Fabrication and in vitro–in vivo evaluation of ligand appended isoniazid loaded nanoparticulate systems for the treatment of tuberculosis

Abstract

Isoniazid (INH) is amongst the first-line antibiotics that have been employed for the treatment of Tuberculosis (TB). Despite its potent anti-tubercular action, susceptibility to rapid hepatic first-pass metabolism and elimination largely limits its oral bioavailability, and has been associated with the induction of drug resistance and adverse effects. This presents study aims at the development and evaluation of unique mannosylated INH loaded solid lipid nanoparticles (Mn-INH-SLNs) for the treatment of TB. The Mn-INH-SLNs demonstrated a particle size of 466 ± 11 nm, which was acceptable for macrophage targeting and had % entrapment efficiency of 80.41 ± 1.37% (n = 6). The dissolution studies depicted a dual-phase drug release profile, i.e., burst release followed by a sustained release, revealing the best fit with the Korsmeyer-Peppas model. The MTT assay (cytotoxicity study) performed utilizing J774A.1 cells with optimized Mn-INH-SLNs deemed them to be safe and nontoxic. Mannosylated SLNs tagged with coumarin-6 (C6 – an established fluorescent marker) showed a substantially high intracellular internalization (1.11-folds) when analyzed through flow cytometric analysis (FACS). The in vivo pharmacokinetic evaluation following per-oral administration in rats demonstrated a significant rise in relative bioavailability (∼5.5-folds) with Mn-INH-SLNs compared to pure drug solution. The bio-distribution (drug disposition) studies exhibited greater lung accumulation of Mn-INH-SLNs (2.13-folds) in comparison to the unconjugated INH-SLNs (Un-INH-SLNs). The promising results of the study depict that the targeted-optimized Mn-INH-SLNs may be a propitious and potent tool to fight TB.

Graphical Abstract

Keywords:

• Alveolar macrophage
• targeted drug delivery
• mannose receptors
• cell viability
• pharmacokinetic

Acknowledgements

Authors are thankful to the Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India, for providing the necessary facilities to generate the manuscript that is a part of Doctor of Philosophy (Ph.D.) research work of Mr. Nimitt Chokshi, submitted to Nirma University, Ahmedabad, India.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethical approval

According to the guidelines of Committee for the objective of Control and Supervision of Experiments on Animals (CPCSEA), Government of India, the approval for protocols of all in vivo experiments were taken from the Institutional Animal Ethics Committee (IAEC). The in vivo pharmacokinetic and biodistribution studies of the optimized SLNs was performed under protocol no. IP/PCEU/PHD/18/013.

Additional information

Funding

The authors are highly grateful to Department of Science and Technology (DST), Fund for Improvement of S&T Infrastructure (FIST) (Grant No.: SR/FST/LSI-607/2014), Government of India for providing the necessary funding to establish equipment facility in laboratory.