Novel Oral Trojan-Horse Agents for Osteolytic Cancer

描述（由申请人提供）：双膦酸盐已成为治疗骨转移和癌症骨溶解的强大新武器。这些代谢稳定的焦磷酸盐模拟物结合在骨中，并通过各种生化途径与破骨细胞和成骨细胞相互作用，以阻止骨吸收，抑制肿瘤细胞粘附和细胞外基质的侵袭。尽管双膦酸盐在肿瘤学中具有既定的疗效，但其主要缺点是由于口服生物利用度差，必须通过静脉输注给药。在这个I期SBIR/FLAIR提案中，我们的目标是通过开发一种药物递送策略来提高现有fda批准的双膦酸盐的口服可用性，该策略针对已知的肠道载体系统，其结构与载体的天然底物基本相同-即特洛伊木马前药。我们认为，这些特洛伊木马前药中的一种或多种会劫持肠道载体并有效地将隐藏的二膦酸盐运输到细胞中，然后隐藏的二膦酸盐将从前药中释放到全身循环或作用部位。口服双膦酸盐可避免静脉注射政府将的必要性，立即使目前接受双膦酸盐治疗的骨转移肿瘤患者受益，并可能允许未来测试高剂量/高频口服给药方案。

DESCRIPTION (provided by applicant): The bisphosphonates have emerged as powerful new weapons in the therapeutic arsenal employed to treat bone metastases and cancer osteolysis. These metabolically stable pyrophosphate mimetics incorporate in bone and interact with osteoclasts and osteoblasts through various biochemical pathways to prevent bone resorption and inhibit tumor cell adhesion and invasion of the extracellular matrix. Despite their established efficacy in oncology, a major disadvantage of bisphosphonates is that they must be administered by intravenous infusion because of their poor oral bioavailability. In this Phase I SBIR/FLAIR proposal, we aim to enhance the oral availability of existing FDA-approved bisphosphonates by developing a drug delivery strategy that targets a known intestinal carrier system with a bisphosphonate prodrug whose structure is substantially identical to the native substrate of the carrier- that is, a Trojan-Horse prodrug. We propose that one or more of these Trojan-Horse prodrugs will hijack the intestinal carrier and efficiently transport the cloaked bisphosphonate into the cell, whereupon the cloaked bisphosphonate will be released from the prodrug in the general circulation or at the site of action. An orally available bisphosphonate that obviates the necessity for intravenous administration would immediately benefit oncology patients with bone metastases currently treated with bisphosphonates, and may permit the future testing of high-dose/high-frequency oral delivery protocols.