Chemotherapy is a major component of all pediatric medulloblastoma treatment plans. However, reports suggest that less than 1% of drugs administered intravenously reach brain tumors. One of the challenges of delivering drugs to brain tumors is the blood brain barrier (BBB), which restricts drug penetration into brain tumors. Targeted drug delivery systems and targeted interventional procedures capable of traversing the BBB could improve drug delivery into brain tumors. These targeted drug delivery systems will tremendously benefit from noninvasive imaging approaches to monitor the drug delivery process. Also critical is the need for noninvasive prognostic imaging markers, capable of predicting early tumor response or tumor resistance to therapy, following drug delivery. These imaging tools will be essential in validating the efficiency of the drug delivery process and will enable more effective patient management, by permitting the rapid selection of the most effective treatment option and dose escalation scale. These efforts will bring personalized therapeutic regimens one step closer to realization. The overall objective of this project is to develop molecular magnetic resonance imaging (MRI) biosensors capable of directly and noninvasively imaging drug delivery across the BBB and into brain tumors, and also capable of imaging early molecular changes associated with tumor response or tumor resistance to therapy. Chemical exchange saturation transfer MRI (CEST MRI), is a relatively new MRI technique which shows promise for imaging organic molecules by saturating specific exchangeable protons (such as amine, amide and hydroxyl protons) on the molecules of interest, with defined radiofrequency pulses. Although, CEST MRI is based on a magnetic resonance spectroscopic (MRS) technique, it is several orders of magnitude more sensitive than MRS. We postulate that the labile protons of some DNA alkylating agents generate a pH-dependent CEST MRI contrast signal that can be used to monitor their delivery to brain tumors, and also to report on early molecular tumor changes in response to therapy. This project will be achieved through two specific aims.
In aim 1, we will screen six DNA alkylating agents and evaluate each drug?s potential to act as a CEST MRI biosensor. From this aim we will obtain a signature CEST MRI profile for each drug, which will enable us to detect the drug in tumors after drug delivery.
In aims 2, we will evaluate the feasibility of using the signature CEST MRI contrast profiles of the respective biosensors to detect drug delivery during a targeted interventional procedure and also from targeted drug nanocarriers. We will also evaluate the feasibility of using the pH-dependent CEST signal of the biosensors to image early tumor response or tumor resistance to therapy, in vivo. All CEST MRI results will be validated with bioluminescence imaging, immunohistochemistry using drug- specific antibodies, histology, multi-parametric MRI and positron emission tomography, using [18F] 2-fluoro-2- deoxy-D-glucose. This project will significantly advance the development of more effective and less toxic treatment plans for pediatric medulloblastoma patients.
In this project, we will develop molecular magnetic resonance imaging biosensors capable of directly and noninvasively imaging drug delivery across the blood brain barrier and into brain tumors, and also capable of imaging early molecular changes associated with tumor response or tumor resistance to therapy.
