PORPHYRAZINE TUMOR CONTRAST AGENTS

可靠的、非侵入性的肿瘤检测方法至关重要。当前成像模式的不足使得必须设计新的、可靠的、非侵入性的成像方法，沿着可以频繁施用用于筛查的相应成像剂，以及用于治疗期间和之后的肿瘤监测。 软组织的光学吸收和荧光成像是可能的，其附近的光的波长超过血红蛋白的吸收，λ等于或小于700 nm。 我们在这个建议中表明，一类相对未知的卟啉变体，卟啉（pzs）代表了一个独特的有吸引力的组合的光学，化学和生物学特性作为造影剂在肿瘤的光学吸收和荧光成像。 初步结果已经显示pzs是无毒的，并且被肿瘤细胞吸收。 我们建议通过使用我们开发的合成策略和我们完善的细胞筛选方法来优化pzs作为静脉内递送的肿瘤特异性光学造影剂。具体目标1. 化学合成类pz，同时优化肿瘤吸收，并为近红外光学吸收和荧光特性所需的光学成像。具体目标2. 记录这些新pz的无毒性质，并测量pz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学测试的结果来改进化学合成。目标：将near-it吸收/发射pz的结构修饰与其生物活性相关联，以开发优化的静脉注射光学造影剂。

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.