A nanoparticle prognosticator of chemotherapy outcomes

化疗结果的纳米颗粒预测器

• 批准号: 7744580
• 负责人: RUSSELL M LEBOVITZ
• 金额: $ 13.95万
• 依托单位: MARVAL BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744580
• 关键词: Abdomen; Adenocarcinoma; Adverse effects; Animals; Antitumor Response; Blood; Breast Adenocarcinoma; Cancer Model; Cardiac; Cardiotoxicity; Clinical; Clinical Trials; Contrast Media; Detection; Development; Diagnostic radiologic examination; Doxorubicin; Doxorubicin Hydrochloride Liposome; Encapsulated; Exhibits; Extravasation; Funding; Generic Drugs; Hand; Human; Image; Immune; Individual; Lead; Liposomal Doxorubicin; Liposomes; Lung; Malignant neoplasm of ovary; Mammary Neoplasms; Mammography; Measurement; Methodology; Methods; Modeling; Molecular; Morphology; Mus; Neoplasm Metastasis; Outcome; Patients; Pharmaceutical Preparations; Phase; Positioning Attribute; Production; Rattus; Roentgen Rays; Small Business Innovation Research Grant; Sterically Stabilized Liposome; Structure; Study Section; Testing; Time; Topoisomerase; Topoisomerase II; Toxic effect; Validation; Vascular Permeabilities; Work; X-Ray Computed Tomography; base; chemotherapy; foot; instrument; large scale production; mouse model; nanoparticle; nanoprobe; novel; prognostic; public health relevance; tumor; uptake

DESCRIPTION (provided by applicant): Marval Biosciences Inc. has developed a novel liposomal X-ray contrast agent (NCTX)1. With prior SBIR funding (1R43EB04700), we demonstrated facile blood pool imaging, and enabled the simultaneous imaging of cardiac and pulmonary features, something that is not possible to do with conventional contrast agents. Marval is currently developing large scale production facilities for NCTX, and has demonstrated 4 liter production of the agent. We anticipate producing NCTX at the 50L scale under GLP conditions within the next 12 months, and pursuing an IND application shortly afterwards. In a recent, highly significant discovery it was shown that NCTX can predict the outcome of chemotherapy using Stealth Liposomal Doxorubicin (SLD). NCTX consists of a clinically used Iodinated contrast agent encapsulated in a Pegylated liposome. One expects therefore, that NCTX will extravasate in tumors in the same way that SLD (e.g. Doxil(r)) does, by the so-called Enhanced Permeation and Retention (EPR) effect. In addition to the molecular effect of doxorubicin in inhibiting topoisomerase-II, the efficacy of SLD in treating a tumor is fundamentally dependent on (1) the extent of its localization in the tumor and (2) the release of the active drug from the liposomes after localization. It is well-known that the degree of tumor vasculature leakiness differs not only among same type tumors but even spatially within the same tumor. It was therefore hypothesized that the extent of extravasation of NCTX in individual tumors would be a predictor of the extravasation of SLD, and therefore of the efficacy of SLD in treating a specific tumor. To test these hypotheses, NCTX was used to image rat mammary adenocarcinomas using a clinical mammography instrument. It was demonstrated that in individual rats bearing tumors of identical size and morphology, those specific tumors that exhibited high NCTX uptake as visualized by X-ray imaging were the most susceptible to treatment by SLD. There are currently 128 ongoing clinical trials in the US (www.ClinicalTrials.gov), of Stealth Liposomal Doxorubicin (Doxil(r) and various generic equivalence candidates). Even if a small fraction of these trials are successful, one anticipates that the number of patients treated with SLD will dramatically increase in coming years. While liposomal doxorubicin does reduce the side effects of chemotherapy, it still has significant side effects of its own, including cardiotoxicity and hand-foot syndrome12. The ability to predict the efficacy of liposomal doxorubicin in treating a specific tumor, in a patient-specific manner, would therefore be of enormous clinical utility. In Phase 1 of this SBIR project therefore, we seek to develop NCTX as a prognosticator of SLD efficacy. If successful, this project will lead to a new indication for NCTX. To date, we have demonstrated the prognostication ability in a syngeneic rat mammary tumor, the MAT B-III adenocarcinoma. Yet, liposomal doxorubicin (specifically Doxil) is primarily used for Ovarian cancer. In this project, we therefore propose to test the prognostic ability of NCTX in relevant ovarian cancer mouse models. PUBLIC HEALTH RELEVANCE: Marval Biosciences Inc. has developed a novel liposomal X-ray contrast agent (NCTX)1. With prior SBIR funding (1R43EB04700), we demonstrated facile blood pool imaging, and enabled the simultaneous imaging of cardiac and pulmonary features, something that is not possible to do with conventional contrast agents. Marval is currently developing large scale production facilities for NCTX, and has demonstrated 4 liter production of the agent. We anticipate producing NCTX at the 50L scale under GLP conditions within the next 12 months, and pursuing an IND application shortly afterwards. In a recent, highly significant discovery it was shown that NCTX can predict the outcome of chemotherapy using Stealth Liposomal Doxorubicin (SLD). NCTX consists of a clinically used Iodinated contrast agent encapsulated in a Pegylated liposome. One expects therefore, that NCTX will extravasate in tumors in the same way that SLD (e.g. Doxil(r)) does, by the so-called Enhanced Permeation and Retention (EPR) effect. In addition to the molecular effect of doxorubicin in inhibiting topoisomerase-II, the efficacy of SLD in treating a tumor is fundamentally dependent on (1) the extent of its localization in the tumor and (2) the release of the active drug from the liposomes after localization. It is well-known that the degree of tumor vasculature leakiness differs not only among same type tumors but even spatially within the same tumor. It was therefore hypothesized that the extent of extravasation of NCTX in individual tumors would be a predictor of the extravasation of SLD, and therefore of the efficacy of SLD in treating a specific tumor. To test these hypotheses, NCTX was used to image rat mammary adenocarcinomas using a clinical mammography instrument. It was demonstrated that in individual rats bearing tumors of identical size and morphology, those specific tumors that exhibited high NCTX uptake as visualized by X-ray imaging were the most susceptible to treatment by SLD. There are currently 128 ongoing clinical trials in the US (www.ClinicalTrials.gov), of Stealth Liposomal Doxorubicin (Doxil(r) and various generic equivalence candidates). Even if a small fraction of these trials are successful, one anticipates that the number of patients treated with SLD will dramatically increase in coming years. While liposomal doxorubicin does reduce the side effects of chemotherapy, it still has significant side effects of its own, including cardiotoxicity and hand-foot syndrome12. The ability to predict the efficacy of liposomal doxorubicin in treating a specific tumor, in a patient-specific manner, would therefore be of enormous clinical utility. In Phase 1 of this SBIR project therefore, we seek to develop NCTX as a prognosticator of SLD efficacy. If successful, this project will lead to a new indication for NCTX. To date, we have demonstrated the prognostication ability in a syngeneic rat mammary tumor, the MAT B-III adenocarcinoma. Yet, liposomal doxorubicin (specifically Doxil) is primarily used for Ovarian cancer. In this project, we therefore propose to test the prognostic ability of NCTX in relevant ovarian cancer mouse models.

