title: Tumor Microenvironment-Responsive Nanoparticle Delivery of Chemotherapy for Enhanced Selective Cellular Uptake and Transportation within Tumor.
abstract: A novel drug delivery strategy featured with enhanced uptake of nanoparticles (NPs) by targeted tumor cells and subsequent intratumoral cellular hitchhiking of chemotherapy to deep tumor regions was described. The NP delivery system was obtained from assembly of poly(lactic acid-co-glycolic acid)-grafted hyaluronic acid (HA-g-PLGA) together with an anticancer drug, SN38, in aqueous phase, followed by implementing the NP surface with a layer of methoxypoly(ethylene glycol)-b-poly(histamine methacrylamide) (mPEG-b-PHMA) via hydrophobic association to improve the colloidal stability both in vitro and in vivo. Upon arrival of these PEGylated NPs at the acidic tumor site through the EPR effect, mPEG-b-PHMA became detached from the NP surface by the charge transition of the PHMA blocks from neutral (hydrophobic) to positively charged (hydrophilic) state via acid-induced protonation of their imidazole groups in tumor microenvironment. The exposure of HA shell on the naked NP thus resulted in enhanced uptake of NPs by CD44-expressed tumor cells, including cancer cells and tumor-associated macrophages (TAMs). Along with the TAMs being further chemotactically recruited by hypoxia cells, the engulfed nanotherapeutics was thus transported into the avascular area in which the anticancer action of chemotherapy occurred by virtue of the drug release alongside PLGA degradation, similar to those arising in other tumor nonhypoxia regions.
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University , Hsinchu 300, Taiwan.
authors.forename: Wen-Chia
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University , Hsinchu 300, Taiwan.|Department of Anesthesiology, National Taiwan University Hospital-Hsinchu Branch , Hsinchu 300, Taiwan.
authors.forename: Shih-Hong
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University , Hsinchu 300, Taiwan.
authors.forename: Wen-Hsuan
authors.initials: WH
authors.lastname: Chiang
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University , Hsinchu 300, Taiwan.
authors.forename: Chu-Wei
authors.initials: CW
authors.lastname: Huang
authors.affiliation: Department of Biomedical Engineering, National Yang-Ming University , Taipei 112, Taiwan.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Lo
authors.affiliation: Department of Chemical Engineering, National Taiwan University of Science and Technology , Taipei 106, Taiwan.
authors.forename: Chorng-Shyan
authors.initials: CS
authors.lastname: Chern
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University , Hsinchu 300, Taiwan.
authors.forename: Hsin-Cheng
authors.initials: HC
authors.lastname: Chiu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D006820:Hyaluronic Acid / Q000737:chemistry*; D000077146:Irinotecan; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011091:Polyesters; D011100:Polyglycolic Acid; C033616:poly(lactide); D000077146:Irinotecan; D006820:Hyaluronic Acid; D002166:Camptothecin