Evaluations of Unformulated and FormulatedDendrimer-Based Microbicide Candidates in Mouse and Guinea PigModels of GenitalHerpes

Abstract

Prevention of sexually transmitted infections is a priority in developed and developing countries. One approach to prevention is the use of topical microbicides, and one promising approach is the use of dendrimers, highly branched macromolecules synthesized from a polyfunctional core. Three new dendrimer products developed to provide stable and cost-efficient microbicides were initially evaluated in vitro for anti-herpes simplex virus activity and then in vivo by using a mouse model of genital herpes. From these experiments one product, SPL7013, was chosen for further evaluation to define the dose and duration of protection. Unformulated SPL7013 provided significant protection from genital herpes disease and infection at concentrations as low as 1 mg/ml and for at least 1 h following topical (intravaginal) administration of 10 mg/ml. This compound was then formulated into three vehicles and further evaluated in mouse and guinea pig models of genital herpes infection. In the murine evaluations each of the formulations provided significant protection at concentrations of 10 and 50 mg/ml. Formulated compounds provided protection for at least 1 h at a concentration of 10 mg/ml. From these experiments formulation 2V was chosen for dose ranging experiments using the guinea pig model of genital herpes. The guinea pig evaluations suggested that doses of 30 to 50 mg/ml were required for optimal protection. From these studies a lead compound and formulation (2V of SPL7013) was chosen for ongoing evaluations in primate models of simian immunodeficiency virus and Chlamydia trachomatis infection.

Peptide-derivatized dendrimers inhibit human cytomegalovirus infection by blocking virus binding to cell surface heparan sulfate

“…Among these, dendrimers and dendrimer-like molecules have recently been generated with surfaces formed of negative charges and screened for potential anti-herpes activities. Indeed, in vitro analysis has revealed that sulfonated and carboxylated polylysine dendrimers effectively block the HSV-1 and -2 infection of cells and non-primate animal studies have shown that they were able to protect animals against an intravaginal HSV-2 challenge (Bourne et al, 2000;Bernstein et al, 2003;Gong et al, 2005). However, in addition to inhibiting the HSV attachment, the sulfonate ddendrimers were also shown to act at a post-entry level by apparently inhibiting HSV DNA synthesis, which suggests that they could be used not only for prevention of HSV infection but also as inhibitors of viral replication (Gong et al, 2005).…”

Dendrimers as therapeutic agents: a systematic review

“…Unmodified polycationic PAMAM dendrimer showed greater affinity towards TAR-RNA than viral Tat protein. [70] Bernstein and colleagues [67] also reported that the outer sulfonic acid surface of lysine-based dendrimers attaches through thiourea (SPL2999) or amide (SPL7013, SPL7015 and SPL7032) linkages (Figures 4a and b). They evaluated these compounds in vivo in mouse and guinea-pig models of HSV-2-induced genital herpes infection.…”

“…[66] Bernstein and colleagues have also investigated the potential of sulfonated polylysine dendrimer with a benhydrylamine core in vivo in mice and guinea-pigs and found that they protected against intravaginal challenge with HSV. [67] Sulfonated dendrimer also protected female pigtail macaques against intravaginal infection with SIV/HIV chimera virus. [31] Similar results were obtained by Bourne and colleagues upon administration of sulfonated (BRI-2999) and carboxylated (BRI-6741) dendrimers (Figure 3d) to mice prior to exposure to HSV.…”

Dendrimers as tunable vectors of drug delivery systems and biomedical and ocular applications

“…When administered in mouse vaginas, it rendered a dose-related protection from HSV-2 infection. 46 In macaque monkeys, SPL7013 gels administered in a single intravaginal application was found to be safe and protected macaques against vaginal simian HIV infection.…”