This leads to poor tumor penetration of traditional chemotherapeutic nanomedicines and resulting drug resistance. In this study, we use a novel tumor stroma-targeted nanovehicle (FH-SSL-Nav) to specifically eradicate CAFs, promote tumor penetration of nanomedicines and cut off the stroma's support to cancer cells. FH-SSL-Nav exhibited excellent and comprehensive tumor microenvironment modulation including downregulation ECM deposition, decreasing interstitial fluid pressure (IFP) and facilitating blood perfusion. As a result, more chemotherapeutic drug delivery systems penetrated deep into tumor spheroids in vitro and tumor tissues in vivo. Furthermore, chemotherapeutic drug resistance induced by microenvironment was partly reversed by FH-SSL-Nav. In a human Hep G2 xenograft nude mouse model, FH-SSL-Nav greatly improved the tumor suppression of cancer cell-targeted liposomal doxorubicin (7pep-SSL-DOX) with low dose and low toxicity. Since Nav and DOX exhibited no synergy against Hep G2 cells, it was clear that the improved antitumor efficacy was basically due to the comprehensive tumor microenvironment priming by FH-SSL-Nav.
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100191, China.
authors.forename: Binlong
authors.initials: B
authors.lastname: Chen
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: pawpaw009@126.com.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Mei
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100191, China.
authors.forename: Tongzhou
authors.initials: T
authors.lastname: Liu
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100191, China.
authors.forename: Suxin
authors.initials: S
authors.lastname: Li
authors.affiliation: School of Basic Medical Sciences, Peking University, Beijing 100191, China.
authors.forename: Bo
authors.initials: B
authors.lastname: He
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100191, China.
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.affiliation: Medical and Healthy Analytical Center, Peking University, Beijing 100191, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Beijing 100191, China. Electronic address: zqdodo@bjmu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001692:Biological Transport; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000493:pharmacokinetics; D018920:Coculture Techniques; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008081:Liposomes; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D008081:Liposomes; D013449:Sulfonamides; C528561:navitoclax
keywords: Cancer-associated fibroblasts; Combination therapy; Liposomal doxorubicin; Navitoclax; Tumor microenvironment; Tumor penetration