Rifampicin Nanoformulation Enhances Treatment of Tuberculosis in Zebrafish

Abstract

Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of alveolar macrophages. These cells avidly take up nanoparticles, even without the use of specific targeting ligands, making the use of nanotherapeutics ideal for the treatment of such infections. Methoxy poly­(ethylene oxide)-block-poly­(ε-caprolactone) nanoparticles of several different polymer blocks’ molecular weights and sizes (20–110 nm) were developed and critically compared as carriers for rifampicin, a cornerstone in tuberculosis therapy. The polymeric nanoparticles’ uptake, consequent organelle targeting and intracellular degradation were shown to be highly dependent on the nanoparticles’ physicochemical properties (the cell uptake half-lives 2.4–21 min, the degradation half-lives 51.6 min–ca. 20 h after the internalization). We show that the nanoparticles are efficiently taken up by macrophages and are able to effectively neutralize the persisting bacilli. Finally, we demonstrate, using a zebrafish model of tuberculosis, that the nanoparticles are well tolerated, have a curative effect, and are significantly more efficient compared to a free form of rifampicin. Hence, these findings demonstrate that this system shows great promise, both in vitro and in vivo, for the treatment of tuberculosis.

Recent Advances in Polymeric Nanoparticle-Encapsulated Drugs against Intracellular Infections

“…In recent years, a large number of drug delivery systems have been described in many medical areas, including intracellular infections [ 3 , 5 , 7 , 8 , 10 , 18 , 29 , 30 , 33 ]. Indeed, the global infectious disease therapeutics market size was valued at $46.88 billion in 2018 and is estimated to reach $64.5 in 2023 [ 34 ].…”

“…Besides, nanocarriers injected intravenously are mostly recognized and cleaned either by phagocytic cells from the endothelial reticulum system (RES) or by the mononuclear phagocyte system (MPS) going “passively” to the macrophages, the reservoir of most intracellular pathogens [ 35 ]. Another challenge of nanocarriers is the necessity to increase their drug loading capacity to administrate less amount of material but sufficient to reach a therapeutic concentration of drug at the site of infection that avoids toxicity and side effects [ 33 , 36 , 37 , 38 , 39 ]. Other imminent necessities are related to the increase of stability and better control of the drug release profile.…”

Magnetic Temperature-Sensitive Solid-Lipid Particles for Targeting and Killing Tumor Cells

“…Optionally, acceleration of matrix melting, and thus release of the IO-OA in the target location, can be achieved by local heating produced by exposition to AMF. Biocompatible and biodegradable BL (Trousil et al, 2019;Urbánek et al, 2019) was used to stabilize the SLPs and simultaneously to provide a coating that is capable to reduce prospective engulfment by the reticuloendothelial system. Surface modification of particles with poly(ethylene oxide) is a well-established approach to effectively prolong their systemic circulation by limiting particle aggregation, opsonization, and uptake via phagocytosis (Suk et al, 2016).…”

“…All other chemicals were purchased from Sigma-Aldrich. Poly(ethylene oxide)-block-poly(ε-caprolactone) (BL; M n = 6,500 Da, M w = 7,100 Da, polydispersity = 1.1) was synthesized by a ring-opening polymerization of ε-caprolactone initiated by poly(ethylene oxide) monomethyl ether (degree of polymerization = 45), as previously described (Trousil et al, 2019). Ultrapure water for the magnetic particle synthesis was obtained from a Milli-Q Gradient A10 system (Millipore; Molsheim, France).…”

Preclinical Models of Nontuberculous Mycobacteria Infection for Early Drug Discovery and Vaccine Research

“…This technique correlates well with the results of CFU count after the plating of infected embryos [ 166 ]. By combining bacteria expressing fluorescent proteins and nanoparticles containing fluorescent dye, such as coumarin [ 167 , 168 ], some authors were able to localize nanoparticles inside the cells and visualize fluorescent phagocytes in real-time.…”