Creation of a long-acting nanoformulated dolutegravir

Abstract

Potent antiretroviral activities and a barrier to viral resistance characterize the human immunodeficiency virus type one (HIV-1) integrase strand transfer inhibitor dolutegravir (DTG). Herein, a long-acting parenteral DTG was created through chemical modification to improve treatment outcomes. A hydrophobic and lipophilic modified DTG prodrug is encapsulated into poloxamer nanoformulations (NMDTG) and characterized by size, shape, polydispersity, and stability. Retained intracytoplasmic NMDTG particles release drug from macrophages and attenuate viral replication and spread of virus to CD4+ T cells. Pharmacokinetic tests in Balb/cJ mice show blood DTG levels at, or above, its inhibitory concentration90 of 64 ng/mL for 56 days, and tissue DTG levels for 28 days. NMDTG protects humanized mice from parenteral challenge of the HIV-1ADA strain for two weeks. These results are a first step towards producing a long-acting DTG for human use by affecting drug apparent half-life, cell and tissue drug penetration, and antiretroviral potency.

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

“…Stability in PBS containing 2% bovine serum albumin showed after testing by all parameters used in this report were unchanged after a week in a spectrum of environmental conditions (Fig.1A). In addition, the crystalline properties of nanoformulations could also influence particle stability and the in vivo drug pharmacokinetics and biodistribution parameters [18, 40]. Undesirable in vivo burst release PK patterns and ultimately rapid clearance from tissues and plasma depend on variables that include type of drug, surfactants, process and duration of making nanoformulations [41].…”

“…The potential of LASER ART in the prevention, treatment and eradication of HIV/AIDS is of the highest significance [18]. This is linked, in part, to improvements of drug penetration into target organs, reduced systemic toxicities, simplified regimens, reduced pill burdens, and enabling the availability of drug to larger numbers of patients [48].…”

“…These assessments must include subcellular, cellular and tissue drug distribution studies [25, 77, 79]. Moreover, before any animal injection, the drug particle properties such as uptake, retention, subcellular location, toxicities, and antiretroviral activity were investigated in macrophages and served as confirmation of the current data sets [18, 80]. Dynamic light scattering showed that the hydrodynamic size of the EuCF-RPV particles was similar to that of NRPV.…”

“…Culture supernatants were collected and analyzed for progeny virion production by RT activity assay [35]. At the same time, cells were washed with PBS and fixed in 4% PFA for 15 min for HIV-p24 staining [18]. Images were analyzed using a Nikon TE300 microscope with a 20X magnification objective.…”

“…Each and all of these limitations have led to the development of longer acting nanoformulated ART [16, 17] and recently to the chemical synthesis of lipophilic prodrug nanocrystals coined long acting slow effective release (LASER) ART. The noted scientific advances have further extended drug ARV half-lives and potencies [18, 19]. LASER ART rests on four pillars; creation hydrophobic prodrug nanocrystals, the enhanced drug lipophilicity associated with improved cell membrane drug penetration, slow drug release and hydrolysis, and facilitated viral reservoir drug penetrance.…”