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Nanobody conjugated PLGA nanoparticles for active targeting of African Trypanosomiasis.

Abstract
Targeted delivery of therapeutics is an alternative approach for the selective treatment of infectious diseases. The surface of African trypanosomes, the causative agents of African trypanosomiasis, is covered by a surface coat consisting of a single variant surface glycoprotein, termed VSG. This coat is recycled by endocytosis at a very high speed, making the trypanosome surface an excellent target for the delivery of trypanocidal drugs. Here, we report the design of a drug nanocarrier based on poly ethylen glycol (PEG) covalently attached (PEGylated) to poly(D,L-lactide-co-glycolide acid) (PLGA) to generate PEGylated PLGA nanoparticles. This nanocarrier was coupled to a single domain heavy chain antibody fragment (nanobody) that specifically recognizes the surface of the protozoan pathogen Trypanosoma brucei. Nanoparticles were loaded with pentamidine, the first-line drug for T. b. gambiense acute infection. An in vitro effectiveness assay showed a 7-fold decrease in the half-inhibitory concentration (IC50) of the formulation relative to free drug. Furthermore, in vivo therapy using a murine model of African trypanosomiasis demonstrated that the formulation cured all infected mice at a 10-fold lower dose than the minimal full curative dose of free pentamidine and 60% of mice at a 100-fold lower dose. This nanocarrier has been designed with components approved for use in humans and loaded with a drug that is currently in use to treat the disease. Moreover, this flexible nanobody-based system can be adapted to load any compound, opening a range of new potential therapies with application to other diseases.
AuthorsJosé L Arias, Juan D Unciti-Broceta, José Maceira, Teresa Del Castillo, José Hernández-Quero, Stefan Magez, Miguel Soriano, José A García-Salcedo
JournalJournal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 197 Pg. 190-8 (Jan 10 2015) ISSN: 1873-4995 [Electronic] Netherlands
PMID25445702 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier B.V. All rights reserved.
Chemical References
  • Drug Carriers
  • Epitopes
  • Single-Domain Antibodies
  • Trypanocidal Agents
  • polylactic acid-polyglycolic acid copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Pentamidine
Topics
  • Animals
  • Drug Carriers (administration & dosage, chemistry)
  • Endocytosis
  • Epitopes (immunology)
  • Female
  • Lactic Acid (chemistry)
  • Mice, Inbred C57BL
  • Nanoparticles (administration & dosage, chemistry)
  • Pentamidine (administration & dosage, chemistry)
  • Polyglycolic Acid (chemistry)
  • Single-Domain Antibodies (administration & dosage, chemistry, immunology)
  • Trypanocidal Agents (administration & dosage, chemistry)
  • Trypanosoma brucei brucei (drug effects)
  • Trypanosomiasis, African (drug therapy)

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