Nanoparticle-based antibiotic delivery for targeting intracellular bacteria

Abstract

Intracellular bacterial infections, such as Burkholderia spp, are notoriously difficult to treat, in part due to poor membrane permeability and intracellular bioavailability of antibiotics. Current treatment options involve high doses of antibiotics for sustained periods of time, therefore contributing to the issues of antibiotic resistance, and potentially causing off-target effects in the patient. In the absence of novel antibiotic compounds, intracellular targeting polymersome (PM)- encapsulated antibiotics may increase the efficacy of existing antibiotics by promoting targeted, infection-specific intracellular uptake in otherwise poorly bioavailable antibiotics. In this study it was hypothesised that PMs composed of widely available polyethylene oxide-polycaprolactone (PEO-PCL) block co-polymers could stably encapsulate antibiotics and release them intracellularly to reduce macrophage infection. PMs were generated via the nanoprecipitation method. Antibiotics doxycycline and rifampicin were retained stably for 14 days within PMs under dialysis. PM-antibiotic preparations did not inhibit the growth of free-living B. thailandensis, highlighting their ability to sequester their payloads until at the target intracellular niche. On uptake by murine macrophages, PMs co-localised with intracellular B. thailandensis and significantly reduced bacterial burden (by factors of ≈100 and 10 for doxycycline and rifampicin-loaded preparations respectively). It was concluded that PMs present a viable approach for the targeted treatment of persistent intracellular B. thailandensis infection.

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