Sustained, target delivery for treatment of cervical pathologies

持续、靶向递送治疗宫颈病变

• 批准号: 8511586
• 负责人: RAMESH C GUPTA
• 金额: $ 4.51万
• 依托单位: 3P BIOTECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511586
• 关键词: Affect; Animal Model; Animals; Ashwagandha; Biological Availability; Biopsy; Blood; Breast; Cancer cell line; Cancerous; Cervical; Cervical Intraepithelial Neoplasia; Cervical dysplasia; Cervix Neoplasms; Cervix Uteri; Cessation of life; Chemopreventive Agent; Clinical Management; Clinical Research; Clinical Trials; Data; Data Analyses; Development; Devices; Diagnosis; Distal; Dose; Drug Delivery Systems; Drug Formulations; Dysplasia; Economics; Excision; Exhibits; FDA approved; Future; Goals; Goat; Hormones; Human; Human Papillomavirus; Human papilloma virus infection; Implant; In Vitro; Individual; Intravenous; Legal patent; Lesion; Loop electrosurgical excision procedure; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measures; Medical; Medicinal Plants; Modeling; Operative Surgical Procedures; Oral; Organ; Pancreas; Pathology; Patient observation; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pilot Projects; Plants; Plasma; Preparation; Procedures; Prophylactic treatment; Prostate; Reaction; Recurrence; Reporting; Research; Research Project Grants; Site; Spermatocidal Agents; Staging; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; United States; Vaccination; Vaccines; Vagina; Viral; Viral Physiology; Vulva; Withania; Woman; Work; anticancer activity; cancer cell; cancer prevention; cancer therapy; cervical cancer prevention; commercial application; controlled release; cost; high risk; implant material; implantation; in vivo; innovation; malignant breast neoplasm; meetings; mortality; novel; pre-clinical; prevent; screening; targeted delivery; technological innovation; tumor; tumor progression; tumor xenograft

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.

描述（由申请人提供）：由HPV感染引起的宫颈癌的特征是发育不良病变的进行性形成，称为宫颈上皮内肿瘤（CIN）。尽管已经开发了预防宫颈癌的疫苗，但目前的疫苗具有很高的成本，仅靶向HPV菌株的三分之二，并且仅在HPV感染之前给药时才有效。仅在美国，有120万例 每年诊断出低级CIN和0.2-030万例高级CIN；但是，没有FDA批准的药物疗法可用于治疗。对于被诊断出患有CIN的女性，标准方法是“注意等待”；具有高级CIN的女性通过循环电外科切除程序（LEEP）处理。尽管进行了这种处理，但仍会出现高级CIN复发率。需要的是在CIN的早期阶段解决这些病变的医疗选择。 项目目标和技术创新。该项目将开发连续释放的植入物，其中包含天然化合物 - 特别是用大化合物A-用于预防性治疗宫颈癌和其他宫颈病理学的高危患者。在目标部位使用的植入物有望在预防癌症和治疗方面有重大进展。口服施用的天然化合物通常伴有有限的生物利用度，而化学治疗剂则静脉内给药会导致血液中不良的大峰值。聚合植入物的开发，以直接将治疗剂递送到目标部位 将大大降低其有效剂量，并最大程度地减少与高口服和I相关的毒性问题。 v。剂量。 该项目的主要目的是使用大型动物模型，山羊在目标位点（即，子宫颈）在目标部位（即，子宫颈）在目标位点（即，子宫颈）释放的聚合物植入物（“颈插入”）。研究描述的是临床前的必要努力，以检查颈植入物中毒素A的潜在毒性和释放速率。此外，癌症化学预防持续局部交付的概念是一种新颖而创新的概念，有可能彻底改变高风险个体的临床管理。新的，对患者友好的设备将是一种经济待遇。此外，在本地递送的天然化合物中预防性治疗可能会消除对LEEP的需求。该植入物交付设备目前处于待处理的专利之下，其中一位PI（Gupta博士）为发明家。 假设和特定目的。我们假设三萜类化的毒蛋白A，它没有已知的毒性，并且在聚合物植入物中嵌入在聚合物植入物中时，针对人类宫颈癌细胞的抗增殖和抗病毒活性将连续释放在目标部位，而无需与材料相关的材料或系统性的毒性或系统的毒性或系统或系统的质量相关。具体目的是（1）优化聚合物宫颈插入物的配方，并在体外确定药物释放的速率； （2）使用大动物（山羊）模型，确定从颈插入物中释放的药物速率，任何全身性和组织毒性以及血浆中的药物水平，以及局部，周围和远端组织。未来的努力将涉及检查长期释放的长期药物以及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。

项目成果

Development of a goat model for evaluation of withaferin A: Cervical implants for the treatment of cervical intraepithelial neoplasia.

开发用于评估withaferin A的山羊模型：用于治疗宫颈上皮内瘤变的宫颈植入物。

• DOI: 10.1016/j.yexmp.2017.11.008
• 发表时间: 2017
• 期刊: Experimental and molecular pathology
• 影响因子: 3.6
• 作者: Sherwood,LeslieC;Aqil,Farrukh;Vadhanam,ManickaV;Jeyabalan,Jeyaprakash;Munagala,Radha;Hoetker,David;Srivastava,Sanjay;Singh,InderP;Cambron,Scott;O'Toole,Martin;Spencer,Wendy;Parker,LynnP;Gupta,RameshC
• 通讯作者: Gupta,RameshC