Noninvasive Monitoring of In Vivo Drug Release

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DESCRIPTION (provided by applicant): In targeted cancer chemotherapy, controlled release is one of the key strategies to increase the efficacy and to reduce systemic side effects. In this project, we have focused attention on a unique feature of magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) to monitor drug release and subsequent drug distribution noninvasively. The long-term goal of this project is to understand in vivo drug release characteristics of anticancer drug-loaded nanocarriers, and thus to elucidate the correlation between anticancer activity and release characteristics of anticancer drug- loaded nanocarriers. We hypothesize that MRI/MRSI can distinguish drug molecules encapsulated in and released from nanocarriers, and allow for the long-term monitoring of sustained release formulation unlike radionuclide modalities which require radiotracers with short half-life. SCID mice bearing MCF-7 xenografts will be used as human breast cancer model, and nanocarriers containing 5-FU, GdDTPA and superparamagnetic iron oxide nanoparticles (SPIO) will be administered intravenously. Bruker 9.4T horizontal bore spectrometer will be used for MRI/MRSI experiments. We will use a multislice multiecho sequence with different repetition delays for MRI and will acquire 19F spectra for MRSI of 5-FU. We will repeat MRI/MRSI experiments at different time points following injection of nanocarriers. Intact nanocarriers will have broad resonance line for 5-FU and generate negative contrast enhancement due to the T2/T2* effect of SPIO. Encapsulated GdDTPA and 5-FU will diffuse once they released while SPIO diffusion is much shorter range due to their large sizes (40- 70 nm). GdDTPA/5-FU that has diffused beyond the negative T2 enhancement region of SPIO will generate positive contrast enhancement and a narrow resonance line of free 5-FU by MRI/MRSI, respectively. We also expect that release pattern of GdDTPA and 5-FU will be identical and will show similar distribution pattern in the tumor. In addition, we intend to compare in vivo release pattern to in vitro release characteristics. Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick end-labeling (TUNEL) assay of excised tumor will tell us the correlation between drug distribution and therapeutic activity. Therefore, we anticipate that MRI/MRSI can noninvasively monitor drug release and subsequent intratumoral drug distribution. In addition, histochemical analysis will validate MRI/MRSI images and further elucidate the correlation between drug release characteristics and therapeutic activity against cancer, and eventually estimate the therapeutic effects from drug release/distribution in the tumor by MRI/MRSI. PUBLIC HEALTH RELEVANCE In targeted cancer chemotherapy, controlled release is one of the key strategies to increase the efficacy and to reduce systemic side effects. To monitor drug release and subsequent intratumoral drug distribution noninvasively, we have focused attention on a unique feature of magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI). We anticipate that our innovative technique using MRI/MRSI will provide a noninvasive monitoring of drug release and subsequent distribution in the tumor.