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  • Magnetic Drug Targeting: A Novel Treatment for High-grade Intramedullary Spinal Cord Tumors.

    Final Number:

    Pouyan Kheirkhah; Steven Denyer BS MS; Abhiraj D. Bhimani; Gregory D Arnone MD; Darian R. Esfahani MD; Tania Aguilar; Jack Zakrzewski BS; Nazia MS Habib; Indu Venugopal PhD; Gary L. Gallia MD; Andreas Linninger PhD; Fady T. Charbel MD; Ankit Indravadan Mehta MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2017 Annual Meeting - Late Breaking Science

    Introduction: High-grade intramedullary spinal cord tumors (IMSCTs) account for 30% of all IMSCTs and carry a poor prognosis. The challenge of IMSCTs is the lack of a clear plane of dissection, making gross total resection hazardous. Radiotherapy has detrimental effects in the spine, especially in children, while chemotherapy exhibits limited penetration and systemic toxicity. In this study, we demonstrate a novel treatment for high-grade IMSCTs using doxorubicin loaded magnetic nanoparticles (MNPs) guided by a magnetic field.

    Methods: Athymic rats (Crl:NIH-Foxn1rnu) underwent laminectomy and intramedullary injection of glioblastoma multiforme cells (GBM; 060919) at the midthoracic level, followed by subcutaneous implantation of a 2cm neodymium-iron-boron magnet (0.01 Tesla) at the surgical site. Two weeks after tumor inoculation, 40 µl of doxorubicin loaded MNPs were injected intrathecally at the lumbar level. One week after nanoparticle injection, rats were sacrificed and spinal cord segments were stained and examined for doxorubicin localization. TUNEL assay was utilized to investigate the effectiveness of MNPs to induce apoptosis.

    Results: H&E stains revealed tumor growth, with separate Prussian Blue staining demonstrating successful magnetic guidance of nanoparticles to the tumor. Nanoparticles were not detected at other spinal levels. Doxorubicin fluorescence was found to be significantly greater at the tumor site than at other spinal levels (P<.001) supporting successful magnetic targeting. TUNEL positive cells were found in the tumor, with evidence of co-localization with doxorubicin, supporting the effectiveness of MNPs to induce apoptosis.

    Conclusions: This study demonstrates proof of concept that chemotherapeutic drugs can be successfully delivered to IMSCTs when loaded on MNPs. Advantages of this technique include intrathecal injection, which bypasses the blood-spine barrier, as well as the potential to achieve higher drug concentrations at the tumor site with lower levels of systemic toxicity. Future animal studies and Stage I clinical trials may help further identify the clinical benefit of this new technique.

    Patient Care: Intramedullary spinal cord tumors are notoriously challenging to treat, with surgery and radiation limited by high morbidity and chemotherapy limited by systemic toxicity and difficulty bypassing the blood-spine barrier. This study demonstrates proof of concept that chemotherapeutic agents loaded to nanoparticles can be successfully delivered to intramedullary spinal cord tumors with magnetic targeting. These findings, if validated in human trials, have the potential to improve patient outcomes by increasing the efficiency and effectiveness of chemotherapy for spinal cord tumors.

    Learning Objectives: By the conclusion of this session, participants should appreciate the need for alternative approaches to high-grade intramedullary spinal cord tumors and recognize the potential benefit of magnetic nanoparticles to localize chemotherapeutic drugs to a tumor site.

    References: 1. Tobin MK, Geraghty JR, Engelhard HH, Linninger AA, Mehta AI. Intramedullary spinal cord tumors: a review of current and future treatment strategies. Neurosurg Focus. 2015;39(2):E14. 2. Samuel N, Tetreault L, Santaguida C, et al. Clinical and pathological outcomes after resection of intramedullary spinal cord tumors: a single-institution case series. Neurosurg Focus. 2016;41(2):E8. 3. Montano N, Papacci F, Trevisi G, Fernandez E. Factors affecting functional outcome in patients with intramedullary spinal cord tumors: results from a literature analysis. Acta Neurol Belg. 2017;117(1):277-282. 4. Verla T, Fridley JS, Khan AB, Mayer RR, Omeis I. Neuromonitoring for Intramedullary Spinal Cord Tumor Surgery. World Neurosurg. 2016;95:108-116. 5. Sandalcioglu IE, Gasser T, Asgari S, et al. Functional outcome after surgical treatment of intramedullary spinal cord tumors: experience with 78 patients. Spinal Cord. 2005;43(1):34-41. 6. Balmaceda C. Chemotherapy for intramedullary spinal cord tumors. J Neurooncol. 2000;47(3):293-307. 7. Chamberlain MC, Tredway TL. Adult primary intradural spinal cord tumors: a review. Curr Neurol Neurosci Rep. 2011;11(3):320-8. 8. Allen JC, Aviner S, Yates AJ, et al. Treatment of high-grade spinal cord astrocytoma of childhood with "8-in-1" chemotherapy and radiotherapy: a pilot study of CCG-945. Children's Cancer Group. J Neurosurg. 1998;88(2):215-20. 9. Hettiarachchi HD, Hsu Y, Harris TJ, Penn R, Linninger AA. The effect of pulsatile flow on intrathecal drug delivery in the spinal canal. Ann Biomed Eng. 2011;39(10):2592-602. 10. Hsu W, Siu IM, Pradilla G, Gokaslan ZL, Jallo GI, Gallia GL. Animal model of intramedullary spinal cord glioma using human glioblastoma multiforme neurospheres. J Neurosurg Spine. 2012;16(3):315-9. 11. Venugopal, I., Pernal, S., Duproz, A., Bentley, J., Engelhard, H., & Linninger, A. (2016). Magnetic field-enhanced cellular uptake of doxorubicin loaded magnetic nanoparticles for tumor treatment. Materials Research Express, 3(9), 095010. doi:10.1088/2053-1591/3/9/095010 12. Schindelin, J.; Arganda-Carreras, I. & Frise, E. et al. (2012), "Fiji: an open-source platform for biological-image analysis", Nature methods 9(7): 676-682, PMID 22743772

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