Sustained, target delivery for treatment of cervical pathologies

描述（由申请人提供）：宫颈癌是由HPV感染引起的，其特征是进行性形成发育异常病变，称为宫颈上皮内瘤变（CIN）。虽然已经开发出预防宫颈癌的疫苗，但目前的疫苗成本高，仅针对三分之二的HPV毒株，并且只有在HPV感染前接种才有效。仅在美国，就有120万例 低级别CIN和20 - 30万例高级别CIN每年被诊断;然而，没有FDA批准的药物疗法可用于其治疗。对于诊断为低度CIN的女性，标准方法是“观察等待”;高度CIN的女性采用环形电切除术（LEEP）治疗。尽管有这种治疗，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病变的医学治疗选择。 项目目标与技术创新。该项目将开发含有天然化合物-特别是醉茄素A -的连续释放植入物，用于预防性治疗宫颈癌和其他宫颈病变的高危患者。该植入物将用于目标部位，有望在癌症预防和治疗方面取得重大进展。口服给药的天然化合物通常伴随有限的生物利用度，而静脉内给药的化疗药物导致血液中不期望的大峰值。聚合物植入物的发展，以提供治疗剂的连续递送，直接到达目标部位 将显著降低其有效剂量，并使通常与高口服和i.剂量。 该项目的主要目的是优化聚合物植入物（“宫颈插入物”），以在靶部位（即，子宫颈），使用大型动物模型，山羊。所描述的研究代表了必要的临床前工作，以检查颈椎植入物的潜在毒性和醉茄素A的释放速率。此外，持续局部递送癌症化学预防剂的概念是一种新颖的创新概念，有可能彻底改变高危个体的临床管理。这种新的、对病人友好的设备将是一种经济的治疗方法。此外，局部递送天然化合物的预防性治疗可减少LEEP的需要。植入物输送装置目前正在申请专利，其中一名PI（Gupta博士）是发明者。 假设和具体目标。我们假设，醉茄素A，一种三萜类化合物，它没有已知的毒性，并具有显着的抗增殖和抗病毒活性，对人宫颈癌细胞在体外和体内，当嵌入聚合物植入物，将被连续释放在目标部位延长时间，并没有组织或全身毒性与药物或聚合物材料将产生。具体目的是（1）优化聚合物宫颈插入物的配方并测定体外药物释放速率;和（2）使用大型动物（山羊）模型，测定宫颈插入物的药物释放速率、任何全身和组织毒性以及血浆、局部、周围和远端组织中的药物水平。未来的工作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批准，并对宫颈发育不良患者进行临床试验。 公共卫生相关性：该研究项目的总体目标是开发聚合物宫颈植入物（“宫颈插入物”），其可以提供对宫颈癌前病变和癌症具有治疗活性的化合物的连续释放，直接到达靶部位。当放置在子宫颈中时，这些植入物可以连续（“24/7”）输送药物数月，可能减少对癌前病变的电外科切除术的需要，并最终防止子宫颈癌的发展。这种预防性治疗仅在美国就将使数十万妇女受益，否则她们将需要外科手术。在世界范围内，这种方法的好处将更大，因为宫颈癌是仅次于乳腺癌的女性第二大常见癌症。在该试点项目中，我们将优化宫颈插入物，并使用大型动物（山羊）模型评估与植入材料和天然化合物（醉茄素A）相关的任何潜在毒性，该化合物对宫颈癌前病变/癌症具有强效抗癌活性。

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. PUBLIC HEALTH RELEVANCE: The overall goal of this research project is to develop polymeric cervical implants ("cervical inserts") that can provide continuous release of compounds with therapeutic activity against cervical pre-cancer and cancer directly to the target site. When placed in the cervix these implants can deliver drugs continuously ("24/7") for months, potentially obviate the need for electrosurgical excision of pre-cancerous lesions, and ultimately prevent the development of cervical cancer. This prophylactic treatment will benefit hundreds of thousands of women in the United States alone, who otherwise would require a surgical procedure. Worldwide, the benefits of this approach will be far greater, because cervical cancer is the second most common cancer among women after breast cancer. In this pilot project, we will optimize cervical inserts and assess any potential toxicity associated with both the implant materials and with a naturally-occurring compound (withaferin A) with potent anticancer activity against cervical pre-cancer/cancer, using a large animal (goat) model.