Thioridazine in PLGA nanoparticles reduces toxicity and improves rifampicin therapy against mycobacterial infection in zebrafish

Abstract

Encapsulating antibiotics such as rifampicin in biodegradable nanoparticles provides several advantages compared to free drug administration, including reduced dosing due to localized targeting and sustained release. Consequently, these characteristics reduce systemic drug toxicity. However, new nanoformulations need to be tested in complex biological systems to fully characterize their potential for improved drug therapy. Tuberculosis, caused by infection with the bacterium Mycobacterium tuberculosis, requires lengthy and expensive treatment, and incomplete therapy contributes to an increasing incidence of drug resistance. Recent evidence suggests that standard therapy may be improved by combining antibiotics with bacterial efflux pump inhibitors, such as thioridazine. However, this drug is difficult to use clinically due to its toxicity. Here, we encapsulated thioridazine in poly(lactic-co-glycolic) acid nanoparticles and tested them alone and in combination with rifampicin nanoparticles, or free rifampicin in macrophages and in a zebrafish model of tuberculosis. Whereas free thioridazine was highly toxic in both cells and zebrafish embryos, after encapsulation in nanoparticles no toxicity was detected. When combined with rifampicin nanoparticles, the nanoparticles loaded with thioridazine gave a modest increase in killing of both Mycobacterium bovis BCG and M. tuberculosis in macrophages. In the zebrafish, the thioridazine nanoparticles showed a significant therapeutic effect in combination with rifampicin by enhancing embryo survival and reducing mycobacterial infection. Our results show that the zebrafish embryo is a highly sensitive indicator of drug toxicity and that thioridazine nanoparticle therapy can improve the antibacterial effect of rifampicin in vivo.

Matryoshka-Type Gastro-Resistant Microparticles for The Oral Treatment of Mycobacterium Tuberculosis

“…Thus, Tukulula et al [36] reported no cytotoxic effect of PLGA NPs and curdlan-conjugated PLGA NPs in THP1 macrophages over a 72 h period (dose range from 0.13 to200 µg/mL). In primary murine macrophages, thioridazine and rifampicin loaded-PLGA NPs and unloaded PLGA NPs did not significantly reduce cell viability throughout a 9 days treatment [37]. Also, PLGA NPs were not toxic to Caco2 cells after 24 h exposition, as long as the concentration was lower than 500 μg/mL [38].…”

Cocktail Strategy Based on Spatio‐Temporally Controlled Nano Device Improves Therapy of Breast Cancer

“…Considering that the intravenous administration of small molecular agents lacks the ability to precisely achieve tumor tissues, the application of chemotherapeutic agents, anti‐CSC agents, and PD‐1/PD‐L1 inhibitors together is badly in need of a vector for their delivery toward tumor cells, otherwise there will not be sufficient accumulation in tumors if administrated in low dosage, or might cause systemic side effects in high dosage . This could be achieved by nano drug delivery systems (NDDS), which own the capacity of encapsulating different drugs at the same time and targeting tumor via the enhanced permeability and retention (EPR) effect .…”

Thioridazine: A Non-Antibiotic Drug Highly Effective, in Combination with First Line Anti-Tuberculosis Drugs, against Any Form of Antibiotic Resistance of Mycobacterium tuberculosis Due to Its Multi-Mechanisms of Action

“…Promising examples of the future use of thioridazine in new short term therapeutic regimens against any form of antibiotic resistance of Mtb come from the recent studies that demonstrated the possibility of effectively using nanoparticles containing thioridazine and rifampicin for rapid tuberculosis treatment in vitro and in a zebrafish model [101,102]. The use of TZ as a therapeutic adjuvant for anti-TB therapy is currently being expanded in Argentina and India.…”