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质溶解的强大新武器。 这些代谢稳定的焦磷酸盐模拟物掺入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，以防止骨吸收并抑制肿瘤细胞粘附和细胞外基质的侵袭。 尽管它们在肿瘤学中具有确定的功效，但双膦酸盐的主要缺点是它们必须通过静脉输注给药，因为它们的口服生物利用度差。 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利用度，该药物递送策略靶向具有双膦酸盐前药的已知肠载体系统，该双膦酸盐前药的结构与载体的天然底物（即特洛伊木马前药）基本相同。 我们提出，一种或多种这些特洛伊木马前药将劫持肠道载体，并有效地运输隐形双膦酸盐进入细胞，于是隐形双膦酸盐将在全身循环或作用部位从前药中释放。 一种口服双膦酸盐，避免了静脉给药的必要性，将立即受益于目前用双膦酸盐治疗的骨转移肿瘤患者，并可能允许未来测试高剂量/高频率口服给药方案。

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.