TUMOR-TARGETING WITH NEW BORONATED PORPHYRINS

该提案解决了开发有效硼递送剂的需求，用于难治性脑肿瘤和其他恶性肿瘤的新治疗模式，硼中子捕获疗法（BNCT）。这种需要来自于高质量中子束的生产和可用性的进步。BNCT是一种基于核反应的二元疗法，当位于肿瘤内的硼-10核捕获低能中子以产生高线性能量转移粒子时发生核反应，该粒子的细胞毒性作用仅限于药物保留的细胞。I/II期BNCT临床试验正在美国进行，欧洲和日本，用于治疗胶质母细胞瘤和黑色素瘤患者;尽管有明确的证据表明BNCT具有治疗反应，但开发具有更高肿瘤细胞特异性、摄取和保留的新型硼递送药物将提高BNCT的普遍接受度，并为所有人类癌症中最难治的癌症之一，高级别胶质瘤提供非常有吸引力和选择性的治疗。我们在上一个资助期间获得的结果表明，碳硼烷卟啉是无毒的，两亲性的，并以中等选择性向动物肿瘤提供治疗量的硼;在研究的新化合物中，两种特别有希望作为硼递送药物：TOCP和HOCP。我们以前的研究还表明，对流增强递送可能是我们化合物给药的最佳方法。我们修订后的计划的具体目标是：1）对我们最有前途的硼化卟啉衍生物进行动物和体外BNCT研究; 2）继续研究我们的第一代化合物的基本性质，并开发具有增强的肿瘤靶向和肿瘤细胞摄取特异性的新类似物; 3）评估我们的硼化卟啉衍生物的体外BNCT功效; 4）评估它们在动物模型中的毒性和生物分布，和5）研究它们通过对流增强递送的施用。我们的研究具有重大的医学意义和紧迫性，并应迅速导致有效的BNCT剂的发现和临床试验。两种基于卟啉的分子被FDA批准用于另一种二元癌症疗法，光动力疗法，其中一种（Photofrin）目前正在进行II期脑肿瘤试验。目前还没有有效的治疗高级别胶质瘤。尽管在手术、放疗和化疗以及使用这些方式的组合的积极治疗方面取得了进展，但诊断为胶质母细胞瘤和间变性星形细胞瘤的成人的中位预期寿命通常不到一年。只有发现、合成新的和改进的BNCT试剂，并对其性质进行彻底研究，才能实现BNCT的潜力。

This proposal addresses the need for the development of efficient boron delivery agents for application in a new treatment modality for intractable brain tumors and other malignancies, boron neutron capture therapy (BNCT). This need arises from advances in the production and availability of high quality neutron beams. BNCT is a binary therapy based on a nuclear reaction which occurs when boron-10 nuclei localized within tumors capture low-energy neutrons to produce high linear energy transfer particles whose cytotoxic effects are confined to the cells in which the drug is retained. Phase I/II BNCT clinical trials are being pursued in the U.S., Europe, and Japan, for the treatment of patients with glioblastomas and melanomas; although there is clear evidence of a therapeutic response to BNCT, the development of new boron delivery drugs with higher tumor cell specificity, uptake and retention will increase the general acceptance of BNCT and provide a very attractive and selective treatment for one of the most therapeutically refractory of all human cancers, high grade gliomas. Our results obtained during the last funding period show that carboranylporphyrins are non-toxic, amphiphilic and deliver therapeutic amounts of boron to animal tumors with moderate selectivity; among the new compounds investigated, two are particularly promising as a boron delivery drug: TOCP and HOCP. Our previous studies also suggest that convection enhanced delivery might be the best method for administration of our compounds. The specific aims for our revised proposed program are: 1) to conduct animal and in vitro BNCT studies on our most promising boronated porphyrin derivatives; 2) to continue the study of the fundamental properties of our first-generation compounds and to develop new analogues with enhanced specificity for tumor targeting and tumor cell uptake; 3) to evaluate the in vitro BNCT efficacy of our boronated porphyrin derivatives; 4) to evaluate their toxicity and biodistribution in animal models, and 5) to investigate their administration via convection enhanced delivery. Our studies have great medical significance and urgency and should rapidly lead to the discovery of efficient BNCT agents and to clinical trials. Two porphyrin-based molecules are FDA approved for use in another binary cancer therapy, photodynamic therapy, and one of them (Photofrin) is currently being investigated in a Phase II brain tumor trial. There is currently no efficient treatment for high grade gliomas. Despite advances in surgery, radiotherapy and chemotherapy, and aggressive treatments using a combination of these modalities, median life expectancy for adults diagnosed with glioblastomas and anaplastic astrocytomas is generally less than one year. The potential of BNCT will only be realized if new and improved BNCT agents are discovered, synthesized and their properties thoroughly investigated.