Journal of Neuro-Oncology

, Volume 24, Issue 2, pp 143–152 | Cite as

Tissue distribution of methotrexate following administration as a solution and as a magnetic microsphere conjugate in rats bearing brain tumors

  • Damayanthi Devineni
  • Andres Klein-Szanto
  • James M. Gallo
Laboratory Investigation


A novel magnetic microsphere-methotrexate (MM-MTX) drug delivery system was synthesized and evaluated in rats bearing rat glioma-2 (RG-2) tumors. Methotrexate was linked to the surface of the magnetic particle via an aminohexanol linker that would release free drug following hydrolysis. Male Fischer 344 rats bearing RG-2 tumors were administered 3 mg/kg of methotrexate (MTX) either as MM-MTX or as a solution (MTXS) over 5 min. A 6000 gauss magnetic field was applied for 15 min from the end of MM-MTX administrations. Serial sacrifices were conducted at 15 min, 30 min and 45 min after drug administrations, organs collected, and analyzed for total MTX by a radioassay. At all times, MTX right brain (ipsilateral), brain tumor, and left brain concentrations were approximately 3.5 to 5-fold greater in the MM-MTX group compared to the MTX-S group. MTX concentrations in all other organs were less following administration of MM-MTX than MTX-S except in lung at 30 and 45 min. The targeting efficacy, an index for site-specificity, for both MM-MTX and MTX-S were similar and indicated some enhancement in MTX localization in brain tumor. Confocal and conventional light microscopic analyses demonstrated a diffuse distribution of MM-MTX in tumor consistent with extravascular uptake, whereas a predominant capillary distribution of MM-MTX was observed in normal brain. Following 45 min, the animals treated with MM-MTX died possibly due to redistribution of particles to the lung. This toxicity was dose-dependent. High brain MTX concentrations coupled with extravascular uptake of MM-MTX provide a basis for further investigations with this novel drug delivery system.

