X. Li, M.R. Szewczuk, C. Malardier-Jugroot
Royal Military College of Canada,
Keywords: drug delivery, cancer research, alternating copolymer, ph responsive delivery systems
Summary:Nanotechnology has been extensively exploited to improve conventional cancer therapy in the recent years1. The designed nanocarriers allow drug to be delivered to cancer cells specifically with prolonged circulation time and controlled drug release2–4. In this study, alternating copolymers are chosen instead of the popular block copolymer as polymeric template. Indeed, alternating copolymers are structurally close to biological systems due to the uniform interaction along the polymer chains. In addition, polymers can self-assemble into very ordered nanoarchitechtures, with cavities that can be as small as 3 nm resulting in increased volume to surface ratio which would further increase the delivering efficiency. As a result, we chose biodegradable and pH-responsive poly(styrene-alt-maleic anhydride), PSMA as our delivering template5,6. At neutral pH, the polymer self-assembles into nanotubes or nanosheets with hydrophobic interior for encapsulating small sized drug molecules and hydrophilic exterior for increased solubility in water or biological media. Once the delivery vehicle reaches the tumour tissue, the decrease pH of the tumour microenvironment would disrupt the nanostructure releasing the drug on site (Figure 1). These unique features of PSMA make it a great candidate for a controlled release drug delivery vehicle for cancer cells. To increase the specificity of the drug delivery vessel, folic acid is attached to the polymeric chain. The folic acid has extremely high affinity (KD~10M) towards its receptors which are over-expressed in certain types of cancers7–10. Previously, our study modeled and synthesized folate‐SMA conjugates via biodegradable molecule 2,4‐diaminobutyric acids, DABA linker. The results indicated that the functionalized SMA polymer will retain its linearity and pH responsiveness. The functionalized polymer was then tested for cellular uptake of hydrophobic drug mimic. Indeed, curcumin was used as a drug mimic and fluorescent dye to characterize the effect of the polymer on cell growth as well as the distribution of the drug within the cells. Human pancreatic cancer cell lines PANC-1 was cultured and the results from fluorescent microscopy indicate the curcumin is taken up by PANC1 with polymers aggregate around the cells into cylindrical filament. This association is specific to cells and the enhanced fluorescent contrast at the filaments indicates the curcumin was located inside the polymers, confirms the aggregation is formed by FA-DABA-SMA polymers. In this talk, we will present results using FDA approved anti-cancer drugs 5-fluorouracil (5-FU) and Paclitaxel encapsulated by FA-DABA-SMA polymeric template in PANC1 cell lines. The progress was monitored using microscope and the cell viability upon incubation with anti-tumour agents were characterized by WST assay. The preliminary results indicate the drugs are being delivered through polymer aggregation around the cells and the drugs are being released slowly. Encapsulation efficiency and release profile of each individual drug will be presented. This research provides strong justification and guidance for the development of folate-conjugated PSMA as an effective and safe tumor targeting drug delivery platform.