A nanoparticle prognosticator of chemotherapy outcomes

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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.