Metformin-conjugated micellar system with intratumoral pH responsive de-shielding for co-delivery of doxorubicin and nucleic acid.

Affiliation

Liu Y(1), Sun J(1), Huang Y(1), Chen Y(1), Li J(1), Liang L(1), Xu J(1), Wan Z(1), Zhang B(1), Li Z(1), Li S(2).
Author information:
(1)Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, United States.
(2)Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, United States. Electronic address: [Email]

Abstract

A novel PMet-P(cdmPEG2K) polymeric micellar carrier was developed for tumor-targeted co-delivery of DOX and nucleic acids (NA), based on polymetformin and a structure designed to lose the PEG shell in response to the acidic extracellular tumor environment. NA/DOX co-loaded micelleplexes exhibited enhanced inhibition of cell proliferation compared to DOX-loaded micelles, and displayed a higher level of cytotoxicity at an acidic pH (6.8) which mimicks the tumor microenvironment. The PMet-P(cdmPEG2K) micelles achieved significantly improved transfection with either a reporter plasmid or Cy3-siRNA, and enhanced DOX intracellular uptake in 4T1.2 cells at pH 6.8. Importantly, PMet-P(cdmPEG2K) micelles showed excellent pEGFP (EGFP expression plasmid) transfection in an aggressive murine breast cancer (4T1.2) model. By using a plasmid encoding IL-12 (pIL-12), we investigated the combined effect of chemotherapy and gene therapy. PMet-P(cdmPEG2K) micelles co-loaded with DOX and pIL-12 were more effective at inhibiting tumor growth compared to micelles loaded with DOX or pIL-12 alone. In addition, this micellar system was effective in co-delivery of siRNA and DOX into tumor cells. Our results suggest that PMet-P(cdmPEG2K) has the potential for chemo and nucleic acid combined cancer therapy.