Presentation Type
Poster
Discipline Track
Biomedical Science
Abstract Type
Research/Clinical
Abstract
Background: Current treatment strategies against breast cancer have limitations due to lack in selectivity. Most drugs, such as tamoxifen, require metabolic activation by cytochrome P450 (CYP) enzymes to perform greater anticancer effects. However, the concentration of CYP varies and is low in tumor cells, resulting in side-effects. In enzyme prodrug therapy (EPT), enzymes are targeted to the tumor cells for prodrug transformation, involving the sequential delivery of the enzyme followed by prodrug. However, differences in pharmacokinetics and pharmacodynamics are a major hindrance. Thus, co-delivery of prodrug and enzyme is essential to ensure their favorable interaction at target site.
Results: This work reports a new class of therapeutic nanocomposites based on P22 virus like particles (VLPs) confining the CYP activity (P22CYP), surface functionalized with glucose oxidase (GOx) that transforms glucose into D-glucono-δ-lactone producing hydrogen peroxide, the final electron acceptor in the CYP-mediated transformation of tamoxifen, and together conjugated with a tamoxifen derivative as prodrug and targeting ligand using polyethylene glycol as a linker. In glucose-rich tumor microenvironment, these nanocomposites with average size ~70 nm can produce active drug in situ. The physicochemical properties were successfully characterized and nanocomposites represented sequential glucose-mediated catalysis. In vitro studies demonstrated a decrease in cell viability in both ER+ and ER- breast cancer cell lines. However, cellular internalization in the absence of glucose showed improved uptake of targeted VLPs in both cell lines demonstrating improved uptake after pegylation. While the uptake in ER+ cells was significantly higher highlighting the targeting efficiency of functionalized tamoxifen.
Conclusions: The co-delivery of enzymes and prodrug with improved localization of developed VLPs after tamoxifen functionalization, suggests the potential of developed nanocomposites to overcome the existing challenges of EPT and improve the therapeutic outcomes with reduced side effects.
Academic/Professional Position
Graduate Student
Recommended Citation
Luna Rios, Astrid Rebeca, "P22 viral capsid nanocomposites for enzyme prodrug therapy of breast cancer" (2024). Research Symposium. 90.
https://scholarworks.utrgv.edu/somrs/2024/posters/90
Included in
P22 viral capsid nanocomposites for enzyme prodrug therapy of breast cancer
Background: Current treatment strategies against breast cancer have limitations due to lack in selectivity. Most drugs, such as tamoxifen, require metabolic activation by cytochrome P450 (CYP) enzymes to perform greater anticancer effects. However, the concentration of CYP varies and is low in tumor cells, resulting in side-effects. In enzyme prodrug therapy (EPT), enzymes are targeted to the tumor cells for prodrug transformation, involving the sequential delivery of the enzyme followed by prodrug. However, differences in pharmacokinetics and pharmacodynamics are a major hindrance. Thus, co-delivery of prodrug and enzyme is essential to ensure their favorable interaction at target site.
Results: This work reports a new class of therapeutic nanocomposites based on P22 virus like particles (VLPs) confining the CYP activity (P22CYP), surface functionalized with glucose oxidase (GOx) that transforms glucose into D-glucono-δ-lactone producing hydrogen peroxide, the final electron acceptor in the CYP-mediated transformation of tamoxifen, and together conjugated with a tamoxifen derivative as prodrug and targeting ligand using polyethylene glycol as a linker. In glucose-rich tumor microenvironment, these nanocomposites with average size ~70 nm can produce active drug in situ. The physicochemical properties were successfully characterized and nanocomposites represented sequential glucose-mediated catalysis. In vitro studies demonstrated a decrease in cell viability in both ER+ and ER- breast cancer cell lines. However, cellular internalization in the absence of glucose showed improved uptake of targeted VLPs in both cell lines demonstrating improved uptake after pegylation. While the uptake in ER+ cells was significantly higher highlighting the targeting efficiency of functionalized tamoxifen.
Conclusions: The co-delivery of enzymes and prodrug with improved localization of developed VLPs after tamoxifen functionalization, suggests the potential of developed nanocomposites to overcome the existing challenges of EPT and improve the therapeutic outcomes with reduced side effects.