Mitochondria and nucleus delivery of active form of 10-hydroxycamptothecin with dual shell to precisely treat colorectal cancer

Nanomedicine (Lond). 2019 Apr;14(8):1011-1032. doi: 10.2217/nnm-2018-0227. Epub 2019 Mar 29.

Abstract

Aim: The objective of this study was to deliver a ring-closed form of 10-hydroxycamptothecin (HCPT) to the mitochondria and nucleus to treat colorectal cancer.

Materials & methods: HCPT-loaded nanoparticle HCPT@PLGA-PEG2k-triphenylphosphonium/PLGA-hyd-PEG4k-folic acid (PT/PHF) and HCPT@PT/PLGA-SS-PEG4k-folic acid (PSF) were prepared by using emulsion-solvent evaporation method.

Results: In vitro experimental results indicated HCPT@PT/PHF and HCPT@PT/PSF maintained a large amount of HCPT in active form, and delivered more HCPT to the nucleus and mitochondria of the tumor cell, which resulted in the enhancement of cytotoxicity of HCPT. In vivo experimental results indicated that HCPT@PT/PHF and HCPT@PT/PSF delivered more ring-closed form of HCPT to tumor tissue, which led to strong antitumor activity.

Conclusion: HCPT@PT/PHF and HCPT@PT/PSF could enhance therapeutic efficacy of HCPT to colorectal cancer.

Keywords: 10-hydroxycamptothecin; GSH responsive; colorectal cancer; drug delivery system; mitochondrial targeting; nucleus targeting; pH responsive; poly(lactic-co-glycolic acid); topoisomerase I; triphenylphosphonium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Biological Transport
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • Cell Survival / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Drug Carriers / chemistry*
  • Drug Liberation
  • Emulsions / chemistry
  • Folic Acid / chemistry
  • Folic Acid / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • Mitochondria / metabolism*
  • Models, Animal
  • Nanoparticles / chemistry
  • Particle Size
  • Polyesters / chemistry
  • Polyethylene Glycols / chemistry
  • Surface Properties
  • Tissue Distribution

Substances

  • Antineoplastic Agents, Phytogenic
  • Drug Carriers
  • Emulsions
  • Polyesters
  • polyethylene glycol-poly(lactide-co-glycolide)
  • Polyethylene Glycols
  • Folic Acid
  • 10-hydroxycamptothecin
  • Caspase 3
  • Camptothecin