Bade, A. N. | Search bioRxiv

bioRxiv2021

Antiretroviral Theranostics Based on Intrinsic CEST Contrasts

Human immunodeficiency virus type-1 (HIV-1) antiretroviral drug (ARV) theranostics facilitates biodistribution and efficacy of therapies designed to target viral reservoirs. To this end, we have now deployed intrinsic drug chemical exchange saturation transfer (CEST) contrast to detect ARV distribution within the central nervous system (CNS). MethodsCEST effects for lamivudine (3TC) and emtricitabine (FTC) were measured by asymmetric magnetization transfer ratio analyses in solutions. CEST magnetic resonance imaging (MRI) was performed on 3TC-treated mice with analysis made by Lorentzian fitting. ResultsCEST effects of 3TC and FTC hydroxyl and amino protons linearly correlated to drug concentrations. 3TC was successfully detected in brain sub-regions by MRI. The imaging results were validated by measurements of CNS drug concentrations. ConclusionCEST contrasts can be used to detect ARVs using MRI. Such detection can be used to assess spatial-temporal drug biodistribution. This is most notable within the CNS where drug biodistribution may be more limited with the final goal of better understanding ARV-associated efficacy and potential toxicity.

bioengineering↗

bioRxiv2021

Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir

A single, once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one (HIV-1) transmission. Extending CAB dosing to a yearly injectable can advance efforts leading to the elimination of viral transmission. The current submission adds rigor, reproducibility and mechanistic insights for the extended apparent half-life of a yearlong antiretroviral injectable. Pharmacokinetic (PK) profiles of a nanoformulated fatty acid ester CAB prodrug (named NM2CAB) were affirmed at two academic and one contract research laboratory. PK profiles showed plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for up to one year after a single dose. Measures of drug biodistribution demonstrated sustained native drug at the muscle injection site and in lymphoid tissues (spleen and lymph nodes). The results paralleled NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals were stable in blood, tissue and liver homogenates. The long apparent drug half-life followed pH-dependent slow prodrug release in weeks from the nanocrystal. In contrast, solubilized prodrug was hydrolyzed in hours in plasma and tissues recorded from multiple mammalian species at basic pH. No measurable toxicities were recorded. These results, taken together, affirm the pharmacological mechanistic properties of a year-long nanoformulated CAB prodrug supporting the established protocol design for formulation safety, rigor and reproducibility.

pharmacology and toxicology↗