描述（由申请人提供）：Marval Biosciences Inc.开发了一种新型脂质体x射线造影剂（NCTX）1。在先前的SBIR资助（1R43EB04700）下，我们展示了简便的血池成像，并实现了心脏和肺部特征的同时成像，这是传统造影剂无法做到的。目前，Marval正在开发NCTX的大规模生产设施，并已演示了4升的生产。我们预计在未来12个月内在GLP条件下以50L的规模生产NCTX，并在不久之后寻求IND申请。最近，一项非常重要的发现表明，NCTX可以预测使用隐形脂质体阿霉素（SLD）化疗的结果。NCTX由临床使用的碘化造影剂包裹在聚乙二醇脂质体中。因此，人们预计NCTX会像SLD（如Doxil）一样通过所谓的增强渗透和保留（EPR）效应在肿瘤中外渗。除了多柔比星抑制拓扑异构酶- ii的分子作用外，SLD治疗肿瘤的疗效从根本上取决于(1)其在肿瘤中的定位程度和(2)定位后活性药物从脂质体中释放的程度。众所周知，肿瘤血管渗漏的程度不仅在同一类型的肿瘤之间存在差异，甚至在同一肿瘤内也存在空间差异。因此，我们假设NCTX在单个肿瘤中的外渗程度可以预测SLD的外渗程度，从而预测SLD治疗特定肿瘤的疗效。为了验证这些假设，使用NCTX在临床乳房x线照像仪上对大鼠乳腺腺癌进行成像。结果表明，在具有相同大小和形态的肿瘤个体中，x射线成像显示NCTX摄取高的特定肿瘤最容易受到SLD的治疗。目前，美国正在进行128项隐形脂质体阿霉素（Doxil(r)和各种通用等效候选药物）的临床试验（www.ClinicalTrials.gov）。即使这些试验中只有一小部分是成功的，人们预计，在未来几年，接受SLD治疗的患者数量将急剧增加。虽然阿霉素脂质体确实减少了化疗的副作用，但它本身仍有明显的副作用，包括心脏毒性和手足综合征。因此，能够预测多柔比星脂质体治疗特定肿瘤的疗效，以患者特异性的方式，将具有巨大的临床效用。因此，在这个SBIR项目的第一阶段，我们寻求开发NCTX作为SLD疗效的预测指标。如果成功，该项目将导致NCTX的新适应症。迄今为止，我们已经证明了在同基因大鼠乳腺肿瘤MAT B-III腺癌中的预测能力。然而，脂质体阿霉素（特别是Doxil）主要用于卵巢癌。因此，在本项目中，我们建议在相关卵巢癌小鼠模型中测试NCTX的预后能力。