Anti-HIV drug conjugates for enhanced mucosal pre-exposure prophylaxis

Mahta Samizadeh
2014
To combat HIV pandemic, targeting HIV mucosal transmission appears to be more effective than targeting later stages of the infection owing to the viral vulnerability and higher efficacy of antiretrovirals at this very early stage of HIV infection. The objective of the current project is to investigate the complementary benefits of combining an anti-HIV drug (amprenavir, APV), a cell-penetrating peptide (bactenicin &, Bac& CPP) and poly (ethylene glycol) (PEG) together as a nanocarrier conjugate
more » ... nocarrier conjugate for fast and efficient cytosolic delivery of the drug. The nanocarrier is to be incorporated into an alcohol-free thermosensitive foam for colonic/rectal delivery. In the initial studies, APV-PEG conjugates were prepared using 2 to 30 kDa PEGs and protease inhibition properties were assessed in buffer using FRET-based protease inhibition assay. The results suggested that PEG size between 2 and 5 kDa is the optimum range for maintaining the protease inhibition activity. For further studies, APV-PEG3.4-FITC (APF) and a PEGylated APV conjugated with Bac& CPP (APV-PEG3.4-Bac& CPP; APB) were prepared. The anti-HIV-1 activities were assessed based on the potency of the conjugates to inhibit the viral replication in HIV-1 infected CD4+ MT-2 T-cells. Compare with free APV (IC50 = 50.29 nM), 160-fold reduction in potency was observed in APF activity (IC50 = 8.064 M) whereas APB conjugate exhibited anti-viral activity close to APV (IC50 = &8.29 nM), suggesting the poor cell penetration of APV-PEG was remedied by conjugating Bac& CPP. Aerosol foams have some distinct advantages for rectal and vaginal drug delivery over conventional dosage forms including greater degree of spread, ease of application and enhanced drug delivery efficiency. Alcohol-free thermosensitive aerosol foams were prepared containing 0.5% to 2.0% of xanthan gum (XG). The foam with 1.5% XG showed the best performance among all the formulations; it was stable at room temperature for over 2 h while in vivo MRI of the foam in mice showed e [...]
doi:10.7282/t32n50ks fatcat:flegidjyufhopkpc6cow64mpky