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Distribution of Small Magnetic Particles in Brain Tumor-bearing Rats

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Abstract

Small (10–20 nm) uncharged magnetic particles (SMP) were evaluated for their ability to target intracerebral rat glioma-2 (RG-2) tumors in vivo. In an effort to determine the influence of particle size on blood-tumor barrier uptake, the tissue distribution of the injected particles was evaluated following intraarterial injection (4 mg/kg SMP) in male Fisher 344 rats bearing RG-2 tumors with a magnetic field of 0 G or 6000 G applied to the brain for 30 min. Animals were sacrificed at 30 min or 6 h post-injection after which tissues were collected and analyzed for magnetite content. In the presence of a magnetic field, SMP localized in brain tumor tissue at levels of 41–48% dose/g tissue after 30 min and 6 h respectively, significantly greater than non-target tissues. In the absence of a magnetic field only 31–23% dose/g tissue was achieved for the same time points. Tumor targeting of the SMP for brain tumor was demonstrated by large target selectivity indexes (ts) of 2–21 for normal brain tissue, indicating a 2–21 fold increase in concentrations compared to normal brain. In comparison with larger (1 µm) diameter magnetic particles, SMP concentrated in brain tumor at significantly higher levels than magnetic neutral dextran (p=0.0003) and cationic aminodextran (p=0.0496) microspheres previously studied. TEM analysis of brain tissue revealed SMP in the interstitial space of tumors, but only in the vasculature of normal brain tissue. These results suggest that changes in the vascular endothelium of tumor tissue promote the selective uptake of SMP and provide a basis for the design of new small drug-loaded particles as targeted drug delivery systems for brain tumors.

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References

  1. Greig NH: Drug delivery to the brain by blood-brain circumvention and drug modification. In: Neuwelt EA (ed) Implications of the Blood-Brain and its Manipulation. Plenum Publishing Company, New York, 1989, pp 311-368

    Google Scholar 

  2. Greig NH, Jones HB, Cavanagh JB: Blood-brain barrier integrity and host responses in experimental metastatic brain tumors. Clin Expl Metastasis 1: 229-246, 1983

    Google Scholar 

  3. Hirano A, Ghatak NR, Becker NH, Zimmerman HM: A comparison of the fine structure of small blood vessels in intracranial and retroperitoneal malignant lymphomas. Acta Neurophathol 27: 93-104, 1974

    Google Scholar 

  4. Deane BR, Lantos TA: The vasculature of experimental brain tumors, Part II. A quantitative assessment of morphological abnormalities. J Neurol Sci 49: 67-77, 1981

    PubMed  Google Scholar 

  5. Nishao S, Ohta M, Abe M, Kitamura K: Microvascular abnormalities in ethylnitrosourea (ENU)-induced rat brain tumors: structural basis for altered blood-brain barrier function. Acta Neuropathol 59: 1-10, 1983

    PubMed  Google Scholar 

  6. Groothius DR, Fischer JM, Lapin G, Bigner DD, Vick NA: Permeability of different experimental brain tumor models to horseradish peroxidase. J Neuropath Exp Neuro 41: 164-185, 1982

    Google Scholar 

  7. Warnke PC, Friedman HS, Bigner DD, Groothius DR: Simultaneous measurements of blood flow and blood-to-tissue transport in xenotransplanted medulloblastomas. Cancer Res 47: 1687-1690, 1987

    PubMed  Google Scholar 

  8. LevinVA, Freeman-DoveM, LandahlHD:Permeability characteristics of brain adjacent to tumor in rats. Arch Neurol 32: 785-791, 1975

    PubMed  Google Scholar 

  9. Widder KJ, Senyei AE, Scarpelli DG: Magnetic microspheres: A model system for site specific drug delivery in vivo. Proc Soc Exp Biol Med 58: 141-146, 1978

    Google Scholar 

  10. Widder KJ, Senyei AE: Magnetic microspheres: A vehicle for selective targeting of drugs. In: Ihler GM (ed) Methods of Drug Delivery. Pergamon Press, Oxford, 1989, pp 39-57

    Google Scholar 

  11. Gupta PK, Hung CT: Magnetically controlled targeted microcarrier systems. Life Sci 44: 175-186, 1989

    PubMed  Google Scholar 

  12. Gallo JM, Gupta PK, Hung CT, Perrier DG: Evaluation of drug delivery following the administration of magnetic albumin microspheres containin adriamycin to the rat. J Pharm Sci 78: 190-194, 1989

    PubMed  Google Scholar 

  13. Widder KJ, Morris RM, Poore G, Jr DPH, Senyei AE: Tumor remission in Yoshida sarcoma-bearing rats by selective targeting of magnetic albumin microspheres containing doxorubicin. Proc Natl Acad Sci 78: 579-581, 1981

