Nanoparticles containing dolutegravir demonstrate efficacy for PrEP delivery

Cellulose acetate phthalate nanoparticles formulated with dolutegravir appear to be an effective vaginal microbicide for use as pre-exposure prophylaxis, or PrEP, according to study results presented at ASM Microbe 2016.

“There is a need for the development of more cost-effective, highly efficacious PrEP options,” said Annemarie Shibata, PhD, associate professor of cellular neuroscience in the department of biology at Creighton University, during her presentation. “Nanoparticles are, potentially, one option.”

The researchers used an oil-in-water homogenization to engineer cellulose acetate phthalate nanoparticles with and without dolutegravir (Tivicay, ViiV Healthcare). Pluronic F-127 (2%), a surfactant polyol, and an organic-to-aqueous phase ratio of 1:1 was used for all nanoparticles. The researchers treated TZM-bl cells with cellulose acetate phthalate nanoparticles containing dolutegravir and dolutegravir solution for 1 or 3 days and then infected the cells with HIV-1_NL-4-3 to assess antiviral activity. Luminescence was measured after 48 hours.

Intracellular delivery of dolutegravir to cell lines was assessed by pretreatment with cellulose acetate phthalate nanoparticles containing dolutegravir or dolutegravir solution. Cell lysates were analyzed by high-performance liquid chromatography; encapsulation efficiency of dolutegravir in the nanoparticles was also validated with high-performance liquid chromatography. The cytotoxicity of cellulose acetate phthalate nanoparticles containing dolutegravir was examined and compared with cellulose acetate phthalate nanoparticles and dolutegravir solution in cell lines and human EpiVaginal 3D tissue models (Cyprotex).

The encapsulation efficiency of dolutegravir was ≥ 26.3% in cellulose acetate phthalate nanoparticles containing the agent. This nanoparticle formulation demonstrated decreased toxicity to cell lines when compared with dolutegravir solution and were nontoxic to endocervical tissues. The cellulose acetate phthalate nanoparticles containing dolutegravir demonstrated full inhibition of HIV-1 at a concentration equivalent to 5 ng/mL of dolutegravir; the dolutegravir solution and cellulose acetate phthalate nanoparticles “showed significantly less inhibition at this concentration (P < .05),” according to the study results. The cellulose acetate phthalate nanoparticles were non-toxic to cell lines or EpiVaginal tissue at concentrations up to 100 μg/mL.

This is the first report of dolutegravir being formulated into a nanoparticle for use as PrEP, according to the study results. Cellulose acetate phthalate nanoparticles containing dolutegravir “would be a novel vaginal microbicide with greater potency than [dolutegravir] in solution and may offer a sustained release PrEP option for HIV,” the researchers wrote.

In her presentation, Shibata said the need for new options for PrEP that are cost effective and efficacious is a “significant issue.”

“Nanoparticles can provide improved permeability of drugs, improve the chemical and enzymatic stability of drugs, and increase and sustain the release of the drugs over time,” she said. “They can, in some cases, target particular cells, organs and tissues. Those advantages, together, allow for a potential reduction in dose and dosing frequency for patients and reduce the side effects that may occur.” – by Julia Ernst, MS

Reference:

Shibata A, et al. Development of dolutegravir combination nanoparticle fabrications for HIV prophylaxis. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Disclosure: The researchers report no relevant financial disclosures.