ABSTRACT
Macromolecular (pro)drugs hold much promise as broad-spectrum antiviral agents as either microbicides or carriers for intracellular delivery of antiviral drugs. Intriguing opportunity exists in combining the two modes of antiviral activity in the same polymer structure such that the same polymer acts as a microbicide and also serves to deliver the conjugated drug (ribavirin) into the cells. We explore this opportunity in detail and focus on the polymer backbone as a decisive constituent of such formulations. Fourteen polyanions (polycarboxylates, polyphosphates and polyphosphonates, and polysulfonates) were analyzed for blood pro/anti coagulation effects, albumin binding and albumin aggregation, inhibitory activity on polymerases, cytotoxicity, and anti-inflammatory activity in stimulated macrophages. Ribavirin containing monomers were designed to accommodate the synthesis of macromolecular prodrugs with disulfide-exchange triggered drug release. Kinetics of drug release was fast in all cases however enhanced hydrophobicity of the polymer significantly slowed release of ribavirin. Results of this study present a comprehensive view on polyanions as backbone for macromolecular prodrugs of ribavirin as broad-spectrum antiviral agents.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Antiviral Agents/administration & dosage , Polymers/administration & dosage , Prodrugs/administration & dosage , Ribavirin/administration & dosage , Animals , Anti-Inflammatory Agents/chemistry , Antiviral Agents/chemistry , Blood Coagulation/drug effects , DNA-Directed DNA Polymerase/genetics , Drug Liberation , Humans , Mice , Polymers/chemistry , Prodrugs/chemistry , RAW 264.7 Cells , Ribavirin/chemistry , Treatment OutcomeABSTRACT
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.
ABSTRACT
Conjugated polymers have been intensively studied due to their unique optical and electronic properties combined with their physical flexibility and scalable bottom up synthesis. Although the bulk qualities of conjugated polymers have been extensively utilized in research and industry, the ability to handle and manipulate conjugated polymers at the nanoscale lacks significantly behind. Here, the toolbox for controlled manipulation of conjugated polymers was expanded through the synthesis of a polyfluorene-DNA graft-type polymer (poly(F-DNA)). The polymer possesses the characteristics associated with the conjugated polyfluorene backbone, but the protruding single-stranded DNA provides the material with an exceptional addressability. This study demonstrates controlled single-molecule patterning of poly(F-DNA), as well as energy transfer between two different polymer-DNA conjugates. Finally, highly efficient DNA-directed quenching of polyfluorene fluorescence was shown.
