Macrophage folate receptor-targeted antiretroviral therapy facilitates drug entry, retention, antiretroviral activities and biodistribution for reduction of human immunodeficiency virus infections

Macrophages serve as vehicles for the carriage and delivery of polymer-coated nanoformulated antiretroviral therapy (nanoART). Although superior to native drug, high drug concentrations are required for viral inhibition. Herein, folate-modified ritonavir-boosted atazanavir (ATV/r)-encased polymers facilitated macrophage receptor targeting for optimizing drug dosing. Folate coating of nanoART ATV/r significantly enhanced cell uptake, retention and antiretroviral activities without altering cell viability. Enhanced retentions of folate-coated nanoART within recycling endosomes provided a stable subcellular drug depot. Importantly, up to a five-fold enhanced plasma and tissue drug levels followed folate-coated formulation injection in mice. Folate polymer encased ATV/r improves nanoART pharmacokinetics bringing the technology one step closer to human use.From the Clinical EditorThis team of authors describes a novel method for macrophage folate receptor-targeted antiretroviral therapy. Atazanvir entry, retention, and antiretroviral activities were superior using the presented method, and so was its biodistribution, enabling a more efficient way to address human immunodeficiency virus infections, with a hoped for clinical application in the near future.

Schematic of the manufacture and macrophage uptake of folic acid coated nanoART. (A) ART drug crystal is coated with folic acid (FA)-conjugated polymer (poloxamer 407, P407) by homogenization. (B) Uptake of FA-nanoART can occur through binding to the Fc receptor and the folic acid receptor 2 (FOLR2). (C) Intracellular distribution of FA-nanoART to recycling endosomes, where the nanoART is protected from degradation.Figure optionsDownload high-quality image (115 K)Download as PowerPoint slide