A bio-responsive 6-mercaptopurine/doxorubicin based "Click Chemistry" polymeric prodrug for cancer therapy

Mater Sci Eng C Mater Biol Appl. 2020 Mar;108:110461. doi: 10.1016/j.msec.2019.110461. Epub 2019 Nov 19.

Abstract

A novel bio-responsive co-delivery system based on Poly(DEA)-b-Poly(ABMA-co-OEGMA) (PDPAO, prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization) copolymers was constructed for enhanced cellular internalization and effective combination therapy. Reduction-sensitive 6-mercaptopurine (6MP) based prodrug and pH-sensitive doxorubicin (DOX) based prodrug were grafted onto PDPAO by an azide-alkyne "Click Chemistry" reaction to acquire a pH/reduction-sensitive polymeric prodrug (PDPAO@imine-DOX/cis-6MP), which was able to self-aggregate to form polymeric micelles (M(DOX/6MP)) with an average particle size of 116 ± 2 nm in the water. The resultant micelles could maintain a stable sphere structure and show stability with a small particles' dispersion index in the blood. Importantly, it has been observed that the pH-sensitive surface charge-conversion accompanied pH-triggered DOX release in the biomimetic extracellular acidic environment of tumor tissue and a rapid dual-drug release triggered by pH and GSH in the intracellular environment. The in vitro evaluation of micelles on human cervical cancer (HeLa) and human promyelocytic leukemia (HL-60) cells showed an enhanced cellular uptake because of charge-conversion and exhibited a higher cell-killing performance. Moreover, the graft ratio of DOX and 6MP showed the ability to adjust the cytotoxicity; the micelles with a graft ratio of 2: 1 (M(DOX2/6MP)) displayed the higher cellular inhibition on either HeLa (combination index (CI) = 0.62) or HL-60 (CI = 0.35) cells. Overall, this novel dual-drug-conjugated delivery system might have important potential applications for combination therapy of cancer.

Keywords: Charge-conversion; Combination therapy; Dual-drug delivery; Polymeric micelles; RAFT polymerization; “Click Chemistry” reaction.

MeSH terms

  • Click Chemistry*
  • Delayed-Action Preparations / chemical synthesis
  • Delayed-Action Preparations / chemistry
  • Delayed-Action Preparations / pharmacology
  • Doxorubicin* / chemistry
  • Doxorubicin* / pharmacology
  • Drug Carriers* / chemical synthesis
  • Drug Carriers* / chemistry
  • Drug Carriers* / pharmacology
  • HL-60 Cells
  • HeLa Cells
  • Humans
  • Mercaptopurine* / chemistry
  • Mercaptopurine* / pharmacology
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Prodrugs* / chemical synthesis
  • Prodrugs* / chemistry
  • Prodrugs* / pharmacology

Substances

  • Delayed-Action Preparations
  • Drug Carriers
  • Prodrugs
  • Doxorubicin
  • Mercaptopurine