Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1

Abstract

In this article a library of polymeric therapeutic agents against the human immunodeficiency virus (HIV) is presented. The library of statistical copolymers of varied molar mass was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The synthesized polymers comprise pendent hydroxyl and sulfonated side chains as well as the reverse transcriptase prodrug lamivudine (3TC) attached via a disulfide self-immolative linker. The glutathione mediated release of 3TC is demonstrated as well as the antiviral efficacy against HIV entry and polymerase activity. Although a high degree of polymer sulfonation is required for effective HIV entry inhibition, polymers with approximately ∼50% sulfonated monomer demonstrated potent kinase independent reverse transcriptase inhibition. In addition, the sulfonated polymers demonstrate activity against DNA-DNA polymerase, which suggests that these polymers may exhibit activity against a broad spectrum of viruses. In summary, the polymers described provide a triple-active arsenal against HIV with extracellular activity via entry inhibition and intracellular activity by kinase-dependent lamivudine-based and kinase-independent sulfonated polymer based inhibition. Since these sulfonated copolymers are easily formulated into gels, we envision them to be particularly suited for topical application to prevent the mucosal transmission of viruses, particularly HIV.

Macromolecular prodrugs of ribavirin: Polymer backbone defines blood safety, drug release, and efficacy of anti-inflammatory effects

“…We note that data in Fig. 7 are rather similar to the drug release data collected in our prior studies via HPLC [43,46,62] and this serves to validate the established herein NMR-based approach to monitor drug release. 1 H NMR based method to quantify drug release was applied to the macromolecular prodrugs based on other polyanions as well as a nonionic carrier, PHPMA, Fig.…”

“…Polymers may thus exhibit significant differences in the drug release kinetics. We have previously investigated the release of RBV and other drugs conjugated to polymers via the same linkage as used in this study (disulfide trigger paired with a self-immolative linker) via HPLC [43,46,62]. Herein, we established an 1 H NMR-based method to quantify the release of RBV as illustrated in Fig.…”

“…Such agents represent a combination therapy wherein the carrier exerts extracellular preventative effect [21] whereas the conjugated drug, once released inside the cell, is an intracellularly active therapeutic [37]. It is also possible that polyanions have an intracellular antiviral effect of their own, that is the inhibition of viral polymerases, [40,45,46] presumably through competitive electrostatic interaction with the protein. In this work, we explore the design of such combination therapy in detail.…”

Long-acting slow effective release antiretroviral therapy

“…The hydrophilic nature of NRTIs pose further challenges to the development of long acting nanoformulations. A recent article described the synthesis of a library of lamivudine prodrug polymer conjugates and evaluated their drug release kinetics through measurement of glutathione-mediated release of lamivudine (3TC) and in vitro antiviral efficacy against HIV entry and polymerase activity [70]. The copolymers were assembled by reversible addition-fragmentation chain transfer (RAFT) polymerization reactions.…”

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.…”