Radiopharmaceuticals for Tumor Imaging and Photodynamic Therapy

描述（由申请人提供）：在体内对特定类型肿瘤进行无创分子成像，然后进行量身定制的医学发明，正在成为癌症治疗的新前沿。我们的初步研究表明，基于肿瘤卟啉的化合物（例如HPPH，一种叶绿素-a类似物）可以用作将放射性核素输送到肿瘤的载体。生物分布结果表明，药物的肿瘤/非肿瘤摄取比取决于时间和肿瘤大小。肿瘤成像的时间被认为是一个重要的参数，因为随着时间的推移，光敏剂从肿瘤中清除的速度比大多数非肿瘤组织慢。因此，在进一步的研究中，用寿命更长的同位素（如ln-111）代替“To”（半衰期6小时）可以提供一种有用的扫描剂。在初步的体内研究中，与HPPH相比，相应的非放射性In（ll）复合物在第3天的体内光敏效果增加了10倍，没有明显的皮肤光毒性。在平行研究中，我们能够以高特异性将3-碘苯醚基团转化为相应的1-124类似物。在初步的体外和体内筛选中，发现该化合物（非放射性类似物）非常有效。在与[F]FDG的比较研究中，相应的1-124光敏剂表现出更好的肿瘤特异性（见初步结果）。另一种改进肿瘤成像和光疗剂（双功能剂）的方法可能是用那些表现出明显更高的肿瘤与非肿瘤比率的化合物取代HPPH，并产生接近750-800 nm的长波吸收（该波长的光治疗可用于治疗大肿瘤和深部肿瘤）。结合物的比较研究将包括：肿瘤吸收的体内反射光谱，肿瘤成像，体外和体内PDT疗效，皮肤光毒性，生物分布研究和一般毒性。肿瘤成像或改进光动力治疗剂的发展本身是重要的一步，但双功能治疗剂（SPECT/PDT或PET/PDT）提供了诊断性身体扫描随后靶向治疗的潜力。

DESCRIPTION (provided by applicant): The non-invasive molecular imaging of the specific type of tumor in vivo followed by tailored medical invention is becoming the new frontier in cancer treatment. Our preliminary study indicates that tumoravid porphyrin-based compounds (e.g. HPPH, a chlorophyll-a analog) can be used as a vehicle to deliver the radionuclide to tumors. The biodistribution results indicate that the tumor/non-tumor uptake ration of the drug depend on time and tumor size. The time for tumor imaging was found to be an important parameter because, with time the clearance of the photosensitizer from tumor was found to be slower than most of the non-tumor tissues. Therefore, for further studies replacing "To (half-life 6 hours) with longer-lived isotope such as ln-111 could provide a useful scanning agent. In preliminary in vivo study compared to HPPH, the corresponding nonradioactive In(lll) complex produced a 10-fold increase in in vivo photosensitizing efficacy with no significant skin phototoxicity on day 3. Ina parallel study, we were able to convert the 3-iodobenzylether group into the corresponding 1-124 analog with high specificity. In preliminary in vitro as well as in vivo screening, this compound (non-radioactive analog) was found to be quite effective. In a comparative study with [ F]FDG, the corresponding 1-124 photosensitizer showed better tumor specificity (see Preliminary Results). Another approach for developing an improved tumor-imaging and phototherapy agents (bifunctional agents) could be to replace HPPH with those compounds that exhibit a significantly higher tumor to nontumor ratio and produce long-wavelength absorption near 750-800 nm (light treatment at this wavelength could be useful for treating large tumors and those that are deeply seated. The comparative study of the conjugate will include: tumor uptake by in vivo reflectance spectroscopy, tumor imaging, in vitro and in vivo PDT efficacy, skin phototoxicity, biodistribution study and general toxicity. The development of tumor imaging or improved photodynamic therapy agent(s) by itself represents an important step, but a dual function agent (SPECT/PDT or PET/PDT) provides the potential for diagnostic body scan followed by targeted therapy.