PORPHYRAZINE TUMOR CONTRAST AGENTS

可靠、无创的肿瘤检测方法至关重要。当前成像方式的缺陷使得必须设计新的、可靠的、非侵入性的成像方法，以及相应的显像剂，这些显像剂可以经常用于筛查，以及治疗期间和治疗后的肿瘤监测。光学吸光度和软组织的荧光成像是可能的近光波长超过血红蛋白的吸光度，λ等于或小于700nm。我们在本提案中展示了一类相对未知的卟啉变体，卟啉嗪（pzs）代表了光学，化学和生物特性的独特吸引力组合，可作为肿瘤光学吸光度和荧光成像的造影剂。初步结果已经表明，pzs是无毒的，并被肿瘤细胞吸收。我们建议通过使用我们已经开发的合成策略和我们已经完善的细胞筛选方法，优化pzs作为静脉给药的肿瘤特异性光学造影剂。具体目标1。化学合成的pzs类，同时优化肿瘤摄取，近红外光学吸收和光学成像所需的荧光特性。具体目标2。记录这些新的pzs的无毒性，并测量pzs在正常和肿瘤细胞系中的摄取、保留和释放动力学。具体目标3。以迭代的方式使用生物测试的结果来改进化学合成。目的：将近吸收/发射pzs的结构修饰与其生物活性联系起来，从而开发出优化的、可iv递送的光学造影剂。

Reliable, non-invasive methods of tumor detection are of vital importance. Shortcomings in current imaging modalities make it imperative to devise new, reliable, non-invasive imaging methods, along with corresponding imaging agents that can be administered frequently for screening, and for tumor monitoring during and after therapy. Optical absorbance and fluorescence imaging of soft tissue is possible with near-it light at wavelengths beyond the absorbance of hemoglobin, lambda equal to or less than 700 nm. We show in this proposal that a relatively unknown class of porphyrin variants, the porphyrazines (pzs) represent a uniquely attractive combination of optical, chemical, and biological properties for use as contrast agents in optical absorbance and fluorescence imaging of tumors. Preliminary results have already revealed that pzs are nontoxic and are taken up by tumor cells. We propose to optimize the pzs as intravenous-delivered, tumor-specific optical contrast agents, through use of synthetic strategies we have developed and cell screening methods we have perfected. SPECIFIC AIM 1. Chemically synthesize classes of pzs that are simultaneously optimized for tumor uptake, and for the near infra-red optical absorption and fluorescence characteristics required for optical imaging. SPECIFIC AIM 2. Document the non-toxic nature of these new pzs and to measure the kinetics of uptake, retention, and release of the pzs in normal and tumor cell lines. SPECIFIC AIM 3. Use the results of the biological tests in an iterative way to refine the chemical syntheses. GOAL: To correlate structural modifications of near-it absorbing/emitting pzs with their biological activity, so as to develop optimized, iv-deliverable optical contrast agents.