Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

Abstract

Antiretroviral therapy (ART) has changed the outcome of human immunodeficiency virus type one (HIV-1) infection from certain death to a life free of disease co-morbidities. However, infected people must remain on life-long daily ART. ART reduces but fails to eliminate the viral reservoir. In order to improve upon current treatment regimens, our laboratory created long acting slow effective release (LASER) ART nanoformulated prodrugs from native medicines. LASER ART enables antiretroviral drugs (ARVs) to better reach target sites of HIV-1 infection while, at the same time, improve ART's half-life and potency. However, novel ARV design has been slowed by prolonged pharmacokinetic testing requirements. To such ends, tri-modal theranostic nanoparticles were created with single-photon emission computed tomography (SPECT/CT), magnetic resonance imaging (MRI) and fluorescence capabilities to predict LASER ART biodistribution. The created theranostic ARV probes were then employed to monitor drug tissue distribution and potency. Intrinsically Indium (In) radiolabeled, europium doped cobalt-ferrite particles and rilpivirine were encased in a polycaprolactone core surrounded by a lipid shell (InEuCF-RPV). Particle cell and tissue distribution, and antiretroviral activities were sustained in macrophage tissue depots. InEuCF-PCL/RPV particles injected into mice demonstrated co-registration of MRI and SPECT/CT tissue signals with RPV and cobalt. Cell and animal particle biodistribution paralleled ARV activities. We posit that particle selection can predict RPV distribution and potency facilitated by multifunctional theranostic nanoparticles.

Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice

“…The sustained human grafts as confirmed by flow cytometry were viable and functional for more than 6 months, which provided a platform that allowed treatment interventions for prolonged time periods and a clear ability during ART to best establish a continuous latent HIV-1 reservoir in peripheral tissues and the brain and the noted immunological responses to the viral infection 12,17,29,36,37,39 . These previously published data support the successful use of humanized mice in studies of HIV/AIDS pathogenesis, therapeutics 40–42 , and treatment 12–14,16,18,29,43,44 . These studies, taken together, clearly provide a rationale for the scientific approaches taken in the current report 12,13,29,43,45–47 .…”

“…In earlier studies, we demonstrated editing of HIV-1 proviral DNA by CRISPR-Cas9 in in vitro and ex vivo T cells 18,22 . Here, we adapted a procedure as schematized in supplementary fig 1 and found that at sub-optimum conditions for CRISPR editing of viral DNA, suppression of viral replication by treatment of cells with ART enhances the efficiency of proviral DNA editing by CRISPR.…”

“…These reduce disease co-morbidity in small animals and maintains effective antiretroviral drug concentrations in blood and tissue viral reservoirs from days to weeks 12–16 . Macrophages enable uptake of significant amounts of intracellular antiretroviral drug crystals and tightly control ongoing viral replication by the cells’ slow drug release and transfer to adjacent CD4 + T cells during cell-to-cell contact or through direct drug uptake 13,14,16–18 . However, LASER ART alone cannot rid the infected host of latent HIV-1 no matter how successful the drugs may prove to be at restricting viral infection.…”

pH-Sensitive Poly(β-amino ester)s Nanocarriers Facilitate the Inhibition of Drug Resistance in Breast Cancer Cells

“…Hydrodynamic diameter and size of the nanocarriers were examined with Zetasizer Nano-S from Malvern Instruments. The stability of nanoparticles was examined as previously described [ 21 ]. The transmission electron microscopy (TEM) analysis was conducted as the following.…”

Reverse Transcriptase Inhibitors Nanosystems Designed for Drug Stability and Controlled Delivery

“…A sustained drug release and antiretroviral activity were observed in HIV infected macrophages. These multi-functional NPs represent a platform for the monitoring and optimization of the antiretroviral drug pharmacokinetic profile [170].…”