SYNTHESIS AND EVALUATION OF BORONATED FOLATES FOR BNCT

描述：(申请人摘要)硼化合物的发展 头颈部鳞状细胞癌的硼治疗 中子俘获疗法(BNCT)要求合成和评价 相比之下，选择性靶向这些恶性细胞的无毒药物 与邻近的正常组织连接，并保留在细胞内。细胞膜 介导叶酸内吞转运到细胞内的受体有 在多种人类肿瘤中表达水平升高。的亲和力 叶酸对其细胞膜受体的作用及其内吞能力 当大分子共价连接到其上时基本上保持不变 伽玛-羧酸盐功能。已经证明，大量的共轭分子 含有治疗剂的叶酸被内化到肿瘤细胞中 通过受体介导的内吞作用过表达叶酸受体 保留在细胞内。因此，叶酸可能是一种很好的载体 硼物种向SCCHN的选择性输送。这样做的具体目的是 建议包括： 发展化学方法学来设计和合成合适的叶酸 具有1-9个碳硼烷和多面体硼烷簇合物的酸衍生物 不管有没有DNA靶向实体。 用含硼树枝状大分子制备叶酸偶联物 作为结合元件的聚乙二醇间隔体。 合成含硼多胺并将其加入脂质体中 使用叶酸-聚乙二醇脂质体。 测定阿司匹林的体外摄取、持久性和亚细胞分布 硼化叶酸衍生物及其脂质体制剂的研究 人鳞状细胞癌中的多胺。 肿瘤体内药代动力学及肿瘤定位特性研究 含硼叶酸衍生物和脂质体的啮齿动物 体外细胞摄取率高的多胺制剂和 坚持不懈。 叶酸结合物治疗BNCT的疗效评价 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.