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pH-responsive microparticles of rifampicin for augmented intramacrophage uptake and enhanced antitubercular efficacy
Amit S Lokhande1, Falguni Panchal2, Renuka Munshi2
1Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai 400019, Maharashtra, India.
Abstract:
In this study we present pH-responsive rifampicin (RIF) microparticles comprising lecithin and a biodegradable hydrophobic polymer, polyethylene sebacate (PES), to achieve high intramacrophage delivery and enhanced antitubercular efficacy. PES and PES-lecithin combination microparticles (PL MPs) prepared by single step precipitation revealed average size of 1.5 to 2.7 µm, entrapment efficiency ∼ 60 %, drug loading 12-15 % and negative zeta potential. Increase in lecithin concentration enhanced hydrophilicity. PES MPs demonstrated faster release in simulated lung fluid pH 7.4, while lecithin MPs facilitated faster and concentration dependent release in acidic artificial lysosomal fluid (ALF) pH 4.5 due to swelling and destabilization confirmed by TEM. PES and PL (1:2) MPs exhibited comparable macrophage uptake which was ∼ 5-fold superior than free RIF, in the RAW 264.7 macrophage cells. Confocal microscopy depicted intensified accumulation of the MPs in the lysosomal compartment, with augmented release of coumarin dye from the PL MPs, confirming pH-triggered increased intracellular release. Although, PES MPs and PL (1:2) MPs displayed comparable and high macrophage uptake, antitubercular efficacy against macrophage internalised M. tuberculosis was significantly higher with PL (1:2) MPs. This suggested great promise of the pH-sensitive PL (1:2) MPs for enhanced antitubercular efficacy.
Insights
New pH-responsive microparticles made with polyethylene sebacate and lecithin improve rifampicin delivery into macrophages. This enhances the drug
Area of Science:
- Materials Science
- Nanotechnology
- Pharmacology
Background:
- Tuberculosis (TB) remains a significant global health challenge, necessitating improved drug delivery systems.
- Intramacrophage delivery is crucial for effective antitubercular therapy as Mycobacterium tuberculosis resides within host cells.
- Current rifampicin formulations may face limitations in achieving optimal intracellular concentrations.
Purpose of the Study:
- To develop pH-responsive microparticles for enhanced intramacrophage delivery of rifampicin (RIF).
- To investigate the role of lecithin and polyethylene sebacate (PES) in microparticle properties and drug release.
- To evaluate the antitubercular efficacy of the developed microparticles against intracellular Mycobacterium tuberculosis.
Main Methods:
- Preparation of PES and PES-lecithin (PL) microparticles via single-step precipitation.
- Characterization of microparticle size, entrapment efficiency, drug loading, and zeta potential.
- In vitro drug release studies at physiological (pH 7.4) and acidic (pH 4.5) conditions.
- Macrophage uptake studies using RAW 264.7 cells and confocal microscopy.
- Assessment of antitubercular efficacy against intracellular M. tuberculosis.
Main Results:
- PES and PL microparticles (MPs) exhibited sizes between 1.5-2.7 µm with high entrapment efficiency (~60%) and drug loading (12-15%).
- Lecithin incorporation enhanced hydrophilicity and facilitated pH-dependent drug release, with faster release in acidic conditions (pH 4.5).
- PL (1:2) MPs demonstrated ~5-fold superior macrophage uptake compared to free RIF, with intensified lysosomal accumulation.
- PL (1:2) MPs showed significantly higher antitubercular efficacy against intracellular M. tuberculosis compared to PES MPs and free RIF.
Conclusions:
- pH-responsive PL microparticles offer a promising strategy for enhanced intramacrophage delivery of rifampicin.
- The combination of lecithin and PES optimizes microparticle characteristics for targeted intracellular drug release.
- These novel microparticles hold great potential for improving the efficacy of antitubercular treatments.
