Decitabine nanoconjugate sensitizes human glioblastoma cells to temozolomide.
In this study, we developed and characterized a delivery system for the epigenetic demethylating drug, decitabine, to sensitize temozolomide-resistant human glioblastoma multiforme (GBM) cells to alkylating chemotherapy. A poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) based nanoconjugate was fabricated to encapsulate decitabine and achieved a better therapeutic response in GBM cells than that with the free drug. After synthesis, the highly efficient uptake process and intracellular dynamics of this nanoconjugate were monitored by single-molecule fluorescence tools. Our experiments demonstrated that, under an acidic pH due to active glycolysis in cancer cells, the PLGA-PEG nanovector could release the conjugated decitabine at a faster rate, after which the hydrolyzed lactic acid and glycolic acid would further acidify the intracellular microenvironment, thus providing positive feedback to increase the effective drug concentration and realize growth inhibition. In temozolomide-resistant GBM cells, decitabine can potentiate the cytotoxic DNA alkylation by counteracting cytosine methylation and reactivating tumor suppressor genes, such as p53 and p21. Owing to the excellent internalization and endolysosomal escape enabled by the PLGA-PEG backbone, the encapsulated decitabine exhibited a better anti-GBM potential than that of free drug molecules. Hence, the synthesized nanoconjugate and temozolomide could act in synergy to deliver a more potent and long-term antiproliferative effect against malignant GBM cells.
Yi
Y
Cui
‡Department of Pharmaceutical Chemistry, University of Karachi, Karachi 75270, Pakistan.
Asia
A
Naz
David H
DH
Thompson
Joseph
J
Irudayaraj
D000964:Antimetabolites, Antineoplastic / Q000737:chemistry; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000737:chemistry; D001672:Biocompatible Materials / Q000737:chemistry; D001896:Boron Compounds; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077209:Decitabine; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008689:Methacrylates; D008768:Methylmethacrylates; D008823:Micelles; D058726:Nanoconjugates / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013050:Spectrometry, Fluorescence; D000077204:Temozolomide
D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D001672:Biocompatible Materials; D001896:Boron Compounds; D008689:Methacrylates; D008768:Methylmethacrylates; D008823:Micelles; D058726:Nanoconjugates; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D000077209:Decitabine; D003606:Dacarbazine; C049495:Super-bond; D001374:Azacitidine; D000077204:Temozolomide
decitabine; drug delivery; glioblastoma multiforme; nanoconjugate; single-molecule spectroscopy; temozolomide