This application addresses broad Challenge Area (13) Smart Biomaterials - Theranostics and specific Challenge Topic, 13-CA-102: Nanotechnology-based multi-functional materials for theranostic applications. The long term goal of this research is to develop mechanism and nanotechnology-based image-guided combination regimens with photodynamic therapy (PDT), an FDA approved treatment for certain cancers and in clinical trials for Ovarian Cancer (OvCa). The poor survival for OvCa stems in large part from residual tumor following surgery and chemotherapy leading to the disease recurrence and due to resistance to radiation and chemotherapy. A minimally invasive imaging modality with sensitivity and resolution to detect sub-millimeter OvCa nodules associated with recurrent disease, early in the treatment cycle would allow for timely disease re-assessment and the initiation of additional treatments if needed. Optical microendoscopy is a minimally invasive imaging modality with high sensitivity and micron-scale resolution. We have developed such a fluorescence microendoscope and shown it is capable of detecting small tumor nodules. We have also demonstrated that PDT sensitizes tumors to anti-VEGF (Avastin) treatment and that this combination (PDT and Avastin) is more effective when Avastin is delivered intracellularly in a nanoconstruct. The hypothesis underlying this proposal is that PDT combined with intracellular targeting of the VEGF pool will be a valuable combination treatment that will be most useful when incorporated with an imaging system that can monitor treatment response. Our strategy is to use a Theranostic Nanocell (TNC) that encapsulates Avastin and the PDT agent benzoporphyrin derivative as therapeutic components. The TNC targets Epidermal Growth Factor Receptor (EGFR) on OvCa cells via fluorescent indocyanine green-labeled anti-EGFR antibody (Cetuximab /C225) and serves as the diagnostic component of TNC. Encapsulation of Avastin inside these molecularly targeted nano-constructs should reduce the severe systemic toxicity of this drug, which is often lethal. The goals will be realized in 3 specific aims: 1) Synthesis and characterization of TNC, 2) Investigate the effect of theranostic nanocell in 3D cell culture models to obtain effective doses and 3) Evaluate the in vivo efficacy of the TNC to detect tumor nodules and establish TNC biodistribution in a murine model of OvCa using microendoscopy. In order to complete the project in the two year funding period, this proposal is focused primarily on developing and characterizing the TNC in vitro with a minor in vivo component. However, if successful, the results will be further substantiated in an extensive animal/human study and the findings of this study will impact a large proportion of OvCa patients with adaptability of the multifunctional platform to other diseases. Major deliverables of this proposal will be i) TNC fabrication and dosing to image and destroy tumor nodules in vitro in 3D cultures as well as detect these disseminated nodules in vivo, and ii) Fluorescence microendoscope for TNC-based sensitive and specific detection of the micrometastatic OvCa.

Public Health Relevance

Current methods to treat OvCa following surgery have failed to drastically improve patient survival and quality of life. Our method will not only help locate the microscopic residual disease but also selectively destroy it with multiple drugs and with reduced side-effects. This study has the potential to improve patient care and could result in the development of a new standard of management for the patients with OvCa following surgery.

National Institute of Health (NIH)
National Cancer Institute (NCI)
NIH Challenge Grants and Partnerships Program (RC1)
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Special Emphasis Panel (ZRG1-OTC-K (58))
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Grodzinski, Piotr
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Massachusetts General Hospital
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Spring, Bryan Q; Bryan Sears, R; Zheng, Lei Zak et al. (2016) A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways. Nat Nanotechnol 11:378-87
Spring, Bryan Q; Abu-Yousif, Adnan O; Palanisami, Akilan et al. (2014) Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates. Proc Natl Acad Sci U S A 111:E933-42
Celli, Jonathan P; Rizvi, Imran; Blanden, Adam R et al. (2014) An imaging-based platform for high-content, quantitative evaluation of therapeutic response in 3D tumour models. Sci Rep 4:3751
Spring, Bryan Q; Palanisami, Akilan; Hasan, Tayyaba (2014) Microscale receiver operating characteristic analysis of micrometastasis recognition using activatable fluorescent probes indicates leukocyte imaging as a critical factor to enhance accuracy. J Biomed Opt 19:066006
Anbil, Sriram; Rizvi, Imran; Celli, Jonathan P et al. (2013) Impact of treatment response metrics on photodynamic therapy planning and outcomes in a three-dimensional model of ovarian cancer. J Biomed Opt 18:098004
Rizvi, Imran; Dinh, Tri A; Yu, Weiping et al. (2012) Photoimmunotherapy and irradiance modulation reduce chemotherapy cycles and toxicity in a murine model for ovarian carcinomatosis: perspective and results. Isr J Chem 52:776-787
Casas, A; Di Venosa, G; Hasan, T et al. (2011) Mechanisms of resistance to photodynamic therapy. Curr Med Chem 18:2486-515
Evans, Conor L; Abu-Yousif, Adnan O; Park, Yong Jin et al. (2011) Killing hypoxic cell populations in a 3D tumor model with EtNBS-PDT. PLoS One 6:e23434
Rahmanzadeh, Ramtin; Rai, Prakash; Celli, Jonathan P et al. (2010) Ki-67 as a molecular target for therapy in an in vitro three-dimensional model for ovarian cancer. Cancer Res 70:9234-42
Rizvi, Imran; Celli, Jonathan P; Evans, Conor L et al. (2010) Synergistic enhancement of carboplatin efficacy with photodynamic therapy in a three-dimensional model for micrometastatic ovarian cancer. Cancer Res 70:9319-28

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