Imaging Nose-to-brain Drug Delivery to Brain Tumors Using Multiple CEST MRI Contrast

Project: Research

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Description

This study will develop a non-invasive multiple-contrast imaging platform to track nose-to-brain drug delivery for monitoring treatment and improving drug availability in the brain. Low drug availability due to the presence of blood-brain barrier (BBB) is a challenge in current brain cancer treatments. This is particularly the case for treating the malignant brain tumors, e.g. glioblastoma multiforme (GBM), which has a high tumor recurrence. Intranasal drug delivery has demonstrated benefits in brain cancer patients in clinical trials, including those with GBM1,2. To monitor both drugs and drug carriers, a non-invasive, multiple-contrast imaging platform is urgently required to monitor the delivered dose and refine treatments. Based on our recent study of MRI-detectable mucus-penetrating liposomes3,4, we will develop a liposome-based drug delivery system to efficiently deliver and image drug delivery to the brain via intranasal administration, which can bypass the BBB. The goal is to monitor both liposome and drug simultaneously to assess the availability and distribution of chemotherapeuticsin vivo. We will investigate this image-guided drug delivery platform using Chemical Exchange Saturation Transfer (CEST) MRI and explore the use of multiple-contrast to evaluate therapeutic efficacy in brain tumors. Our hypothesis is thatmucus-penetrating liposomes (MPLs) will delivery chemotherapeutics to the brain via intranasal administration, and multiple-contrast CEST-MRI will enables the imaging of both liposomes and chemotherapeutics non-invasively and simultaneously for treatment evaluations. In our preliminary studies, we demonstrated for the first time that CEST-MRI can sensitively monitor the MPLs after local vaginal delivery3. Similarly, the nasal cavity has a mucus lining; hence drugs must be able to penetrate this mucus barrier to make their way to the brain5. Our results demonstrated that after the intranasal administration of our new MPLs, we were able to observe dual CEST contrast in the rodent brain6-8. Moreover, only the MPLs (but not the control liposomes) can be detected in the brain8. Our pilot study showed that chemotherapeutics, such as methotrexate (MTX) and gemcitabine (Gem), have inherent CEST contrast9,10, and liposomes have unique CEST contrast too11, i.e. multiple-contrast imaging of drugs at around 2.2 ppm, liposomes at -3.4 ppm, and tumor responses at 3.5 ppm (a well known CEST contrast for tumor assessment17,24). Collectively, our preliminary results strongly suggested that the new MPLs could enable imaging of chemotherapeutics to determine their site of delivery, concentration and biodistribution simultaneously after intranasal administration. Tracking drug delivery in patients is necessary, and we anticipate that our molecular imaging platform will be capable of evaluating the concentration of drugs delivered and predicting therapeutic outcomes, thereby yielding a more precise assessment of drug efficacy and guiding drug development. In this proposed study, we will develop a multiple-contrast imaging approach with enhanced intranasal drug delivery to the brain, and to image the amount of drug delivered to guide treatments. First, we will develop and optimize liposome formulations to provide a high loading of drugs and high mucus penetration efficiency, importantly CEST-detectable. Second, we will image and correlate the CEST contrast with the number of liposomes and intraliposomal chemotherapeuticsin vitro, and the cytotoxicity of drug-loaded MPLs. Finally, we will image the drug distribution in the brain using CEST-MRI (at 2.2, 3.5 and -3.4 ppm) to evaluate the percentage of dose delivered to the mouse brain tumor. We aim to analyze the therapeutic outcomes in five cohorts of mice using histology. Neuropathology will then be applied to correlate with the CEST-MRI findings. This study will provide a non-invasive monitoring of intranasal drug delivery to the brain without additional labeling of drugs, an approach applicable to both preclinical drug development and clinical evaluation. 

Detail(s)

Project number9043305
Grant typeGRF
StatusNot started
Effective start/end date1/01/23 → …