Sustained, target delivery for treatment of cervical pathologies

描述(申请人提供)：宫颈癌是由HPV感染引起的，其特征是进行性形成的异常增生性病变，称为宫颈上皮内瘤变(CIN)。尽管已经开发出预防宫颈癌的疫苗，但目前的疫苗成本很高，只针对三分之二的HPV毒株，而且只有在感染HPV之前接种才有效。仅在美国，就有120万起 每年诊断出低级别CIN和高级别CIN的病例分别为200-30万例；然而，目前还没有FDA批准的药物治疗方法。对于诊断为低度CIN的女性，标准的治疗方法是“警惕等待”；高度CIN的女性则接受环状电切手术(LEEP)治疗。尽管进行了这种治疗，高级别CIN的复发率仍然很高。需要的是在CIN的早期阶段解决这些损害的药物治疗选择。项目目标和技术创新。该项目将开发持续释放植入物，其中包含一种天然化合物--特别是与黄素A--用于预防治疗患有宫颈癌和其他宫颈疾病的高危患者。将在目标部位使用的植入物有望在癌症预防和治疗方面取得重大进展。口服天然化合物往往伴随着有限的生物利用度，而静脉注射化疗药物会导致血液中不受欢迎的大峰值。聚合物植入物的发展，可将治疗剂直接连续输送到靶点 将大大降低其有效剂量，并将通常与高口服和静脉注射剂量相关的毒性问题降至最低。该项目的主要目标是利用大型动物模型山羊，优化聚合物植入物(“宫颈植入物”)，以在目标部位(即，宫颈)连续(“24/7”)释放维他命A。所描述的研究代表了必要的临床前努力，以检查潜在的毒性和从宫颈植入物中的威达菲A的释放速率。此外，癌症化学改良剂持续局部给药的概念是一个新颖和创新的概念，有可能彻底改变高危个体的临床管理。这种新的、对患者友好的设备将是一种经济的治疗方法。此外，使用当地提供的天然化合物进行预防性治疗可能会消除LEEP的必要性。植入物输送装置目前正在申请一项专利，其中一名PI(古普塔博士)是发明者。假设和具体目标。我们假设，在铁蛋白A中，一种三萜类化合物，在体外和体内对人宫颈癌细胞具有显著的抗增殖和抗病毒活性，但没有已知的毒性，当嵌入到聚合物植入物中时，将在目标部位持续释放较长时间，并且不会产生与药物或聚合物材料相关的组织或系统毒性。具体目的是(1)优化聚合物宫颈植入物的处方并测定其体外释药速率；(2)利用大动物(山羊)模型，测定宫颈植入物的释药速率、全身和组织毒性，以及药物在血浆、局部、周围和远端组织中的浓度。未来的努力将包括检查更长期的药物释放和潜在的长期或延迟毒性，获得FDA的批准，并对宫颈发育不良患者进行临床试验。

DESCRIPTION (provided by applicant): Cervical cancer, which is caused by HPV infection, is characterized by the progressive formation of dysplastic lesions, known as cervical intraepithelial neoplasia (CIN). Although vaccinations for the prevention of cervical cancer have been developed, the current vaccine has a high cost, targets only two-thirds of HPV strains, and is effective only when administered prior to HPV infection. In the U.S. alone, 1.2 million cases of low-grade CIN and 0.2-0.3 million cases of high-grade CIN are diagnosed annually; yet, no FDA- approved drug therapies are available for its treatment. For women diagnosed with low-grade CIN, the standard approach is "watchful waiting;" women with high-grade CIN are treated with the loop electrosurgical excision procedure (LEEP). Despite this treatment, a significant recurrence rate of high-grade CIN occurs. What is needed is a medical treatment option for resolving these lesions during the early stages of CIN. Project Goal and Technological Innovation. This project will develop continuous-release implants, containing a natural compound - specifically withaferin A - for the prophylactic treatment of high-risk patients with cervical cancer and other cervical pathologies. The implant to be used at the target site, promises a significant advance in cancer prevention and treatment. Natural compounds administered orally are often accompanied by limited bioavailability while chemotherapeutics administered intravenously result in undesirable large spikes in the blood. The development of polymeric implants to provide continuous delivery of therapeutic agents directly to the target site would substantially lower its effective dose, and minimize toxicity concerns generally associated with high oral and i. v. doses. The main objective of this project is to optimize polymeric implants ("cervical inserts") for continuous ("24/7") release of withaferin A at the target site (ie., the cervix) using a large animal model, the goat. The studies described represent the necessary pre-clinical efforts to examine potential toxicity and rate of release of withaferin A from the cervical implants. In addition, the concept of continuous local delivery of cancer chemopreventives is a novel and innovative concept that has the potential to revolutionize the clinical management of high-risk individuals. The new, patient-friendly device would be an economic treatment. Furthermore, prophylactic treatment with natural compounds delivered locally may obviate the need for LEEP. The implant delivery device is currently under a pending patent, with one of the PIs (Dr. Gupta) as the inventor. Hypothesis and Specific Aims. We hypothesize that withaferin A, a triterpenoid, which has no known toxicity and has significant antiproliferative and anti-viral activities against human cervical cancer cells in vitro and in viv, when embedded in polymeric implants, will be released continuously at the target site for extended periods, and that no tissue or systemic toxicity associated with either the drug or the polymeric materials will be produced. The specific aims are to (1) optimize the formulation of polymeric cervical inserts and determine rate of drug release in vitro; and (2) using a large animal (goat) model, determine, the rate of drug release from cervical inserts, any systemic and tissue toxicity, and the levels of the drug in plasma, and local, surrounding and distal tissues. Future efforts will involve examining still longer-term drug release and potential longer-term or delayed toxicity, obtaining FDA approval, and conducting a clinical trial with cervical dysplasia patients.