Emergence of Nanotechnology to Fight HIV Sexual Transmission: The Trip of G2-S16 Polyanionic Carbosilane Dendrimer to Possible Pre-Clinical Trials

Abstract

Development of new, safe, and effective microbicides to prevent human immunodeficiency virus HIV sexual transmission is needed. Unfortunately, most microbicides proved ineffective to prevent the risk of HIV-infection in clinical trials. We are working with G2-S16 polyanionic carbosilane dendrimer (PCD) as a new possible vaginal topical microbicide, based on its short reaction times, wide availability, high reproducibility, and quantitative yields of reaction. G2-S16 PCD exerts anti-HIV activity at an early stage of viral replication, by blocking gp120/CD4/CCR5 interaction, and providing a barrier against infection for long periods of time. G2-S16 PCD was stable at different pH values, as well as in the presence of seminal fluids. It maintained the anti-HIV activity against R5/X4 HIV over time, did not generate any type of drug resistance, and retained the anti-HIV effect when exposed to semen-enhanced viral infection. Importantly, G2-S16 PCD did not modify vaginal microbiota neither in vitro or in vivo. Histopathological examination did not show vaginal irritation, inflammation, lesions, or damage in the vaginal mucosa, after administration of G2-S16 PCD at different concentrations and times in female mice and rabbit animal models. Based on these promising data, G2-S16 PCD could become a good, safe, and readily available candidate to use as a topical vaginal microbicide against HIV.

Safety of G2-S16 Polyanionic Carbosilane Dendrimer as Possible HIV-1 Vaginal Microbicide

“…The DPV has been tested in several application forms, including vaginal gels, films or intravaginal rings [ 29 , 30 , 31 , 32 , 33 , 34 ]. In spite of reaching phase II clinical trials, DPV has been shown to cause side effects such as inflammation, reddening or swelling of the cervix, urinary tract infection, loss of bladder control, headache, pain during sex, and pelvic pain [ 32 , 35 , 36 ] (Else, Taylor et al, 2011; Baeten, Palanee-Phillips et al, 2016; Nel, van Niekerk et al, 2016) [ 1 , 2 , 3 ]. A vaginal ring containing DPV is being tested in adolescent and young women [ 37 ].…”

“…However, these drugs are presently seldom used in clinical care. Unfortunately, when tested as microbicides in clinical trials, many vaginal microbicide formulations based on entry inhibitors failed to cause a protective effect due to their lack of efficacy and their unsuitable formulation, which led to irritability and inflammation [ 1 , 2 , 3 ]. Additionally, as happens with other drugs, entry inhibitors are affected by drug resistance mutations and could be affected by viral tropism (e.g., CCR5 antagonists) and subtype.…”

“…Moreover, it should not interfere with the normal function of the local immune system against other pathogens or non-infectious diseases [ 8 ]. Researchers have been trying to design efficient options and several drug combinations have reached clinical trials but have so far failed because of unexpected toxicity or lack of efficacy [ 1 , 2 ].…”

Safety and efficacy of G2-S16 dendrimer as microbicide in healthy human vaginal tissue explants

“…Related to treatments, nanotechnology has emerged as a viable therapeutic alternative to develop new drugs and treatments against diverse pathogens. In the case of viral infections, we have previously described the potent efficacy of dendrimers against viruses such as HIV-1 and HSV-2, in vitro as well as in vivo [ 11 – 15 ]. Dendrimers are hyperbranched nanoparticles consisting of a central core and several functional groups in the periphery.…”

G2-S16 Polyanionic Carbosilane Dendrimer Can Reduce HIV-1 Reservoir Formation by Inhibiting Macrophage Cell to Cell Transmission

“…In particular, carbosilane dendrimers have shown great efficacy as microbicides, specifically G2-S16 [5]. This second-generation dendrimer with a silica core and 16 sulfonate end groups has demonstrated in previous assays that it is capable of destabilizing the GP120-CD4 complex by blocking HIV-1 entry and cell-to-cell fusion [6][7][8] (reviewed in [9]).…”