Predicted Drug Concentration Distribution Using a Validated Finite Element Model in Locally Advanced Breast Cancer

摘要

The long-term objective of this study is to develop methods to predict the concentration-distribution of liposomally encapsulated doxorubicin in locally advanced breast cancer. Chemotherapy is frequently ineffective in shrinking these tumors to the point that they can be removed due to heterogeneity in drug delivery. One method to improve the uniformity of drug delivery is use local hyperthermia with thermally sensitive liposome, which releases their contents rapidly under local hyperthermia. In pre-clinical studies, this formulation was superior to non-thermally sensitive liposomes with HT. The difference was directly proportional to the tissue drug concentration. We have developed a novel MR imageable liposome formulation. This liposome contains the chemotherapeutic drug, but also the MR contrast agent manganese. We have developed and validated a MR compatible heating device and obtained temperature distributions. We have shown the uptake of the liposomes and their content release under hyperthermic conditions using MRS in a rodent model. The calculated concentration within the tumor using MRS has been validated with direct tissue measurements by histology sections using fluorescence microscopy. These measurements demonstrate that MRI can be used to non-invasively measure the concentration distribution of chemotherapy drugs delivered with these liposomes. This ability to monitor liposomal/drug delivery and/or content release in real time could allow for development of treatment strategies to improve intratumoral homogeneity of drug concentration presumably increasing treatment efficacy.