The long-term goal of the research is to develop a new, multi-modal nanoparticle (NP)-based therapeutic system to treat residual disease in patients with advanced ovarian cancer (OVCA). The design of Targeted photoSensitizer NanoParticles (TSNAPs) and the investigation of their effectiveness in in vitro and in vivo models of OVCA are the subjects of the proposed project. Photodynamic therapy (PDT), which works by the generation of reactive, cytotoxic species following the absorption of light photons by a photosensitizer molecule (the PDT agent or PS), is a clinically approved method for the treatment of cancerous and various non-cancer diseases in many countries world-wide including in the United States. And yet, we believe that a multi-tiered approach, only made possible by collaborations between researchers in diverse disciplines, will be effective in addressing the growing need of ovarian cancer patients. For these patients, the current outlook is quite dismal as the disease has seen no significant improvement in survival in the last 3 decades primarily because 70% of these patients are diagnosed with advanced disease and a large majority develop resistance to standard chemotherapeutic drugs. As the current line of treatment using traditional chemotherapeutics and surgery has demonstrated itself as severely deficient, we hypothesize that a wholly new approach is needed whereby the individual advantages of using 1) mechanistic PDT, and 2) a nanotechnology-based delivery system are combined through a cohesive collaboration between our own lab here at Wellman and that of Dr. Mansoor Amiji's at Northeastern University. The 'smart' cancer therapy proposed here will combine high selectivity and efficacy against chemotherapeutic resistant and nonresistant OVCA cells. A nanotechnology-based approach holds great promise for achieving this goal by the incorporation of drug delivery and targeting technologies that build upon the failures of traditional chemotherapeutic strategies. With this in mind, the proposed research is directed at the design of a multifunctional polymer NP capable of delivering a drug payload in a controlled and specific matter to a tumor site. We intend to affect tumor selectivity/specificity by the inclusion of a peptide targeting moiety capable of recognizing OVCA cells to the NP architecture. Use of PDT agents, which have demonstrated considerable efficacy against otherwise drug resistant tumor cells in the past, will afford a high degree of control over drug activation, both spatial and temporal. In the project described here, these PDT agents will be encapsulated in the targeted NP vehicles, and thus two forms of selectivity are realized; only targeted cell lines are expected to receive an appreciable drug payload and light exposure is required for activation. ? ? ?
