Targeting the chondrosarcoma extracellular matrix for drug delivery

描述(申请人提供)：软骨肉瘤是第二种最常见的骨原发肿瘤，在美国80岁以上人口中发病率为每百万人8例。研究，特别是对乳腺癌的研究，在通过化疗和放射治疗减少疾病方面取得了长足的进步。然而，手术切除仍然是治疗软骨肉瘤的唯一可行的选择。必须确定新的治疗方案，以改善患者的预后并降低与疾病相关的死亡率。对于最具侵袭性的软骨肉瘤，IV级，肺转移导致80%的患者在确诊后5年内死亡。在这里，我们建议制造新的化疗药物的季铵类似物。氨基结构的正电荷将允许靶向软骨肉瘤的带负电荷的软骨基质。我们的初步结果表明，我们的新型化疗药物在动物模型中对软骨肉瘤细胞具有很强的活性。在这一阶段，我们和爱荷华大学的合作伙伴们试图展示治疗这种疾病的可行性。具体地说，我们提出了两个目标来实现这一目标：1)合成我们的高效抗癌剂的两个新的季铵类似物；2)在细胞培养和软骨肉瘤动物模型中测试它们。我们相信，这一策略很有可能成功地将一种新的药物推向这种孤儿疾病的临床。

DESCRIPTION (provided by applicant): Chondrosarcoma is the second most common primary tumor of the bone having an incidence of 8 per million people in the US population over age 80. Research, particularly on cancer of the breast, has made great strides in curtailment of disease with chemo and radiation therapy. However, surgical removal remains the only viable option for the treatment of chondrosarcoma. New treatment options must to be identified to improve patient outcomes and decrease mortality associated with disease. For the most aggressive chondrosarcoma tumor, a grade IV, metastasis to the lung results in death in 80% of patients within 5 years of diagnosis. Here we propose to make quaternary ammonium analogues of novel chemotherapeutics. The positive charge of the ammonium substructure will allow targeting to the negatively charged cartilaginous matrix of chondrosarcoma. Our preliminary results indicate that our novel chemotherapeutic has highly potent activity against chondrosarcoma cells in animal models. In this phase I STTR application Terpenoid Therapeutics and our partners at the University of Iowa seek to show feasibility of treating this disease. Specifically, we propose two aims to accomplish this goal: 1) synthesize two novel quaternary ammonium analogues of our highly potent anti-cancer agents; and 2) test them in cell culture and animal models of chondrosarcoma. We believe that this strategy has a high likelihood of success in advancing a novel agent to the clinic for this orphan disease.