title: Active Tumor Permeation and Uptake of Surface Charge-Switchable Theranostic Nanoparticles for Imaging-Guided Photothermal/Chemo Combinatorial Therapy.
abstract: To significantly promote tumor uptake and penetration of therapeutics, a nanovehicle system comprising poly(lactic-co-glycolic acid) (PLGA) as the hydrophobic cores coated with pH-responsive N-acetyl histidine modified D-α-tocopheryl polyethylene glycol succinate (NAcHis-TPGS) is developed in this work. The nanocarriers with switchable surface charges in response to tumor extracellular acidity (pHe) were capable of selectively co-delivering indocyanine green (ICG), a photothermal agent, and doxorubicin (DOX), a chemotherapy drug, to tumor sites. The in vitro cellular uptake of ICG/DOX-loaded nanoparticles by cancer cells and macrophages was significantly promoted in weak acidic environments due to the increased protonation of the NAcHis moieties. The results of in vivo and ex vivo biodistribution studies demonstrated that upon intravenous injection the theranostic nanoparticles were substantially accumulated in TRAMP-C1 solid tumor of tumor-bearing mice. Immunohistochemical examination of tumor sections confirmed the active permeation of the nanoparticles into deep tumor hypoxia due to their small size, pHe-induced near neutral surface, and the additional hitchhiking transport via tumor-associated macrophages. The prominent imaging-guided photothermal therapy of ICG/DOX-loaded nanoparticles after tumor accumulation induced extensive tumor tissue/vessel ablation, which further promoted their extravasation and DOX tumor permeation, thus effectively suppressing tumor growth.
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Chia-Chian
authors.initials: CC
authors.lastname: Hung
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Wen-Chia
authors.initials: WC
authors.lastname: Huang
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Lin
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Ting-Wei
authors.initials: TW
authors.lastname: Yu
authors.affiliation: 2. Department of Chemical Engineering, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Hsin-Hung
authors.initials: HH
authors.lastname: Chen
authors.affiliation: 2. Department of Chemical Engineering, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Sung-Chyr
authors.initials: SC
authors.lastname: Lin
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Wen-Hsuan
authors.initials: WH
authors.lastname: Chiang
authors.affiliation: 1. Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Hsin-Cheng
authors.initials: HC
authors.lastname: Chiu
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D003131:Combined Modality Therapy / Q000379:methods*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000493:pharmacokinetics; D004337:Drug Carriers; D004358:Drug Therapy / Q000379:methods; D006979:Hyperthermia, Induced / Q000379:methods; D007208:Indocyanine Green / Q000493:pharmacokinetics; D008297:Male; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage; D017319:Photosensitizing Agents / Q000493:pharmacokinetics*; D010789:Phototherapy / Q000379:methods; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D012878:Skin Neoplasms / Q000175:diagnosis* / Q000628:therapy*; D013386:Succinates / Q000008:administration & dosage*; D000068936:Theranostic Nanomedicine / Q000379:methods; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D017319:Photosensitizing Agents; D013386:Succinates; C514223:poly(lactide)-tocopheryl polyethylene glycol succinate; D011092:Polyethylene Glycols; D004317:Doxorubicin; D007208:Indocyanine Green
keywords: chemotherapy; deep tumor penetration; photothermal therapy; surface charge transition; tumor hypoxia