Abstract 3923: Photoacoustic image guided photodynamic therapy of glioblastoma.

Abstract

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

Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization — a Thomas Dougherty Award for Excellence in PDT paper

“…Using this system, a "prediction map" within 24 h post therapy could assist in deciding on secondary intervention. PAI-based systems present an option for "mapping" of a tumor, and showcase options for monitoring PS tumor uptake as well as providing personalized feedback of dosing and concentration [259,260], or vasculature changes [261,262].…”

Photonanomedicine: a convergence of photodynamic therapy and nanotechnology

“…PAI, a ‘light-in, sound-out’ modality provides 3D optical absorption properties of the tissue being imaged at penetration depths that are significantly deeper than fluorescence imaging. Recent work by Mallidi et al 108 and Ho et al 109 showcases the ability of PAI to monitor PS tumor uptake and directs towards the ability to personalize dosimetry based on the PS concentration at the target site. As an alternative method to assess PDT efficacy without using PS photobleaching or 1 O 2 luminescence, PAI can also quantify changes in blood oxygen saturation levels induced during PDT by 1 O 2 generation.…”

Three-dimensional in vitro cancer spheroid models for photodynamic therapy: strengths and opportunities

“…Given the importance of oxygen to the success of most PDT regimens, there is a significant need for improved methods of oxygen quantification within spheroids to visualize, map, and correlate microscale pO 2 to treatment outcome. While technologies such as photoacoustic tomography are providing new insight into blood oxygen saturation levels during PDT in vivo, [47] such toolkits rely on the presence of blood and do not directly report tissue oxygen levels. Recent efforts developing porphyrin dendrimers capable of penetrating throughout 3D spheroid models show much promise for future PDT studies, as oxygen concentration can be mapped on the cellular level before, during, and after treatment [48].…”