Bile Acid Tethered Docetaxel-Based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes

Angew Chem Int Ed Engl. 2021 Mar 1;60(10):5394-5399. doi: 10.1002/anie.202015173. Epub 2021 Jan 19.

Abstract

In this study, we describe the engineering of sub-100 nm nanomicelles (DTX-PC NMs) derived from phosphocholine derivative of docetaxel (DTX)-conjugated lithocholic acid (DTX-PC) and poly(ethylene glycol)-tethered lithocholic acid. Administration of DTX-PC NMs decelerate tumor progression and increase the mice survivability compared to Taxotere (DTX-TS), the FDA-approved formulation of DTX. Unlike DTX-TS, DTX-PC NMs do not cause any systemic toxicity and slow the decay rate of plasma DTX concentration in rodents and non-rodent species including non-human primates. We further demonstrate that DTX-PC NMs target demethylation of CpG islands of Sparcl1 (a tumor suppressor gene) by suppressing DNA methyltransferase activity and increase the expression of Sparcl1 that leads to tumor regression. Therefore, this unique system has the potential to improve the quality of life in cancer patients and can be translated as a next-generation chemotherapeutic.

Keywords: cancer therapy; docetaxel; epigenetic changes; nanomicelles; toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cell Line, Tumor
  • CpG Islands
  • Demethylation
  • Disease Progression
  • Docetaxel / chemical synthesis
  • Docetaxel / pharmacokinetics
  • Docetaxel / therapeutic use*
  • Epigenesis, Genetic / drug effects*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Lithocholic Acid / analogs & derivatives*
  • Lithocholic Acid / pharmacokinetics
  • Lithocholic Acid / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Micelles
  • Neoplasms / drug therapy*
  • Neoplasms / physiopathology
  • Surface-Active Agents / chemical synthesis
  • Surface-Active Agents / pharmacokinetics
  • Surface-Active Agents / therapeutic use

Substances

  • Antineoplastic Agents
  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • Micelles
  • Sparcl1 protein, mouse
  • Surface-Active Agents
  • Docetaxel
  • Lithocholic Acid