Key words

drug delivery extravascular transport 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Levin VA, Freeman-Dove M, Landahl HD: Permeability characteristics of brain adjacent to tumors in rats. Arch Neurol 32: 785–791, 1975Google Scholar
  2. 2.
    Blasberg RG, Groothuis DR: Chemotherapy of brain tumors: physiological and pharmacokinetic consideration. Seminar in Oncology 13: 70–82, 1986Google Scholar
  3. 3.
    Phillips PC: Antineoplastic drug resistance in brain tumors. Neurologic Clinics 9: 383–404, 1991Google Scholar
  4. 4.
    Cuvier C, Roblot-Treupel L, Millot J, Lizard G, Chevillard S, Manfait M, Couvreur P, Poupou MF: Doxorubicin-loaded nanospheres bypass tumor cell multidrug resistance. Biochem Pharmacol 44: 509–517, 1992Google Scholar
  5. 5.
    Mickisch GH, Rahman A, Pastan I, Gottesman M: Increased effectiveness of liposomal-encapsulated doxorubicin in multidrug-resistant-transgenic mice compared with free doxorubicin. J Natl Cancer Inst 84: 804–805, 1992Google Scholar
  6. 6.
    Kroin JS, Penn DR: Implantable pumps to deliver drugs directly into the CNS. In: Neuweld EA (ed) Implications of the blood-brain barrier and its manipulation, Plenum Publ Corp, New York 601–620, 1989Google Scholar
  7. 7.
    Brem H, Mahaley MS, Vick NA, Black KL, Schold Jr SC, Burger PC, Friedman AH, Ciric IS, Eller TW, Cozzens JW, Kenealy JN: Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 74: 441–446, 1991Google Scholar
  8. 8.
    Neuwelt EA, Goldman D, Dahlborg SA, Crossen J, Ramsey Fet al.: Primary CNS lymphoma treated with osmotic bloodbrain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol 9: 1580–1590, 1991Google Scholar
  9. 9.
    Greig NH, Momma S, Sweetney DJ, Smith QR, Rapoport SI: Facilitated transport of melphalan at the rat blood-brain barrier by the large neutral amino acid carrier system. Cancer Res 47: 1571–1576, 1987Google Scholar
  10. 10.
    Pardridge WM, Buciak JL, Friden PM: Selective transport of an antitransferrin receptor antibody through the bloodbrain barrierin vivo. J Pharmacol Exp Ther 259: 66–70, 1991Google Scholar
  11. 11.
    Friden PM, Walus LR, Musso GF, Taylor MA, Malfroy B, Sturzyk RM: Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proc Natl Acad Sci USA 88: 4771–4775, 1991Google Scholar
  12. 12.
    Gupta PK: Drug targeting in cancer chemotherapy: a clinical perspective. J Pharm Sci 79: 949–962, 1990Google Scholar
  13. 13.
    Douglas SF, Davis SS, Ilium L: Nanoparticles in drug delivery. CRC Crit Rev Ther Drug Carrier Sys 3: 233–261, 1986Google Scholar
  14. 14.
    Hassan EE, Gallo JM: Targeting anticancer drug to the brain, I: Enhanced brain delivery of oxantrazole following administration in magnetic chitosan microspheres. J Drug Targeting 1: 7–14, 1993Google Scholar
  15. 15.
    Fross RD, Warnke PC, Groothuis DR: Blood flow and blood to tissue transport in 9L gliosarcomas: the role of the brain tumor model in drug delivery research. J Neuro-Oncol 11: 185–197, 1991Google Scholar
  16. 16.
    Culling CFA: Endogenous pigments. In: Culling CFA, Allison RT, Bair WT (eds) Cellular Pathology Techniques, Butterworths, London pp 279, 1985Google Scholar
  17. 17.
    CoMOS, Version 6.03, Bio-Rad Microscience Ltd., Hercules, CA, 1991Google Scholar
  18. 18.
    Ranney DF: Magnetically controlled devices and biomodulation. In: Tyle P (ed) Drug Delivery Devices, Marcel Dekker, New York 325–368, 1988Google Scholar
  19. 19.
    Morimoto Y, Okumura MM, Sugibayashi K, Kalo Y: Biomedical applications of magnetic fields. II. Preparation and magnetic guidance of magnetic albumin microspheres for site specific drug deliveryin vivo. J Pharm Dyn 4: 624–631, 1981Google Scholar
  20. 20.
    Widder KJ, Morris RM, Poore GA, Howard DP, Senyei AF: Selective targeting of magnetic albumin microspheres containing low-dose doxorubicin: Total remission in Yoshida sarcoma-bearing rats. Eur J Cancer Clin Oncol 19: 135–140, 1983Google Scholar
  21. 21.
    Gallo JM, Gupta PK, Hung CT, Perrier DG: Evaluation of drug delivery following the administration of magnetic albumin microspheres containing adriamycin to the rat. J Pharm Sci 78: 190–194, 1989Google Scholar
  22. 22.
    Poore GA, Senyei AE: Selective targeting of magnetic albumin microspheres to the Yoshida sarcoma: Ultrastructural evaluation of microsphere disposition. Eur J Cancer Clin Oncol 19: 141–148, 1983Google Scholar
  23. 23.
    Ovadia H, Paterson PY, Hale JR: Magnetic microspheres as drug carriers: Factors influencing localization at different anatomical sites in rats. Israel J Med Sci 19: 631–637, 1983Google Scholar
  24. 24.
    Gallo JM, Hassan EE: Receptor-mediated magnetic carriers: Basis for targeting. Pharm Res 5: 300–304, 1988Google Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Damayanthi Devineni
    • 1
  • Andres Klein-Szanto
    • 1
  • James M. Gallo
    • 1
  1. 1.Fox Chase Cancer CenterPhiladelphiaUSA

Personalised recommendations