Stepwise pH/reduction-responsive polymeric conjugates for enhanced drug delivery to tumor

Mater Sci Eng C Mater Biol Appl. 2018 Jan 1:82:234-243. doi: 10.1016/j.msec.2017.08.079. Epub 2017 Aug 31.

Abstract

In this research, a charge-conversional polymer, poly-l-lysine-lipoic acid (PLL-LA), was prepared by dimethylmaleic anhydride (DA) modification and applied as a carrier with enhanced cell internalization and intracellular pH- and reduction-triggered doxorubicin (Dox) release. The surface charge of dimethylmaleic anhydride-poly-l-lysine-lipoic acid micelles (DA-PLL-LA) was negative at physiological pH and reversed to positive at the extracellular and intracellular pH of cancer cells. At tumor extracellular pH of 6.8, the conjugates underwent a rapid charge-reversible process with almost 80% DA cleavage within 2h, and then endocytosed into the endo/lysosomes more rapidly than at physiological pH of 7.4. The Dox/DA-PLL-LA micelles (Dox-micelles) demonstrated a sustained drug release in vitro under physiological condition, and rapid Dox release was triggered by both extracellular pH and high-concentration reducing glutathione. The Dox-micelles also exhibited enhanced internalization at extracellular pH, rapid intracellular drug release, and improved cytotoxicity against A549 cells in vitro. Excellent tumor-penetrating efficacy was also found in A549 tumor spheroids and solid tumor slices. Moreover, the DA-PLL-LA micelles exhibited excellent tumor-targeting ability in tumor tissues and excellent antitumor efficacy and low systemic toxicity in breast tumor-bearing mice. Therefore, the DA-PLL-LA micelles demonstrated great potential for targeted and efficient drug delivery in cancer treatments.

Keywords: Cancer therapy; Charge reversion; Drug delivery; Smart; Stimuli-responsive.

MeSH terms

  • A549 Cells
  • Animals
  • Antibiotics, Antineoplastic / chemistry*
  • Antibiotics, Antineoplastic / therapeutic use
  • Antibiotics, Antineoplastic / toxicity
  • Cell Survival / drug effects
  • Doxorubicin / chemistry*
  • Doxorubicin / therapeutic use
  • Doxorubicin / toxicity
  • Drug Carriers / chemical synthesis
  • Drug Carriers / chemistry*
  • Drug Liberation
  • Humans
  • Hydrogen-Ion Concentration
  • Mice
  • Mice, Inbred BALB C
  • Micelles
  • Microscopy, Confocal
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Oxidation-Reduction
  • Phagocytosis / drug effects
  • Polylysine / chemistry
  • Polymers / chemical synthesis
  • Polymers / chemistry*
  • Thioctic Acid / chemistry
  • Transplantation, Heterologous

Substances

  • Antibiotics, Antineoplastic
  • Drug Carriers
  • Micelles
  • Polymers
  • Polylysine
  • Thioctic Acid
  • Doxorubicin