Ovarian cancer (OC) has the highest mortality rate of all cancers of the female reproductive system and outcomes have not changed over the past four decades. This year, over 20,000 women will be diagnosed with OC in the United States more than 14,000 women will die from this disease. Platinum-based therapy is the main therapeutic option for OC patients and ultimately, systemic toxicity limits the dosage given and this, in part, limits its effectiveness. To overcome this therapeutic roadblock, alternative routes of administration have been sought and include the practically difficult intraperitoneal (IP) injection, and more recently, the emerging strategy of combining Pt (II) chemotherapy with tumor vasculature-targeting agents. The overarching goal of this study is to develop a nanoparticle (NP)-based therapy for targeted delivery of high dose Pt (II) and a vascular disrupting agent directly to cancer cells and endothelium, to enhance treatment outcomes. As proof- of-principle, we have chosen combretastatin CA4 as the vascular targeting agent. Our proposal explores a second generation, slow releasing polymer NP platform, with poly(lactic-co-glycolic) (PLGA) acid core encapsulating Pt (II) and CA4. The NP?s coating is comprised of a RGDFFF peptide that stabilizes the NP and simultaneously serves as a targeting ligand to ?v?3 integrin via its RGD moiety. The PLGA is FDA-approved and amino acids of the peptide have Generally Regarded As Safe (GRAS) status. The NP is completely biodegradable. Encapsulation of Pt (II) and CA4 will reduce systemic toxicity and allow us to explore the use of effectively higher dosages than currently feasible. Upon the NP?s accumulation in the tumor interstitium, via enhanced permeability and retention (EPR) effects, the cellular NPs uptake will be enhanced via receptor- mediated endocytosis. The effect of the cytotoxic activity of Pt (II) and CA4 towards cancer cells and the tumor?s vasculature, will be measured through therapeutic outcomes. A small percentage of near infrared fluorophore (NIRF) will be incorporated into the NP?s coating to enable noninvasive optical imaging. The combination of therapeutic and diagnostic features will transform the NP into a ?theranostic? platform. In vitro studies will include evaluation of NPs targeting to cancer cells, their biological activity, and compatibility with the immune system. In vivo studies will focus on the assessment of NPs pharmacologic parameters, tumor targeting, tolerability, and, finally, therapeutic efficacy. Combined in vitro and in vivo studies will employ microscopy, immunochemistry, and histology, to define the best NP-based treatment regimen resulting in therapeutic outcomes rivaling free drug routines currently used in the clinic. Thus, the proposed specific aims are:
Aim 1 : Synthesize and characterize an RGDFFF-coated NP platform for targeting, visualizing and treating ovarian cancer.
Aim 2 : Test targeting efficacy and therapeutic potential of CA4-NPs and Pt-NPs in vitro.
Aim 3 : Study the biodistribution and targeted ?trapping? of NPs in a preclinical OC mouse model via in vivo imaging.
Aim 4 : Conduct a therapy study wherein CA4-NPs and Pt-NPs, are applied to a preclinical OC mouse model.
In this project, we propose the optimization of peptide-stabilized nanoparticle formulations with platinum and combretastatin loading capabilities for combined cancer therapy. Nanoparticles will be tested on different ovarian cancer cell lines in vitro, and the therapy assessment in vivo will be supported by noninvasive optical imaging. We expect our approach to have a broad and profound impact on the management of cancer therapy.