    PubMed  Google Scholar 

  14. Widder KJ, Morris RM, Poore GA, Howards DP, Senyei AE: Selective targeting of magnetic albumin microspheres containing low-dose doxorubicin: A total remission in Yoshida sarcoma-bearing rats. Eur J Cancer Clin Oncol 19: 135-139, 1983

    PubMed  Google Scholar 

  15. Morimoto Y, Okumura MM, Sugibayashi K, Kato Y: Preparation and magnetic guidance of magnetic albumin microspheres for site specific drug delivery in vivo. J Pharm Dyn 4: 624-631, 1981

    Google Scholar 

  16. Widder KJ, Marino PA, Morris RM, Howard DP, 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: 1941-147, 1983

    Google Scholar 

  17. Gupta PK, Hung CT, Rao NS: Ultrastructural disposition of adriamycin-associated magnetic albumin microspheres in rats. J Pharm Sci 78: 290-294, 1989

    PubMed  Google Scholar 

  18. Devineni D, Klein-Szanto A, Gallo JM: Tissue distribution of methotrexate following administration as a solution and as a magnetic microsphere conjugate in rats bearing brain tumors. J Neuro-Onc 24: 143-152, 1995

    Google Scholar 

  19. Hassan EE, Gallo JM: Targeting anticancer drugs to the brain. I: Enhanced brain delivery of oxantrazole following administration in magnetic cationic microspheres. J Drug Targeting 1: 7-14, 1993

    Google Scholar 

  20. Gallo JM, Hassan EE: Receptor-Mediated Magnetic Carriers: Basis for Targeting. Pharm Res 5: 300-304, 1988

    PubMed  Google Scholar 

  21. Wusteman FS: The involvement of glycosaminoglycans at the endothelium. In: CryerA(ed) Biochemical Interactions at the Endothelium. Elsevier Scientific Publishers, Amsterdam, 1983, pp 79-109

    Google Scholar 

  22. Ausprunk DH, Boudreau CL, Nelson DA: Proteoglycans in the microvasculature. Am J Pathol 101: 353-366, 1981

    Google Scholar 

  23. Simionescu N, Simionescu M, Palade GE: Differentiated microdomains on the luminal surface of the capillary endothelium. J Cell Biol 90: 605-613, 1981

    PubMed  Google Scholar 

  24. Pardridge WM: Recent advances in blood-brain barrier transport. Ann Rev Pharmacol Toxicol 28: 25-39, 1988

    Google Scholar 

  25. Kumagai AK, Eisenberg JB, Pardridge WM: Absorptivemediated endocytosis of cationized albumin and a bendorphincationized albumin chimeric peptide by isolated brain capillaries. J Biol Chem 262: 15214-15291, 1987

    PubMed  Google Scholar 

  26. Pitha J: Polymer-cell surface interactions and drug targeting. In: Goldberg EP (ed) Target Drugs. John Wiley and Sons, New York, 1983, pp 113-126

    Google Scholar 

  27. Pulfer SK, Gallo JM: Targeting magnetic microspheres to brain tumors. In: Hafeli U, SchuttW, Teller J, et al (eds) Scientific and Clinical Applications of Magnetic Carriers. Plenum Press, New York, 1997, pp 445-455

    Google Scholar 

  28. Pulfer SK, Gallo JM: Enhanced brain tumor selectivity of cationic magnetic polysaccharide microspheres. J Drug Targeting, in press, 1998

  29. Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jam RK: Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res 54: 3352-3356, 1994

    PubMed  Google Scholar 

  30. Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torcilin VP, Jain RK:Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 55: 3752-3756, 1995

    PubMed  Google Scholar 

  31. Heath TD, Lopez NG, Papahadjopoulos D: The effects of liposome size and surface charge on liposome-mediated delivery of methotrexate--aspartate to cells in vitro. Biochim Biophys Acta 820: 74-84, 1985

    PubMed  Google Scholar 

  32. Litzinger DC, Buiting AM, Rooijen Nv, Huang L: Effect of liposome size on the circulation time and intraorgan distribution of amphipathic poly(ethylene glycol)-containing liposomes. Biochim Biophys Acta 1190: 99-107, 1994

    PubMed  Google Scholar 

  33. Yamaoka T, Tabata Y, Ikada Y: Blood clearance and organ distribution of intravenously administered polystyrene microspheres of different size. J Bioactive Comp Pol 8: 220-235, 1993

    Google Scholar 

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Pulfer, S.K., Ciccotto, S.L. & Gallo, J.M. Distribution of Small Magnetic Particles in Brain Tumor-bearing Rats. J Neurooncol 41, 99–105 (1999). https://doi.org/10.1023/A:1006137523591

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