TUMOR-TARGETING WITH NEW BORONATED PORPHYRINS

使用新型硼卟啉靶向肿瘤

• 批准号: 7584613
• 负责人: MARIA DA GRACA HENRIQUES VICENTE
• 金额: $ 19.53万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-10 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7584613
• 关键词: Address; Adult; Anaplastic astrocytoma; Animal Model; Animals; Apoptosis; Biodistribution; Biological; Blood - brain barrier anatomy; Boron; Boron Delivery Agent; Boron Neutron Capture Therapy; Brain Neoplasms; Cell Line; Cell Nucleus; Cell membrane; Cell-Mediated Cytolysis; Cells; Cellular Membrane; Cessation of life; Clinic; Clinical Treatment; Clinical Trials; Collaborations; Complex; Convection; Detection; Development; Diagnosis; Disease; Drug Delivery Systems; Drug Kinetics; Effectiveness; Equilibrium; Europe; Evaluation; Exposure to; FDA approved; Feedback; Funding; Generations; Glioblastoma; Glioma; Goals; Head and Neck Neoplasms; Human; Hydrophobicity; In Vitro; Inbred BALB C Mice; Japan; Kidney; Laboratories; Lead; Life Expectancy; Light; Linear Energy Transfer; Liver; Malignant Neoplasms; Medical; Metals; Methods; Metric; Modality; Modeling; Mus; Neutrons; Nuclear; Ohio; Operative Surgical Procedures; Oxygen; Patients; Peptides; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Photochemotherapy; Porfimer Sodium; Porphyrins; Preparation; Production; Property; Public Health; Radiation therapy; Rattus; Reaction; Refractory; Research; Screening procedure; Specificity; Therapeutic; Therapeutic Agents; Therapy Clinical Trials; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; Universities; analog; base; cancer therapy; chemotherapy; cytotoxic; hydrophilicity; improved; in vivo; irradiation; malignant mouth neoplasm; melanoma; meningioma; metal complex; neoplastic cell; particle; professor; programs; response; therapy development; treatment planning; tumor; tumor specificity; uptake

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.

这项建议解决了开发高效的硼递送剂的需要，用于治疗难治性脑瘤和其他恶性肿瘤的新治疗方式，即硼中子俘获疗法(BNCT)。这一需求源于高质量中子束的生产和可获得性的进步。BNCT是一种基于核反应的二元疗法，核反应发生在肿瘤内的B-10原子核捕获低能中子产生高线性能量转移粒子时，其细胞毒作用仅限于药物所在的细胞。BNCT的I/II期临床试验正在美国、欧洲和日本进行，用于治疗胶质母细胞瘤和黑色素瘤患者；虽然有明确证据表明BNCT对治疗有疗效，但具有更高肿瘤细胞特异性、摄取率和滞留率的新型硼输送药物的开发将增加BNCT的普遍接受度，并为人类所有癌症中最难治疗的癌症之一--高级别胶质瘤提供一种非常有吸引力和选择性的治疗方法。我们在上一次资助期间获得的结果表明，Carboranylporrins是无毒的、两亲性的，可以中等选择性地将治疗量的硼输送到动物肿瘤；在所研究的新化合物中，有两种化合物作为硼输送药物特别有希望：TOCP和HOCP。我们以前的研究也表明，对流增强输送可能是给药的最好方法。我们修订后的计划的具体目标是：1)对我们最有希望的硼化卟啉衍生物进行动物和体外BNCT研究；2)继续研究我们第一代化合物的基本性质，并开发具有增强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疗效；4)评估它们在动物模型中的毒性和生物分布；以及5)研究它们通过对流增强给药的给药方式。我们的研究具有重大的医学意义和紧迫性，应该会迅速导致发现有效的BNCT药物并进行临床试验。FDA批准了两种基于卟啉的分子用于另一种二元癌症疗法-光动力疗法，其中一种(Photofrin)目前正在进行脑瘤二期试验。目前还没有治疗高级别胶质瘤的有效方法。尽管在手术、放疗和化疗方面取得了进展，并使用这些方法的组合进行了积极的治疗，但被诊断为胶质母细胞瘤和间变性星形细胞瘤的成年人的平均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，并彻底研究它们的性质，才能实现BNCT的潜力。