Improved delivery of polymer therapeutics to prostate tumors using plasmonic photothermal therapy.

摘要

When a patient is presented with locally advanced prostate cancer, it is possible to provide treatment with curative intent. However, once the disease has formed distant metastases, the chances of survival drops precipitously. For this reason, proper management of the disease while it remains localized is of critical importance. Treating these malignant cells with cytotoxic agents is effective at cell killing; however, the nonspecific toxicity profiles of these drugs often limit their use until the disease has progressed and symptom palliation is required. Incorporation of these drugs in nanocarriers such as polymers help target them to tumors with a degree of specificity, though major vascular barriers limit their effective delivery. In this dissertation, it is shown that plasmonic photothermal therapy (PPTT) can be used to help overcome some of these barriers and improve delivery to prostate tumors. First, the concept of using PPTT to improve the delivery of macromolecules to solid tumors was validated. This was done by measuring the tumor uptake of albumin. Next, the concept of targeting gold nanorods (GNRs) directly to the tumor's vasculature to better modulate vascular response to heating was tested. Surface conjugation of cyclic RGD (Arg-Gly-Asp) to GNRs improved their binding and uptake to endothelial cells in vitro, but not in vivo. Nontargeted GNRs and PPTT were then utilized to guide the location of polymer therapeutic delivery to prostate tumors. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, which were designed to be targeted to cells previously exposed to heat shock, were used in this study. Treatment of tumors with PPTT facilitated a burst accumulation of the copolymers over 4 hours, and heat shock targeting to cells allowed them to be retained for an extended period of time. Finally, the tumor localization of the HPMA copolymers following PPTT was evaluated by magnetic resonance imaging (MRI). These results show that PPTT may be a useful tool to enhance delivery of polymeric drug carriers to locally advanced prostate tumors.