Abstract
We formulated and tested a targeted nanodrug delivery system to help treat life-threatening invasive fungal infections, such as cryptococcal meningitis. Various designs of iron oxide nanoparticles (IONP) (34–40 nm) coated with bovine serum albumin and coated and targeted with amphotericin B (AMB-IONP), were formulated by applying a layer-by-layer approach. The nanoparticles were monodispersed and spherical in shape, and the lead formulation was found to be in an optimum range for nanomedicine with size (≤36 nm), zeta potential (−20 mV), and poly dispersity index (≤0.2), and the drug loading was 13.6 ± 6.9 µg of AMB/mg of IONP. The drug release profile indicated a burst release of up to 3 h, followed by a sustained drug release of up to 72 h. The lead showed a time-dependent cellular uptake in C. albicans and C. glabrata clinical isolates, and exhibited an improved efficacy (16–25-fold) over a marketed conventional AMB-deoxycholate product in susceptibility testing. Intracellular trafficking of AMB-IONP by TEM and confocal laser scanning microscopy confirmed the successful delivery of the AMB payload at and/or inside the fungal cells leading to potential therapeutic advantages over the AMB-deoxycholate product. A short-term stability study at 5 °C and 25 °C for up to two months showed that the lyophilized form was stable.
Highlights
The systemic and invasive fungal infections (IFIs) are associated with high morbidity and mortality, in immunocompromised hosts who are at substantial risk for these infections
The advantages of this system over existing line of therapy is that (i) it has the potential for enhanced cellular uptake due to the targeted-binding and nanozised nature; (ii) it represents a potential for use in diagnosing and monitoring the infection due to the magnetic contrast nature of iron oxide nanoparticles (IONP); and (iii) it can be loaded with multiple drugs/different targeting agents that have different binding domains on the albumin
The formulations were lyophilized to develop a stable Amphotericin B (AMB)-loaded targeted IONP (AMB-IONP). We anticipated that these in vitro studies would produce a proof of concept to allow preclinical animal studies. This nanosystem has the potential to be developed into a theranostic product that could cure IFIs with better therapeutic efficacy and lesser toxicity when compared to the current therapies
Summary
The systemic and invasive fungal infections (IFIs) are associated with high morbidity and mortality, in immunocompromised hosts who are at substantial risk for these infections. In the recent development of nanomedicines, iron oxide nanoparticles (IONP) have gained increasing attention for biomedical applications [8,9] These particulate systems are ideal for a higher accumulation in the target tissues or organs due to their host cell tropism, biophysical nature, and low toxicity [10]. This research has a high priority for the Centers for Disease Control, as many of our current antibiotic formulations do not eliminate certain deadly microbes [13] The advantages of this system over existing line of therapy is that (i) it has the potential for enhanced cellular uptake due to the targeted-binding and nanozised nature; (ii) it represents a potential for use in diagnosing and monitoring the infection due to the magnetic contrast nature of IONPs; and (iii) it can be loaded with multiple drugs/different targeting agents that have different binding domains on the albumin. This nanosystem has the potential to be developed into a theranostic product that could cure IFIs with better therapeutic efficacy and lesser toxicity when compared to the current therapies
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