Late detection and drug resistance have maintained the grim statistics for ovarian cancer (OvCa) for over 30 years (with a projected 21,880 new cases and 13,850 deaths in 2010). New approaches using combination therapies with mechanistically distinct components are hypothesized to be most effective. However, sequential administration of multiple therapies has failed to impact survival. This proposal addresses this issue along with other key barriers in the treatment of OvCa. The long term goal is to develop, integrate and validate key platform technologies to combine quantitative fluorescence imaging for drug delivery monitoring and customized dosimetry with """"""""Targeted Phototoxic Multi-Inhibitor Liposomes"""""""" (TPMILs) that selectively target and simultaneously block interconnected survival pathways associated with aggressive OvCa. To address the grueling toxicities and frequent recurrence that cause OvCa-related deaths, we leverage our nanotechnology program to fabricate TPMILs for simultaneous intracellular delivery of targeted inhibitors, and deliver combination regimens with photodynamic therapy (PDT), an FDA-approved photochemistry-based treatment that has shown clinical promise for OvCa. PDT is effective on chemo and radiation resistant cells and synergizes with chemotherapeutic and biologic agents resulting in improved efficacy. The goals will be realized in 4 specific aims: (1) Synthesize, optimize and characterize TPMILs for triple combination therapy of OvCa. (2) Customize and calibrate hyperCFME for online, in vivo imaging of TPMILs and micronodular OvCa. (3) Establish image-guided treatment planning for OvCa-targeted PDT. (4) Evaluate the impact of using TPMILs and customized PDT-dosimetry on acute treatment response and survival enhancement. Major deliverables of this proposal will be (i) two reproducible, well-characterized TPMILs for multi-agent delivery with optimized targeting moiety surface densities and therapeutic agent payloads;(ii) a custom built, high-resolution, minimally-invasive imaging system calibrated for online tumor burden and drug concentration quantification;(iii) the optimal drug-light interval that provides sufficient BPD accumulation at the best TPMIL TNR, and the threshold PDT dose;(iv) determination of customized dosimetry benefit to treatment tolerance, acute tumor reduction, and survival;and, (v) identification of the optimal targeting moiety (mAb versus customized cyclic peptide). The findings from this study will impact outcomes for patients with advanced (stage II-IV) and resistant OvCa and those receiving salvage therapies. The infrastructure developed through this highly integrated approach will create a new framework to rapidly evaluate and optimize new therapeutic strategies that will be adaptable to a broad array of metastatic tumors and molecular targets. Because molecular expressions and responses can be idiosyncratic, the proposed rapid monitoring of biomarker expression and treatment-induced biomarker changes creates the possibility of patient-customized treatments in the future. The platform will also impact scientific research by providing new investigative tools.
The outcomes of the proposed studies will impact ovarian cancer patients with resistant disease by establishing tumor-targeted, co-delivery of cytotoxic agents and multiple inhibitors of interconnected, compensatory biological treatment resistance mechanisms. New minimally-invasive imaging tools are developed to inform patient-tailored treatments and for the visualization and eradication of small volume, microscopic disease beyond resectable macroscopic tumors. The approach developed here will be adaptable to treating a broad range of diseases.
|Obaid, Girgis; Jin, Wendong; Bano, Shazia et al. (2018) Nanolipid Formulations of Benzoporphyrin Derivative: Exploring the Dependence of Nanoconstruct Photophysics and Photochemistry on Their Therapeutic Index in Ovarian Cancer Cells. Photochem Photobiol :|
|Broekgaarden, Mans; Rizvi, Imran; Bulin, Anne-Laure et al. (2018) Neoadjuvant photodynamic therapy augments immediate and prolonged oxaliplatin efficacy in metastatic pancreatic cancer organoids. Oncotarget 9:13009-13022|
|Huang, Huang-Chiao; Rizvi, Imran; Liu, Joyce et al. (2018) Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery. Cancer Res 78:558-571|
|Bulin, Anne-Laure; Broekgaarden, Mans; Hasan, Tayyaba (2017) Comprehensive high-throughput image analysis for therapeutic efficacy of architecturally complex heterotypic organoids. Sci Rep 7:16645|
|Obaid, Girgis; Spring, Bryan Q; Bano, Shazia et al. (2017) Activatable clinical fluorophore-quencher antibody pairs as dual molecular probes for the enhanced specificity of image-guided surgery. J Biomed Opt 22:1-6|
|Wang, Sijia; Hüttmann, Gereon; Scholzen, Thomas et al. (2016) A light-controlled switch after dual targeting of proliferating tumor cells via the membrane receptor EGFR and the nuclear protein Ki-67. Sci Rep 6:27032|
|Tangutoori, Shifalika; Spring, Bryan Q; Mai, Zhiming et al. (2016) Simultaneous delivery of cytotoxic and biologic therapeutics using nanophotoactivatable liposomes enhances treatment efficacy in a mouse model of pancreatic cancer. Nanomedicine 12:223-34|
|Huang, Huang-Chiao; Mallidi, Srivalleesha; Liu, Joyce et al. (2016) Photodynamic Therapy Synergizes with Irinotecan to Overcome Compensatory Mechanisms and Improve Treatment Outcomes in Pancreatic Cancer. Cancer Res 76:1066-77|
|Mallidi, Srivalleesha; Anbil, Sriram; Bulin, Anne-Laure et al. (2016) Beyond the Barriers of Light Penetration: Strategies, Perspectives and Possibilities for Photodynamic Therapy. Theranostics 6:2458-2487|
|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|
Showing the most recent 10 out of 24 publications