A Multimodal Molecular Imaging Study Evaluates Pharmacological Alteration of the Tumor Microenvironment to Improve Radiation Response

Yoichi Takakusagi, Sarwat Naz, Kaori Takakusagi, Masahiro Ishima, Hiroshi Murata, Keisuke Ohta, Masahiko Miura, Fumio Sugawara, Kengo Sakaguchi, Shun Kishimoto, Jeeva P Munasinghe, James B Mitchell, Murali C Krishna
Cancer Research2018
Hypoxic zones in solid tumors contribute to radioresistance, and pharmacological agents that increase tumor oxygenation prior to radiation, including anti-angiogenic drugs, can enhance treatment response to radiotherapy. Although such strategies have been applied, imaging assessments of tumor oxygenation to identify an optimum time window for radiotherapy have not been fully explored. In this study, we investigated the effects of alpha-sulfoquinovosylacyl-1,3-propanediol (SQAP; a synthetic derivative of an anti-angiogenic agent) on the tumor microenvironment in terms of oxygen partial pressure (pO2), oxyhemoglobin saturation (sO2), blood perfusion, and microvessel density using electron paramagnetic resonance imaging, photoacoustic imaging, dynamic contrast-enhanced MRI with Gd-DTPA injection, and T2*-weighted imaging with ultrasmall superparamagnetic iron oxide (USPIO) contrast. SCCVII and A549 tumors were grown by injecting tumor cells into the hind legs of mice. Five days of daily radiation (2 Gy) combined with intravenous injection of SQAP (2 mg/kg) 30 min prior to irradiation significantly delayed growth of tumor xenografts. Three days of daily treatment improved tumor oxygenation and decreased tumor microvascular density on T2*-weighted images with USPIO, suggesting vascular normalization. Acute effects of SQAP on tumor oxygenation were examined by pO2, sO2, and Gd-DTPA contrast-enhanced imaging. SQAP treatment improved perfusion and tumor pO2 (ΔpO2: 3.1±1.0 mmHg) and was accompanied by decreased sO2 (20-30% decrease) in SCCVII implants 20-30 min after SQAP administration. These results provide evidence that SQAP transiently enhances tumor oxygenation by facilitating oxygen dissociation from oxyhemoglobin and improving tumor perfusion. Therefore, SQAP-mediated sensitization to radiation in vivo can be attributed to increased tumor oxygenation.

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