Poly(glutamyl-glutamate) paclitaxel (PGG-PTX) is a potential anticancer therapeutic in preclinical development. There has been increasing attention on how structural and functional properties of therapeutic nanoparticles, such as size, shape, flexibility, surface hydrophilicity, and aggregation, influence efficacy. This thesis demonstrates the application of computer simulations to elucidate these properties of PGG-PTX candidates, which would otherwise be tedious or inaccessible to achieve experimentally. Computer simulations were carried out by running molecular dynamics (MD) simulations on eighteen coarse-grained (CG) PGG-PTX models, varying in the PTX loading fraction (f/PTX = 0.18, 0.24, and 0.37) and spatial PTX arrangement (uniform : 'even' and 'random', clustered : 'clusters' and 'ends', concentrated : 'middle' and 'side') on the PGG backbone. The results show that PGG-PTX molecules with concentrated spatial PTX arrangements produce filamentous shapes and are more flexible, while PGG-PTX molecules with uniform PTX arrangements generate globular morphologies and are less flexible. The PTX loading fraction and spatial PTX arrangement have a minimal effect on the size of a PGG-PTX molecule. Intermolecular aggregation increases with increasing PTX loading fraction, while surface hydrophilicity decreases with increasing PTX loading fraction. The PGG-PTX molecules at f/PTX = 0.24 with concentrated spatial PTX distributions exhibit nonspherical shape, high flexibility, low aggregation, and high surface hydrophilicity. Since these properties have been shown to be clinically advantageous, we recommend the PGG-PTX molecules at f/PTX = 0.24 with concentrated spatial PTX distributions for experimental testing. The shape, flexibility, and surface hydrophilicity of nonpeptide RGD-targeted PGG-PTX systems varying in poly(ethylene glycol) (PEG) spacer length (500 Da, 1000 Da, and 2000 Da) and npRGD ligand density (4, 8, 12, and 16 per PGG-PTX-PEG-npRGD molecule) were also examined. Results from CG MD simulations show that the PGG-PTX- PEG1000-npRGD₈ and PGG-PTX-PEG1000-npRGD₁₂ molecules were the most promising candidates, given their filamentous shape, high flexibility, and high surface hydrophilicity. Overall, we introduce computer simulations as a tool for facilitating the preclinical development of polymeric drug delivery systems

Background

Black men who have sex with men (BMSM) and some who also have sex with women (BMSMW) account for over 70% of new HIV infections in the United States representing an elevated HIV risk in this group, also informing risks of HIV transmission to other BMSM and female sexual partners.

Settings

We examined trajectories of self-reported substance use, HIV-related sexual risk behaviors, and psychosocial vulnerabilities among BMSMW versus BMSM over a 1-year study period.

Methods

We analyzed baseline, 6-, and 12-month follow-up data from the HIV Prevention Trials Network "BROTHERS" Study (HPTN 061; n = 1126). Categorizing participants by sexual partner type across 3 time points: (1) BMSMO: having male and no female partners across assessments and (2) BMSMW: having sex with male and one or more female partners at least at 1 time point. Using generalized estimating equations, we estimated associations between being BMSMW (versus BMSMO) and changes in psychosocial vulnerability, substance use, and HIV-related sexual risk behaviors.

Results

Generalized estimating equation models controlling for sociodemographics, time-varying effects, and intervention status showed that BMSMW versus BMSMO had 50% increased odds of crack use, 71% increased odds of alcohol use during condomless anal intercourse (CAI), 51% greater odds of using drugs at last CAI, and twice the odds of receiving goods at last CAI.

Conclusions

Findings show stable and comparatively elevated illicit drugs, alcohol, and exchange sex during last CAI among BMSMW. Future intervention research should focus on ways to address changes in substance-related HIV-transmission behaviors over time in this population of men.