PORPHYRAZINE TUMOR CONTRAST AGENTS

可靠的、非侵入性的肿瘤检测方法至关重要。目前成像方式的缺陷使得设计新的、可靠的、非侵入性的成像方法，以及相应的成像试剂，可以频繁地用于筛查和治疗过程中和治疗后的肿瘤监测是势在必行的。软组织的光吸收和荧光成像是可能的，其波长超过了血红蛋白的吸光度，波长等于或小于700 nm。在这项提案中，我们展示了一类相对未知的卟啉变体，即卟嗪(PZS)，它代表了光学、化学和生物学特性的独特组合，可用于肿瘤的光吸收和荧光成像中的造影剂。初步结果已经显示，PZs无毒，可被肿瘤细胞摄取。我们建议通过使用我们开发的合成策略和完善的细胞筛选方法来优化PZS作为静脉注射的肿瘤特异性光学造影剂。具体目的1.化学合成同时优化了肿瘤摄取和光学成像所需的近红外光学吸收和荧光特性的PZs。具体目的2.记录这些新的PZs的无毒性质，并测量PZs在正常和肿瘤细胞系中的摄取、滞留和释放的动力学。具体目的3.以迭代的方式利用生物试验的结果来改进化学合成。目的：将近红外吸收/发射PZs的结构修饰与其生物活性联系起来，以开发优化的静脉递送光学造影剂。

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.