Real-time visualization of pH-responsive PLGA hollow particles containing a gas-generating agent targeted for acidic organelles for overcoming multi-drug resistance
Journal
Biomaterials
Journal Volume
34
Journal Issue
1
Pages
1-10
Date Issued
2013
Author(s)
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 CO2 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. ? 2012 Elsevier Ltd.
SDGs
Other Subjects
Acidic environment; Acidic organelle; Cancer cells; Cell nucleus; Confocal image; Doxorubicin; Drug release; Endosomes; Fluorescence probes; Hollow particle; Hydrochloride salts; Late endosomes; Multidrug resistance; P-glycoprotein; Passive diffusions; PH-responsive; Poly(D , L-lactic-co-glycolic acid); Real time visualization; Shell wall; Sodium bicarbonates; Stimuli-responsive; Carbon dioxide; Carbonates; Cells; Chemotherapy; Copolymers; Cytology; Drug delivery; Pharmacodynamics; bicarbonate; carbon dioxide; doxorubicin; polyglactin; acidification; article; breast cancer; cell death; cell maturation; cell migration; cell nucleus; cell organelle; cell strain MCF 7; controlled study; cytotoxicity; diffusion; drug release; endosome; fluorescence; human; human cell; lysosome; multidrug resistance; pH; pinocytosis; priority journal; Cell Death; Cell Survival; Computer Systems; Doxorubicin; Drug Resistance, Multiple; Endocytosis; Flow Cytometry; Gases; Humans; Hydrogen-Ion Concentration; Image Processing, Computer-Assisted; Intracellular Space; Lactic Acid; MCF-7 Cells; Microscopy, Confocal; Nanoparticles; Organelles; Polyglycolic Acid; X-Ray Diffraction
Type
journal article