Poly(lactic acid-glycolic acid) nanoparticles markedly improve immunological protection provided by peptide P10 against murine paracoccidioidomycosis.

Abstract

BACKGROUND AND PURPOSE:

The present study reports on the preparation and testing of a sustained delivery system for the immunomodulatory peptide P10 aimed at reducing the in vivo degradation of the peptide and the amount required to elicit a protective immune response against paracoccidioidomycosis.

EXPERIMENTAL APPROACH:

BALB/c mice were infected with the yeast Paracoccidioides brasiliensis to mimic the chronic form of paracoccidioidomycosis. The animals were treated daily with sulfamethoxazole/trimethoprim alone or combined with peptide P10, either emulsified in Freund's adjuvant or entrapped in poly(lactic acid-glycolic acid) (PLGA) nanoparticles at different concentrations (1 microg, 5 microg, 10 microg, 20 microg or 40 microg.50 microL(-1)). Therapeutic efficacy was assessed as fungal burden in tissues and the immune response by quantitative determination of cytokines.

KEY RESULTS:

Animals given combined chemotherapy and P10 nanotherapy presented a marked reduction of fungal load in the lungs, compared with the non-treated animals. After 30 days of treatment, P10 entrapped within PLGA (1 microg.50 microL(-1)) was more effective than 'free' P10 emulsified in Freund's adjuvant (20 microg.50 microL(-1)), as an adjuvant to chemotherapy. After treatment for 90 days, the higher doses of P10 entrapped within PLGA (5 or 10 microg.50 microL(-1)) were most effective. Treatment with P10 emulsified in Freund's adjuvant (20 microg.50 microL(-1)) or P10 entrapped within PLGA (1 microg.50 microL(-1)) were accompanied by high levels of interferon-gamma in lung.

CONCLUSIONS AND IMPLICATIONS:

Combination of sulfamethoxazole/trimethoprim with the P10 peptide entrapped within PLGA demonstrated increased therapeutic efficacy against paracoccidioidomycosis. P10 incorporation into PLGA nanoparticles dramatically reduced the peptide amount necessary to elicit a protective effect.

• Authors: André C Amaral, Alexandre F Marques, Julián E Muñoz, Anamélia L Bocca, Andreza R Simioni, Antonio C Tedesco, Paulo C Morais, Luiz R Travassos, Carlos P Taborda, Maria Sueli S Felipe
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 159 Issue 5 Pg. 1126-32 (Mar 2010) ISSN: 1476-5381 [Electronic] England
• PMID: 20136827 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Infective Agents
• Delayed-Action Preparations
• Drug Carriers
• Glycoproteins
• Immunologic Factors
• P10 peptide, Paracoccidioides brasiliensis
• Peptide Fragments
• Polylactic Acid-Polyglycolic Acid Copolymer
• Polyglycolic Acid
• Lactic Acid
• Trimethoprim, Sulfamethoxazole Drug Combination
• Freund's Adjuvant

Topics

• Animals
• Anti-Infective Agents (therapeutic use)
• Delayed-Action Preparations
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Carriers (chemistry)
• Drug Therapy, Combination
• Freund's Adjuvant (chemistry)
• Glycoproteins (administration & dosage, pharmacology)
• Immunologic Factors (administration & dosage, pharmacology)
• Lactic Acid (chemistry)
• Male
• Mice
• Mice, Inbred BALB C
• Nanoparticles
• Paracoccidioides (immunology)
• Paracoccidioidomycosis (drug therapy, immunology)
• Peptide Fragments (administration & dosage, pharmacology)
• Polyglycolic Acid (chemistry)
• Polylactic Acid-Polyglycolic Acid Copolymer
• Trimethoprim, Sulfamethoxazole Drug Combination (therapeutic use)