Abstract SNACC-53

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Transient Cerebral Hypoperfusion Assisted Intraarterial Delivery of Mitoxantrone in C6 Glioma Bearing Rats

1Joshi S, 1Singh-Moon R, 1Wang M, 2Bigio I
1College of Physicians and Surgeons, Columbia University, New York, NY, USA; 2Boston University, Boston, MA, USA

Introduction: Mitoxantrone (MTO) is an antineoplastic drug that is locally effective for glioma treatment.(1) Although simulations and experimental data show a significant improvement in intraarterial (IA) drug delivery with the reduction of cerebral blood flow, we failed to observe any such improvement in IA MTO deposition in rabbits.(2-4) Subsequent studies revealed that the uptake of MTO was a function of blood brain barrier (BBB) permeability and that hyperosmotic BBB disruption was unreliable in this species.(5, 6) Since the BBB is impaired around brain tumors we re-evaluated IA mitoxantrone delivery in C6 glioma bearing Sprague Dawley rats.
Methods: Preliminary dose response studies with IA-TCH (IA injection during transient cerebral hypoperfusion) drug delivery were conducted on healthy rats with hyperosmotic BBB disruption with intracarotid mannitol. Using diffuse reflectance spectroscopy (DRS) we determined the brain tissue concentrations of MTO after injection of 0.1,0.25,0.5 and 1 mg of MTO, intravenously (IV), IA and with IA-TCH. Surgical preparation and technical details of the DRS method are available in our earlier publications.(4, 7) Next, we injected healthy rats with 1 million C6 cells that resulted in significant tumor development after 1 week. We then evaluated 0.5 mg IA-TCH MTO delivery in the tumor bearing hemisphere and contralateral brain. Six tumor bearing rats were sacrificed 5 min after injection and 6 were sacrificed 4 hrs after injection after letting the animals recover form anesthesia.
Results: IA-TCH drug delivery was well tolerated by the animals and resulted in significant improvements in MTO delivery with all doses. Significant uptake of MTO was clearly evident in the tumor tissue when compared to the contralateral brain, at both 5 mins and 4 hrs after injection, Figure. Further, tissue fluorescence imaging with confocal microscopy of histological sections also revealed robust uptake by glioma cells.
Conclusions: The experiments show that it is feasible to deliver MTO to C6 glioma implants by IA-TCH assisted drug delivery. BBB impairment due to tumor infiltration is sufficient to permit tumor tissue uptake. Furthermore, it is possible that the cationic nature of MTO also improves its uptake after IA injections, as we have recently reported with liposomes.(7) Experiments are now underway to assess impact of IA-TCH MTO delivery on tumor size, histology and survival.

References:
1. A. Boiardi et al., Ital J Neurol Sci 20, 43 (Feb, 1999).
2. R. L. Dedrick, Journal of the National Cancer Institute 80, 84 (1988).
3. S. Joshi et al., Anesthesiology 109, 543 (Sep, 2008).
4. S. Joshi et al., Neurosurgery, (Mar 23, 2011).
5. A. Ergin, et al., J Biomed Opt 17, 057008 (May, 2012).
6. S. Joshi et al., J Neurooncol, (Dec 12, 2011).
7. S. Joshi et al., J Neurooncol, (Mar 25, 2014).

Acknowledgements: NIH R01s CA127500 and CA138643

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