Long-Acting, Potent Delivery of Combination Antiretroviral Therapy

Abstract

Antiretroviral therapy (ART) has revolutionized HIV treatment, yet grand challenges remain: (i) short blood and body residence time of the antiviral drugs, (ii) relative poor antiretroviral drug penetrance into key tissue reservoirs of viral infection, namely, the spleen and lymph nodes, and (iii) obstacles in different pharmacokinetics of the necessary combination drugs. We present a novel drug delivery approach that simultaneously overcomes these limitations. We designed albumin−polymer−drug conjugates where albumin ensures long body residence time as well as lymphatic accumulation of the conjugate. The polymer enabled the delivery of combinations of drugs in precise ratios affording potency superior to the individual antiretroviral drugs and strong protection from HIV infection in primary human T cells.

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

“…Innate inflammatory and adaptive immune responses tied to HIV-1 infection continue despite therapeutic drug regimens, leading to diabetes, osteoporosis, cardiovascular diseases and neurocognitive disorders [10–15]. 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].…”

Biomimetic Nanomaterial Strategies for Virus Targeting: Antiviral Therapies and Vaccines

“…Andersen et al described the formation of polymerprotein-drug complexes that enable long-duration therapy with multiple antiviral drugs. [31] A polymer-protein complex comprised of a single, ≈7 kDa N-(2-hydroxypropyl) methacrylamide (PHPMA) chain per covalently attached albumin molecule was designed and exhibited much longer circulation half-time and higher concentrations in mice upon intravenous or subcutaneous administration, as compared to free PHPMA alone. Marked accumulation of the polymer-protein complex in mouse lymph nodes was also reported.…”

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

“…Combined with novel linker chemistry, for example self-immolative linkers (SIL), both polymer size and complexity as well as triggered release of drug can be controlled, yielding a very attractive drug-delivery strategy [81]. Some of the most commonly used polymer systems are poly(hydroxypropyl methacrylamide) (PHPMA) [82][83][84][85][86][87], poly(lactic-co-glycolic acid) (PLGA) [88], poly(methacrylates) (PMA) [89,90] and poly(ethylene glycol) (PEG) [91]. The benefit of combining direct conjugation to a polymer via linker chemistry is the possibility to co-deliver different pharmaceutical drugs on the same polymer scaffold.…”

“…Our group sought to develop and utilize these features of polymers. We have focused on combining antiviral small molecule drugs with synthetic polymers in combination with lipids such as DSPE or endogenous proteins like albumin to develop long-acting drug-delivery platforms [81][82][83][84][85][86][87]92]. Because albumin has an incredible long circulation time in vivo in humans (i.e., 19-21 days [93]), it can be used to traffic compounds through circulation.…”