Structure activity relationship of dendrimer microbicides with dual action antiviral activity.

BACKGROUND: Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published. METHODS AND FINDINGS: Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina. CONCLUSIONS: Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGel(R) and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides.

Impact of surface derivatization of poly-L-lysine dendrimers with anionic arylsulfonate or succinate groups on intravenous pharmacokinetics and disposition.

Tritium-labeled poly- l-lysine dendrimers displaying 8 or 16 surface lysines have been capped with benzene sulfonate (BS), benzene disulfonate (BDS), or succinate (Succ) groups, and the intravenous pharmacokinetics and disposition profiles of the resulting dendrimers (Lys(8)(BS)(16), Lys(16)(BS)(32), Lys(16)(BDS)(32), Lys(16)(Succ)(32)) have been evaluated. Lys(16)(Succ)(32) was rapidly removed from the plasma primarily via renal elimination. Lys(16)(BS)(32) and Lys(16)(BDS)(32) were opsonized, resulting in more prolonged plasma elimination kinetics and increased uptake by the liver. Data obtained at higher doses suggested some evidence of nonlinear pharmacokinetics. Lys(8)(BS)(16) had reduced affinity for plasma proteins and was cleared more rapidly than the larger Lys(16)(BS)(32) or Lys(16)(BDS)(32) dendrimers. Lys(8)(BS)(16) and Lys(16)(BS)(32) were metabolized in vivo, resulting in the production of a low molecular weight species (possibly the cleavage product Lys(BS) (2)) that was extensively renally eliminated and accounted for almost all of the radioactivity recovered in urine ( approximately 20-45% of administered (3)H). In contrast, only 3-5% of the administered (3)H was recovered in the urine of rats administered Lys(16)(BDS)(32), suggesting increased resistance to in vivo degradation. The plasma clearance, distribution, and metabolic profiles of lysine dendrimers are therefore significantly influenced by the structure and charge of the capping groups. In particular, larger arylsulfonate-capped lysine dendrimers are rapidly opsonized and initially cleared from the plasma by the reticuloendothelial organs. The degree of metabolism is subsequently dictated by the nature of the surface capping group with BDS surfaces seemingly more resistant to breakdown. In contrast, smaller arylsulfonate-capped dendrimers are less readily opsonized and phagocytozed but are metabolically labile, and succinate-capped dendrimers are rapidly eliminated by the kidneys.