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Novel anti-tumor therapy with liposomal glucocorticoids: MRI monitoring of drug delivery
Ewelina Kluza1, Sin Yuin Yeo1, Daisy W. J. van der Schaft1,2, Willem Mulder3, Raymond M. Schiffelers4, Gert Storm4, Gustav J. Strijkers1 and 1Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; 2 Soft Tissue Biomechanics and Engineering, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; 3 Translational and Molecular Imaging Institute, Department of Radiology, Mount Sinai School of Medicine, New York, USA; 4 Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands High daily doses of corticoid drugs can effectively inhibit tumor growth [1]. Unfortunately the acute side effects make prolonged therapy impossible. In order to overcome the toxicity, a soluble prednisolone disodium phosphate (PLP) was encapsulated into long circulating liposomes (PLP-L) [2]. This novel treatment was found to effectively inhibit tumor growth at low weekly doses [2].The observed anti-tumor effects have been attributed to the local anti-angiogenic activity of prednisolone phosphate [3]. This implies that the magnitude of the therapeutic outcome depends on the efficacy of drug-carrying liposomes to reach the tumor site. In order to verify this hypothesis, in the present study, we investigated the correlation between the intratumoral accumulation of PLP-L and the post-treatment tumor volumes. For this purpose, treatment and imaging capabilities were combined in one agent by incorporating Gd-DTPA-bis(stearylamide) into the lipid membrane of drug-carrying liposomes (Gd-PLP-L). This modification enabled the delivery of Gd-PLP-L to be noninvasively monitored with Magnetic Resonance Imaging (MRI). Moreover, we used MRI for therapy monitoring, since it can provide anatomical and functional information about therapy-induced changes in tumor. In the present study, T1-weighted imaging and T1 mapping were applied to obtain quantitative information about the accumulation rate of Gd-PLP-L at early (up to 2h) and late (24h) time points after administration. We used T2- and diffusion weighted images obtained at the start and at the end of the treatment to monitor tumor growth. In order to bring further insights into the therapy mechanism, we investigated the effects of Gd-PLP- L on the white blood cell level, which is a key marker of systemic activity of prednisolone phosphate. Treatment with Gd-PLP-L significantly inhibited tumor growth, in similar extent as PLP-L. We were able to monitor the delivery of Gd-PLP-L to the tumor with MRI. Contradictory to expectations, we found no correlation between the efficacy of tumor growth inhibition and the MRI parameters, used as quantitive markers of intratumoral Gd-PLP-L. This implies that the observed anti-tumor effects may not originate exclusively from local activity of prednisolone phosphate in the tumor. However, we found a strong correlation between pre- and post-treatment tumor volumes, which suggests that the post-treatment tumor volume might not be an appropriate marker of therapy outcome. Interestingly, we observed a dramatic decrease in white blood cell levels induced by Gd-PLP-L. Considering the involvement of inflammatory/immune response elements in the stimulation of tumor angiogenesis, the observed strong anti-immune effects may play an important role in tumor growth inhibition. References [1] Folkman J, Science, 1983 [2] Raymond M. Schiffelers, Neoplasia, 2005 [3] Manuela Banciu, Journal of Controlled Release, 2006


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