title: Real-time visualization of pH-responsive PLGA hollow particles containing a gas-generating agent targeted for acidic organelles for overcoming multi-drug resistance.
abstract: Chemotherapy research highly prioritizes overcoming the multi-drug resistance (MDR) effect in cancer cells. To overcome the drug efflux mediated by P-glycoprotein (P-gp) transporters, we developed pH-responsive poly(D,L-lactic-co-glycolic acid) hollow particles (PLGA HPs), capable of delivering doxorubicin (DOX) into MDR cells (MCF-7/ADR). The shell wall of PLGA HPs contained DiO (a hydrophobic dye), and their aqueous core carried DOX hydrochloride salt and sodium bicarbonate, a gas-generating agent when present in acidic environments. Both DiO and DOX could serve as fluorescence probes to localize HPs and visualize their intracellular drug release in real-time. Real-time confocal images provided visible evidences of the acid-responsive intracellular release of DOX from PLGA HPs in MDR cells. Via the macropinocytosis pathway, PLGA HPs taken up by cells experienced an increasingly acidic environment as they trafficked through the early endosomes and then matured into more acidic late endosomes/lysosomes. The progressive acidification of the internalized particles in the late endosomes/lysosomes generated CO(2) bubbles, leading to the disruption of HPs, prompt release of DOX, its accumulation in the nuclei, and finally the death of MDR cells. Conversely, taken up via a passive diffusion mechanism, free DOX was found mainly at the perimembrane region and barely reached the cell nuclei; therefore, no apparent cytotoxicity was observed. These results suggest that the developed PLGA HPs were less susceptible to the P-gp-mediated drug efflux in MDR cells and is a highly promising approach in chemotherapy.
authors.affiliation: Department of Chemical Engineering and Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC.
authors.forename: Cherng-Jyh
authors.initials: CJ
authors.lastname: Ke
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Chiang
authors.forename: Zi-Xian
authors.initials: ZX
authors.lastname: Liao
authors.forename: Hsin-Lung
authors.initials: HL
authors.lastname: Chen
authors.forename: Ping-Shan
authors.initials: PS
authors.lastname: Lai
authors.forename: Jui-Sheng
authors.initials: JS
authors.lastname: Sun
authors.forename: Hsing-Wen
authors.initials: HW
authors.lastname: Sung
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003199:Computer Systems; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D005740:Gases / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D015388:Organelles / Q000187:drug effects / Q000378:metabolism*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014961:X-Ray Diffraction
chemical_list: D005740:Gases; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004317:Doxorubicin