PUBLICATION

Polymeric nanobiotics as a novel treatment for mycobacterial infections

Authors
Batalha, I.L., Bernut, A., Schiebler, M., Ouberai, M.M., Passemar, C., Klapholz, C., Kinna, S., Michel, S., Sader, K., Castro-Hartmann, P., Renshaw, S.A., Welland, M.E., Andres Floto, R.
ID
ZDB-PUB-191026-10
Date
2019
Source
Journal of controlled release : official journal of the Controlled Release Society   314: 116-124 (Journal)
Registered Authors
Renshaw, Steve A.
Keywords
Mycobacterium tuberculosis, antibiotic, clofazimine, isoniazid, nanoparticles, polymer-drug conjugate, zebrafish
MeSH Terms
  • Animals
  • Antitubercular Agents/administration & dosage*
  • Antitubercular Agents/pharmacology
  • Clofazimine/administration & dosage
  • Clofazimine/pharmacology
  • Delayed-Action Preparations
  • Disease Models, Animal
  • Drug Combinations
  • Drug Delivery Systems
  • Humans
  • Isoniazid/administration & dosage*
  • Isoniazid/pharmacology
  • Macrophages/microbiology
  • Mycobacterium tuberculosis/drug effects*
  • Nanoparticles*
  • Polymers/chemistry
  • Tuberculosis/drug therapy
  • Tuberculosis/microbiology
  • Zebrafish
PubMed
31647980 Full text @ J. Control Release
Abstract
Mycobacterium tuberculosis (Mtb) remains a major challenge to global health, made worse by the spread of multi-drug resistance. Currently, the efficacy and safety of treatment is limited by difficulties in achieving and sustaining adequate tissue antibiotic concentrations while limiting systemic drug exposure to tolerable levels. Here we show that nanoparticles generated from a polymer-antibiotic conjugate ('nanobiotics') deliver sustained release of active drug upon hydrolysis in acidic environments, found within Mtb-infected macrophages and granulomas, and can, by encapsulation of a second antibiotic, provide a mechanism of synchronous drug delivery. Nanobiotics are avidly taken up by infected macrophages, enhance killing of intracellular Mtb, and are efficiently delivered to granulomas and extracellular mycobacterial cords in vivo in an infected zebrafish model. We demonstrate that isoniazid (INH)-derived nanobiotics, alone or with additional encapsulation of clofazimine (CFZ), enhance killing of mycobacteria in vitro and in infected zebrafish, supporting the use of nanobiotics for Mtb therapy and indicating that nanoparticles generated from polymer-small molecule conjugates might provide a more general solution to delivering co-ordinated combination chemotherapy.
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