Nanoparticle encapsulated lipopeptide conjugate of antitubercular drug isoniazid: in vitro intracellular activity and in vivo efficacy in a Guinea pig model of tuberculosis

Bioconjug Chem. 2014 Dec 17;25(12):2260-8. doi: 10.1021/bc500476x. Epub 2014 Nov 26.


Considering that Mycobacterium tuberculosis (Mtb) can survive in host phagocytes for decades and currently applied drugs are largely ineffective in killing intracellular Mtb, novel targeted delivery approaches to improve tuberculosis chemotherapy are urgently needed. In order to enhance the efficacy of a clinically used antitubercular agent (isoniazid, INH) a novel lipopeptide carrier was designed based on the sequence of tuftsin, which has been reported as a macrophage-targeting molecule. The conjugate showed relevant in vitro activity on Mtb H37Rv culture with low cytotoxicity and hemolytic activity on human cells. The conjugate directly killed intracellular Mtb and shows much greater efficacy than free INH. To improve bioavailability, the conjugate was encapsulated into poly(lactide-co-glycolide) (PLGA) nanoparticles and tested in vivo in a guinea pig infection model. External clinical signs, detectable mycobacterial colonies in the organs, and the histopathological findings substantiate the potent chemotherapeutic effect of orally administered conjugate-loaded nanoparticles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology
  • Antitubercular Agents / toxicity
  • Disease Models, Animal
  • Drug Carriers / pharmacology
  • Female
  • Guinea Pigs
  • Humans
  • Isoniazid / administration & dosage
  • Isoniazid / chemistry*
  • Isoniazid / pharmacology*
  • Isoniazid / toxicity
  • Lactic Acid / chemistry
  • Lipopeptides / administration & dosage*
  • Lipopeptides / chemistry
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Nanoparticles / toxicity
  • Polyglycolic Acid / chemistry
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Tuberculosis / drug therapy*
  • Tuberculosis / microbiology


  • Antitubercular Agents
  • Drug Carriers
  • Lipopeptides
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Isoniazid