Professor Saint Louis University, Missouri, United States
Introduction: : Prostate cancer is a leading cause of cancer-related deaths in men, with current treatments such as radical prostatectomy, chemotherapy, and radiation—carrying significant risks of invasiveness and systemic side effects. Chemoembolization, a technique proven effective in treating liver cancer, has not yet been applied to prostate cancer. This method involves deliberately blocking blood vessels to restrict blood flow to the tumor, depriving it of oxygen and nutrients, allowing for targeted drug delivery, and potentially reducing side effects. However, a key limitation of this approach is the difficulty in visualizing the microspheres during treatment. This study aims to develop imageable, degradable, drug-eluting hydrogel microspheres containing barium sulfate (BaSO₄) that are visible under a variety of imaging techniques. The objective is to evaluate their cytotoxicity and drug release profiles for use in chemoembolization therapy for prostate cancer. By incorporating the chemotherapeutic agent docetaxel and bicalutamide with BaSO₄, the study seeks to provide a more effective and traceable therapeutic option.
Materials and
Methods: : Hydrogels and microgels were prepared from 4-arm polyethylene glycol acrylate (4-arm PEG-Ac) and polyethylene glycol dithiol (PEG-diSH), with BaSO₄ incorporated to enhance radiopacity, along with the chemotherapy drug docetaxel and the hormone therapy bicalutamide. Microspheres were fabricated via a rotational flow device, rinsed, lyophilized, and subsequently swelled in a drug solution to conduct the release study. We analyzed the cumulative and fractional release profiles and determined the effective diffusion coefficient of the drugs. In vitro cytotoxicity of the drug-loaded hydrogels and microgels was evaluated by using PC3 prostate cancer cell line. The hydrogels or microspheres were placed in trans well inserts for 72 h, and cell viability was measured via a resazurin assay.
Results, Conclusions, and Discussions:: To enhance hydrogel radiopacity, BaSO₄ was incorporated into the hydrogel (Figure 1A). Subsequently, drug-loaded microspheres containing BaSO₄ were prepared to further assess imageability. Microscopic images revealed that the addition of drugs did not affect the visibility of the BaSO₄ hydrogels or microspheres. The imageable microspheres were stable in buffer for over 30 days but degraded within 60 days. To evaluate whether the inclusion of BaSO₄ influenced drug release, cumulative mass release was measured (Figure 1B). A substantial burst release occurred within the first 24 h, with over 80% of the total drug released during this initial period. This rapid release likely resulted from the small size of the drug molecules in relation to the PEG hydrogel mesh size. Notably, the presence of BaSO₄ did not alter the drug release profiles. Initial dose-response studies on PC3 cells without hydrogels revealed that a combination of docetaxel and bicalutamide at 100 nM reduced cell viability to below 20%, indicating potent cytotoxic effects (Figure 1C). Using this concentration as a bolus dose, we further assessed cytotoxicity of drugs eluted from PEG hydrogels with or without BaSO₄ using transwell inserts (Figure 1D and 1E). Cell viability between PEG only and PEG-BaSO4 was similar, suggesting that the inclusion of BaSO₄ did not impact cell viability or alter the drug release profiles. BaSO₄-loaded PEG microspheres were imageable and degradable, without affecting drug release or cytotoxicity. Both docetaxel and bicalutamide showed potent, rapid release with strong effects on PC3 cells. BaSO₄ did not interfere with drug efficacy. These results support their potential for image-guided prostate cancer chemoembolization.
