title: Synergistic active targeting of dually integrin αvβ3/CD44-targeted nanoparticles to B16F10 tumors located at different sites of mouse bodies.
abstract: Conventional enhanced permeation and retention (EPR) mediates the effects of many drugs, including the accumulation of nanocarriers at tumor sites, but its efficiency remains low. In this study, this limitation was overcome by developing a dual-targeting delivery system based on hyaluronan (HA, a major ligand of CD44) and tetraiodothyroacetic acid (tetrac, a specific ligand of αvβ3), which was exploited to carry docetaxel (DTX) for the synergistic active targeting to tumors. First, a tetrac-HA (TeHA) conjugate was synthesized and grafted onto the surfaces of solid lipid nanoparticles (SLNs) (TeHA-SLNs/DTX), with a high encapsulation efficiency of >91.6%. The resulting SLNs exhibited an approximately toroid morphology revealed using TEM. The cellular uptake and cytotoxicity of various formulations on CD44/αvβ3-enriched B16F10 cells were then assessed, and both results confirmed the selective uptake and high cytotoxicity of the TeHA-SLNs/DTX in a TeHA-dependent manner. In vivo imaging and vessel distribution tests revealed the efficiency of synergistic active targeting was higher than that of EPR-mediated passive targeting by the TeHA-SLNs to αvβ3-expressing tumor blood vessels and CD44-expressing tumor cells via selective targeting. Finally, in both xenograft tumor mice and in situ lung metastasis tumor mice, tumor growth was significantly inhibited by TeHA-SLNs/DTX. Therefore, TeHA-SLNs are an efficient system for the dual-targeted delivery of drugs to treat cancer in vivo.
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China. Electronic address: shisanjuns@163.com.
authors.forename: Sanjun
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Chenwen
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Sheng
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Zhuoheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Guolin
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Minghe
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Ruoqiu
authors.initials: R
authors.lastname: Fu
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Xiang
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China. Electronic address: lulab2014@126.com.
authors.forename: Laichun
authors.initials: L
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D065546:Drug Liberation; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D013974:Thyroxine / Q000031:analogs & derivatives / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D039302:Integrin alphaVbeta3; D043823:Taxoids; D000077143:Docetaxel; D006820:Hyaluronic Acid; C011126:tetraiodothyroacetic acid; D013974:Thyroxine
keywords: Docetaxel; Dual-targeting delivery system; Hyaluronan; Synergistic active targeting; Tetraiodothyroacetic acid