Optimizing ablation of cervical precancer with ethyl cellulose ethanol to enable translation to women in low and middle-income countries

摘要 宫颈癌每年影响全世界50万妇女的生活，其中一半以上的妇女死亡。 在富裕国家广泛使用的预防性解决方案对于医疗服务不足的国家来说并不实用。 由于维持这些解决方案所需的尖端技术和专门知识，因此，替代 需要采用低成本、简单易用的技术来预防宫颈癌。我们的愿景是 制定在中低收入国家有效的高质量、低成本干预措施 解决目前预防宫颈癌解决方案的不足。卡拉健康基金会是 开发必要的工具，以帮助实现世卫组织在未来100年消除宫颈癌的指标。 在快速通道SBIR资助（R44 CA 240019）下，我们正在开发床旁筛查工具， 诊断.然而，如果出现以下情况，筛查和诊断本身不会导致宫颈癌死亡率下降， 获得护理点治疗的机会仍然有限。而环形电外科切除术（LEEP）是 冷冻疗法是高收入环境中最广泛使用的治疗方法，但冷冻疗法更常用于中低收入国家。最近， 热凝术已被接受用于宫颈癌前病变的消融，因为它不需要消耗品 （持续供应加压液氮用于冷冻治疗）或稳定的电源（用于LEEP）。然而，在这方面， 热凝固受到生物热传递的限制，因此其可以达到的坏死深度也受到限制。发展 作为热凝术的补充治疗方法，我们第一阶段SBIR资助的目标是建立 一种基于普遍存在的药剂乙醇的控制递送的可注射低成本消融疗法， 癌症前期具体来说，我们开发了一种新的配方乙醇使用聚合物称为乙基纤维素（EC） 作为限制脱靶毒性的缓释凝胶和自动注射器， 感兴趣的区域。展望未来，我们的第二阶段SBIR赠款的目标是开发测试版的 自动注射器，开发EC-乙醇的包装和质量控制指标，并评估组合 对子宫颈连续应用EC-乙醇消融和热凝的治疗是协同的 并增强功效。这项工作将包括以下具体目标：1）评估可用性和可重复性 2）建立EC-乙醇稳定性和效力测试计划， 发布标准; 3）评估连续EC-乙醇消融和热凝的安全性和有效性 与单一疗法相比;以及4）评估单一疗法的临床工作流程和人群健康影响，以及 组合疗法

Abstract Cervical cancer affects the lives of half a million women worldwide each year, and over half of these women die. Preventative solutions that are widely used in wealthy countries are not practical for use in medically underserved regions due to sophisticated technologies and expertise needed to sustain these solutions. Thus, alternative protocols that employ low-cost, simple-to-use technologies are needed to prevent cervical cancer. Our vision is to develop high quality, low-cost interventions that will be effective in low and middle-income countries (LMICs) to address shortcomings of current solutions for cervical cancer prevention. The Calla Health Foundation is developing the tools needed to help meet the WHO metrics for cervical cancer elimination in the next 100 years. Under fast track SBIR funding (R44CA240019), we are developing tools for point-of-care screening and diagnosis. However, screening and diagnosis alone will not lead to decreases in cervical cancer mortality if access to point-of-care treatment remains limited. While Loop Electrosurgical Excision procedure (LEEP) is the most widely used treatment in high-income settings, cryotherapy is more commonly used in LMICs. Recently, thermocoagulation has gained acceptance for ablation of cervical pre-cancer as it does not require consumables (continuous supply of pressurized liquid nitrogen for cryotherapy) or a stable power supply (for LEEP). However, thermocoagulation is limited by bioheat transfer and therefore the depth of necrosis it can achieve. To develop a complementary therapeutic approach to thermocoagulation, the goal of our Phase I SBIR grant was to establish an injectable low-cost ablative therapy based on controlled delivery of a ubiquitous agent, ethanol to treat cervical pre-cancer. Specifically, we developed a new formulation of ethanol using a polymer called ethyl cellulose (EC) to act as a slow-release gel limiting off target toxicity and an automated injector to reliably deliver ethanol into the region of interest. Moving forward, the goal of our Phase II SBIR grant is to develop beta versions of the automated injector, develop packaging and quality control metrics for EC-ethanol, and assess if a combinatorial therapy in which sequential EC-ethanol ablation and thermocoagulation are applied to the cervix is synergistic and enhances efficacy. This work will include the following specific aims: 1) evaluate usability and repeatability of hand-held injectors for EC-ethanol delivery; 2) establish EC-ethanol stability and potency testing plan and release criteria; 3) assess safety and efficacy of sequential EC-ethanol ablation and thermocoagulation compared to monotherapies; and 4) assess clinical workflow and population health impact of monotherapies and combinatorial therapy.