Prostate cancer is the most prevalent diagnosed disease among men in the United States. Currently diagnosis is achieved through assessment of multiple data including PSA blood levels and digital rectal exams. Since the introduction of PSA testing significantly more men have been diagnosed and treated for the disease. The course of therapeutic action for diagnosed prostate cancer depends on staging of the disease and breaks down to essentially 3 interventions depending on stage: 1) Radical prostatectomy for cancers that are contained within the prostate; 2) Radiation therapy which can be used for both early and more advanced cancer; and 3) Watchful waiting, or active surveillance. With current screening and public awareness approximately 91% of prostate cancers detected are estimated to be clinically localized when first detected and potentially these patients are candidates for surgery, which is only used for localized disease. However, there is no way to know with certainty if the cancer is localized within the prostate capsule during surgery, and, of the patients that undergo radical prostatectomy, approximately 20% do not achieve surgical cures because of disease spread outside of the prostate gland. Moreover, surgery is associated with significant morbidities including incontinence and erectile dysfunction. The need to perform more complete prostatectomies and reduce surgical morbidities defines an unmet clinical need. The development of a technology that would improve the ability of the surgeon to distinguish among these structures, assess extra-capsular invasion of the cancer during prostatectomy, improve surgical decisions, and ablate cancer tissue that is not resectable, would improve quality of care. We propose to use a highly selective prostate biomarker, PSMA, to drive the binding of a targeted theranostic nanoparticle agent to prostate cancer. This nanoparticle contains a photodynamic therapeutic agent, Pc4 that is both fluorescent and a potent cancer therapeutic. The goal of the proposed studies is to derivatize the nanoparticle containing Pc4 with a ligand for PSMA, thusly driving its selective uptake and delivery of Pc4 into prostate tumors. During surgery the fluorescent aspects of Pc4 would be exploited to visually differentiate the tumor from surrounding normal tissues, which do not take up the nanoparticle. This would allow the surgeon to decide in real time how aggressive the surgical intervention need be, i.e. the degree of morbidity potentially incurred to fully remove diseased tissues. Upon completion of the surgical resection, light of a specific wavelength can be used to excite the Pc4 resulting in free radical generation and robust cancer killing of the remaining cancer tissues that were not removed by the surgical procedure.
The proposed methods will develop theranostic nanoparticle technology that will provide image-guidance and cancer ablation capabilities for prostatectomies. Future clinical translation of the technology will have the potential to impact th quality of surgical resections, removing more cancerous tissues and reducing the incidence of surgically- induced morbidities.
