SYNTHESIS AND EVALUATION OF BORONATED FOLATES FOR BNCT

描述：（申请人摘要）硼化合物的开发 硼治疗头颈鳞状细胞癌 (SCCHN) 中子俘获疗法 (BNCT) 需要合成和评估 相比之下，选择性靶向这些恶性细胞的无毒药物 与邻近的正常组织结合并保留在细胞内。细胞膜 介导叶酸内吞转运至细胞内的受体是 在多种人类肿瘤中表达水平升高。亲和力为 叶酸的细胞膜受体及其被内吞的能力 当大分子与其共价连接时，基本保持不变 γ-羧酸酯功能。研究表明，大量的缀合物 叶酸与治疗剂一起被内化到肿瘤细胞中， 通过受体介导的内吞作用过度表达叶酸受体，并且 保留在细胞内。因此，叶酸可能是一种极好的载体。 将硼物质选择性输送至 SCCHN。本次活动的具体目标 提案是： 开发化学方法来设计和合成合适的叶酸 具有1至9个碳硼烷和多面体硼烷簇的酸衍生物 有或没有DNA靶向实体。 使用硼化星爆树枝状聚合物制备叶酸缀合物 聚乙二醇间隔基作为结合元件。 合成硼化多胺并将其掺入脂质体制剂中 使用叶酸-PEG-脂质体。 确定体外摄取、持久性和亚细胞分布 硼化叶酸衍生物及其脂质体制剂 人类鳞状细胞癌中的多胺。 研究肿瘤的体内药代动力学和肿瘤定位特性 携带那些硼化叶酸衍生物和脂质体的啮齿动物 多胺制剂在体外表现出高细胞摄取率 坚持。 评估这些叶酸结合物对 BNCT 的治疗效果 具有良好的体内肿瘤定位特性。

DESCRIPTION: (Applicant's Abstract) The development of boron compounds for the treatment of squamous cell carcinoma of the head and neck (SCCHN) by Boron Neutron Capture Therapy (BNCT) requires the synthesis and evaluation of non-toxic agents which selectively target these malignant cells in contrast with adjacent normal tissue and are retained intracellularly. Cell membrane receptors mediating endocytotic transport of folic acid into cells are expressed in elevated levels in a variety of human tumors. The affinity of folic acid for its cell membrane receptors and its ability to be endocytosed remains essentially unaltered when a macromolecule is covalently linked to its gamma-carboxylate function. It has been shown that large numbers of conjugates of folic acid with therapeutic agents are internalized into tumor cells that overexpress the folate receptors by receptor-mediated endocytosis and are retained intracellularly. Therefore, folic acid may be an excellent carrier for the selective delivery of boron species to SCCHN. The specific aims of this proposal are: To develop the chemical methodology to design and synthesize suitable folic acid derivatives possessing 1 to 9 carborane and polyhedral borane clusters with or without a DNA-targeting entity. To prepare folic acid conjugates with boronated starburst dendrimers using polyethylene glycol spacers as binding elements. To synthesize and incorporate boronated polyamines into a liposomal formulation using folic acid-PEG-liposomes. To determine the in vitro uptake, persistence and subcellular distribution of boronated folic acid derivatives and liposomal formulations of boronated polyamines in human squamous cell carcinoma. To study the in vivo pharmacokinetics and tumor-localizing properties in tumor bearing rodents of those boronated folate derivatives and liposomal formulations of polyamines that show high in vitro cellular uptake and persistence. To evaluate the therapeutic efficacy for BNCT of those folic acid conjugates having favorable in vivo tumor-localizing properties.