Ovarian cancer (OvCA) has the highest mortality of all cancers of the female reproductive system. Every year, over 20,000 women are diagnosed with ovarian cancer in the United States alone, which results in more than 16,000 deaths a year. Platinum-based therapy, such as cisplatin, has been used as pre- or post-surgical adjuvant therapy or as the main therapeutic option for ovarian cancer patients. Although the effectiveness of cisplatin is high, its systemic toxicity limits the dosage. To overcome this, cisplatin can be applied intraperitoneally (IP), combined with other chemotherapy agents or with ionizing radiation (IR). Nevertheless, difficulties/impracticality associated with IP injection in the clini or low cisplatin concentrations applied intravenously that reach cancer cells limit the effectiveness of treatment leading to eventual chemoresistance to the drug and failed treatment. The goal of this study is to develop a nanoparticle (NP)-based therapy for targeted delivery of high dose cisplatin and enhanced IR directly to cancer cells. Our proposal explores a second generation slow releasing lipid-polymer NP platform, with poly(lactic-co-glycolic) (PLGA) acid core encapsulating 1-3 nm gold nanocrystals (AuNCs) - the potent IR sensitizers, and new pH sensitive cisplatin (cisPt) complexes attached to the AuNCs surface. The PLGA polymer is biocompatible and biodegradable while lipidic coating of the NP provides long NP circulation in vivo. The stability of cisPt complexes under physiological pH will decrease systemic toxicity to the drug, allowing higher dosages. Upon NPs accumulation in the tumor interstitium, the low pH environment will prompt the release of cisPt. The intercalations of DNA by cisPt and concurrent DNA damage by AuNCs-enhanced IR are expected to lead to collateral DNA damage and quick cancer cell apoptosis, thus resulting in heightened therapeutic outcomes. The small percentage of near infrared fluorophore (NIRF) is incorporated into the NP's coating to enable noninvasive optical imaging. The combination of therapeutic and diagnostic features renders the NP a theranostic platform. The in vitro studies will include evaluation of NPs targeting to cancer cells, their biological activity, and compatibility with the immune system. The in vivo studies wil focus on the assessment of NPs pharmacologic parameters, evaluation of NPs tumor targeting, and tolerability of the NPs. The in vitro and in vivo examination will employ microscopy, immunochemistry, and histology to ultimately elucidate the NPs therapeutic potential.
The specific aims are:
Aim 1 : Establish a library of AuNC-cisplatin NPs and evaluation of their biological activity.
Aim 2 : Pilot in vivo a) pharmacokinetic/pharmacodynamic, b) tumor targeting, and c) tolerability studies with PLGA-AuNC- cisPt NPs in an OvCA mouse model in collaboration with John Martignetti MD, PhD from Ovarian Cancer Research Program (OCTRP) at Mount Sinai.
Aim 3 : Career development. The proposed research will lead to establishing a NP platform to deliver Pt-based therapy with enhanced IR that will provide a foundation for future studies on NPs for therapy of solid tumors, to be carried out in our group.
In this project we propose the optimization of lipid-polymer nanoparticle formulations with cisplatin and gold nanocrystals loading capabilities for combined cancer therapy. Nanoparticle candidates will be created and tested on different cell lines in vitro and in vivo tumor targeting will be evaluated in mouse models using non- invasive in vivo imaging. We expect our approach to have a broad and profound impact on the management of cancer therapy.
