title: Integrin-mediated active tumor targeting and tumor microenvironment response dendrimer-gelatin nanoparticles for drug delivery and tumor treatment.
abstract: Due to the high morbidity and mortality of cancer, it has become an urgent matter to develop an effective and a safe treatment strategy. Nanoparticles (NP) based drug delivery systems have gained much attention nowadays but they faced a paradoxical issue in delivering drugs into tumors: NP with large size were characterized with weak tumor penetration, meanwhile NP with small size resulted in poor tumor retention. To solve this problem, we proposed a multistage drug delivery system which could intelligently shrink its size from large size to small size in the presence of matrix metalloproteinase-2 (MMP-2) which were highly expressed in tumor tissues, therefore the multistage system could benefit from its large size for better retention effect in tumor and then shrunk to small size to contribute to better penetration efficiency. The multistage drug delivery system, RGD-DOX-DGL-GNP, was constructed by 155.4nm gelatin NP core (the substrate of MMP-2) and surface decorated with doxorubicin (DOX) and RGD peptide conjugated dendritic poly-l-lysine (DGL, 34.3nm in diameter). In vitro, the size of multistage NP could effectively shrink in the presence of MMP-2. Thus, the RGD-DOX-DGL-GNP could penetrate deep into tumor spheroids. In vivo, this multistage drug delivery system showed higher tumor retention and deeper penetration than both DOX-DGL and DOX-GNP. Consequently, RGD-DOX-DGL-GNP successfully combined the advantages of dendrimers and GNP in vivo, resulting in an outstanding anti-tumor effect. In conclusion, the multistage drug delivery system could intelligently shrink from large size to small size in the tumor microenvironment and displayed better retention and penetration efficiency, making it an impressing system for cancer treatment.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041,China.
authors.forename: Guanlian
authors.initials: G
authors.lastname: Hu
authors.affiliation: Huashan Hospital North, Fudan University, 108 Lu Xiang Road, Shanghai 201907, China.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041,China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041,China.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Ruan
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041,China.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041,China. Electronic address: gaohuile@scu.edu.cn.
authors.forename: Huile
authors.initials: H
authors.lastname: Gao
mesh_terms: D000818:Animals; D050091:Dendrimers / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D005780:Gelatin / Q000737:chemistry*; D016023:Integrins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009842:Oligopeptides / Q000737:chemistry; D014018:Tissue Distribution; D059016:Tumor Microenvironment
chemical_list: D050091:Dendrimers; D016023:Integrins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin; D005780:Gelatin
keywords: Breast cancer; Gelatin nanoparticles; Matrix metalloproteinase-2; Multistage drug delivery system; Tumor penetration and retention