Pancreatic cancer is a disease with an incredibly poor survival rate. As only about 20% of patients are eligible for surgical resection, neoadjuvant treatments that can relieve symptoms and shrink tumors for surgical resection become critical. Many forms of treatments rely on increased vulnerability of cancerous cells, but tumors or regions within the tumors that may be hypoxic could be drug resistant. Particularly for neoadjuvant therapies such as the tyrosine kinase inhibitors utilized to shrink tumors, it is critical to monitor changes in vascular function and hypoxia to predict treatment efficacy. Current clinical imaging modalities used to obtain structural and functional information regarding hypoxia or oxygen saturation (StO2) do not provide sufficient depth penetration or require the use of exogenous contrast agents. Recently, ultrasound-guided photoacoustic imaging (US-PAI) has garnered significant popularity, as it can noninvasively provide multiparametric information on tumor vasculature and function without the need for contrast agents. Here, we built upon existing literature on US-PAI and demonstrate the importance of changes in StO2 values to predict treatment response, particularly tumor growth rate, when the outcomes are suboptimal. Specifically, we image xenograft mouse models of pancreatic adenocarcinoma treated with suboptimal doses of a tyrosine kinase inhibitor cabozantinib. We utilize the US-PAI data to develop a multivariate regression model that demonstrates that a therapy-induced reduction in tumor growth rate can be predicted with 100% positive predictive power and a moderate (58.33%) negative predictive power when a combination of pretreatment tumor volume and changes in StO2 values pretreatment and immediately posttreatment was employed. Overall, our study indicates that US-PAI has the potential to provide label-free surrogate imaging biomarkers that can predict tumor growth rate in suboptimal therapy.

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Introduction: Glioblastoma multiforme(GBM) is an aggressive cancer with bleak survival rates and limited new treatment options. Fluorescence guided resection of GBM followed by photodynamic therapy (PDT) has shown promise in several chemo-or radiotherapy non-responsive GBM treatments clinically. PDT causes cytotoxicity with a combination of specific wavelength of light and photosensitizer (PS). Fluorescence is used in PDT research for detection of tumors, as the PS is also fluorescent. However, typically these molecules have low fluorescence quantum yields but good singlet oxygen yields to cause photodynamic damage. Also, in-vivo florescence images are surface-weighted and donot provide 3D image of the tumoral drug accumulation. In this study we utilize photoacoustic imaging (PA), a non-invasive, non-ionizing technique that provides contrast based on optical absorption properties of the tissue, to obtain 3D biodistribution of different fluorophores and PDT agents such as methylene blue (MB) free or encapsulated in liposomes in orthotopic brain tumors. We encapsulated verteporfin and MB in liposomes to increase its circulation half-life in-vivo and tumoral accumulation due to the enhanced-permeation and retention effect. Moreover, PA imaging can also be used to monitor tumoral blood oxygen saturation and this information is critical in PDT as oxygen plays a major role in creation of singlet oxygen cytotoxic species. Methods and Results: In this study, U87 glioma cells and patient derived GBM6 glioma cells were implanted orthotopically in the brain in 4-6 weeks old nude mice. 10 days post implantation, a burr hole was made in the skull to image intravenously injected liposomal methylene blue (10 mg/kg) uptake in the tumor. The liposomes were ∼110 nm in diameter evaluated using dynamic light scattering. A methylene blue loading efficiency of ∼50% was obtained in these liposomes. We observed that 2 hours post I.V. injection, the photoacoustic signal in brain tumor region increased ∼2.3 times and remained the same in non-tumor regions within the brain. We performed pilot studies in orthotopic glioma models that demonstrated: i) the efficacy of the photosensitizer encapsulated liposomes to accumulate in the glioma tumors, ii) ability of PA imaging technique to monitor the 3D heterogeneous uptake of the liposome constructs and iii) monitor PDT-induced changes in tumor vascular oxygen saturation non-invasively in real time. Conclusions: Taken together, we anticipate significant tumor burden reduction in our on-going in-vivo studies where the PDT light dose will be compensated based on the photoacoustic image information of the PDT agents uptake in the tumor. The findings of this study will form the basis for customized photodynamic therapy for glioblastoma and have the potential to serve as a platform for treatment of other cancers. Citation Format: Srivalleesha Mallidi, Huang-Chiao Huang, Joyce Y. Liu, Lawrence Mensah, Zhiming Mai, Tayyaba Hasan. Photoacoustic image guided photodynamic therapy of glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3923. doi:10.1158/1538-7445.AM2013-3923

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