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Since the introduction of PSA testing, significantly more men have been diagnosed and treated for prostate cancer. Localized prostate cancer typically is treated with prostatectomy, however there is still a high risk of recurrence after surgery, and adjuvant radiation has been shown to mitigate disease progression. X-ray therapy is frequently used as an adjuvant to treat prostate cancer, but is an imperfect tool. In this report we describe the development of a targeted-radiosensitizing nanoparticle that significantly improves X-ray therapy. Taking advantage of the demonstrated radiosensitizing activity of gold nanoparticles (AuNPs) we developed targeted AuNPs and varied both surface ligand density and AuNP size to develop an optimized AuNP for X-ray radiotherapy. We conjugated a prostate-specific membrane antigen (PSMA) targeting ligand, PSMA-1, to AuNPs and found that the targeting ligand dramatically improved gold uptake by PSMA-expressing PC3pip cells compared with PC3flu cells lacking the PSMA receptors. Further, enhancement of radiotherapy was significantly more pronounced by internalization of smaller PSMA targeted-AuNPs. Our studies provide a foundation for design of size-selected AuNPs for targeted radiotherapy and, for the first time, systematically investigate both the effect of ligand and AuNP size on the cell uptake, tumor targeting and radiotherapy efficacy.

Prostate-specific membrane antigen targeted gold nanoparticles for prostate cancer radiotherapy: does size matter for targeted particles?