In vivo antitumor effects of carboxymethyl chitosan-conjugated triptolide after oral administration

Drug Deliv. 2020 Dec;27(1):848-854. doi: 10.1080/10717544.2020.1770370.

Abstract

The purpose of this study is to evaluate in vitro and in vivo antitumor efficacy and subacute toxicity of triptolide (TP) prodrug, a conjugate between TP and carboxymethyl chitosan (CC). The CCTP conjugate contained 4∼ wt % TP and displayed excellent aqueous solubility (5 mg/mL) as compared to the native TP (17 μg/mL). In vitro cytotoxicity of CCTP conjugate was evaluated by CCK8 assay against human pancreatic cancer (PC) cell lines, showing comparable the half maximal inhibitory concentration (IC50) values to the parent TP. In a mouse model of PC (BxPC-3), the CCTP conjugate administered orally (at dose levels as low as 0.2 mg TP equivalent/kg) showed comparable efficacy in reducing or eliminating xenograft tumor to the same dose of TP, but exhibited much lower subacute toxicity as seen in body weight loss and hematological toxicity.

Keywords: Triptolide; carboxymethyl chitosan; oral administration; pancreatic cancer; toxicity.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Antineoplastic Agents, Alkylating / toxicity
  • Biocompatible Materials / pharmacology
  • Cell Line, Tumor
  • Chitosan / analogs & derivatives*
  • Chitosan / pharmacology
  • Diterpenes* / pharmacology
  • Diterpenes* / toxicity
  • Drug Carriers
  • Drug-Related Side Effects and Adverse Reactions / prevention & control
  • Epoxy Compounds / pharmacology
  • Epoxy Compounds / toxicity
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Pancreatic Neoplasms / drug therapy
  • Phenanthrenes* / pharmacology
  • Phenanthrenes* / toxicity
  • Prodrugs / pharmacology
  • Solubility
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Alkylating
  • Biocompatible Materials
  • Diterpenes
  • Drug Carriers
  • Epoxy Compounds
  • Phenanthrenes
  • Prodrugs
  • carboxymethyl-chitosan
  • triptolide
  • Chitosan

Grants and funding

This project was sponsored by National Natural Science Foundation of China [grant number U1604185], [grant number 21601053]; Henan Scientific and technological Innovation Talents Project [grant number 20HASTIT050]; the Scientific and Technological Brainstorm Project of Henan Province [grant number 182102410012], [grant number 192102310440]; the Educational Committee Foundation of Henan [grant number 20B350003], [grant number 19A360021], [grant number 2019ZY2007; and National undergraduate Innovation and Entrepreneurship Training Program [grant number 201910471013, CXXM[2019]0045].