Controlled Delivery to the Brain

  • Henry Brem
Part of the NATO ASI Series book series (NSSA, volume 199)


Controlled delivery of drugs directly to the site of a growing brain tumor has the potential to increase drug efficacy while reducing systemic side effects. Hochberg and Pruitt (1980) showed that 90% of malignant gliomas recur within a 2 cm margin of the original tumor. Thus, targeting therapy in this region holds the promise of controlling tumor growth and minimizing the systemic toxicity of the drugs. Localized, prolonged delivery of drugs to the brain is now possible by using polymeric delivery systems.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Blasberg, R.G., 1977, Methotrexate, cytosine arabinoside, and BCNU concentration in brain after ventriculocistemal perfusion.Cancer Treat.Rep., 61:625PubMedGoogle Scholar
  2. Blasberg, R.G., Patlak, C.S. and Shapiro, W.R., 1977, Distribution of methotrexate in the cerebrospinal fluid and brain after intraventricular administration.Cancer Treat.Rep., 61:633.PubMedGoogle Scholar
  3. Bouvier, G., Penn, R.S., Kroin, J.S., Beique, R. and Guerard, M.J., 1987, Direct delivery of medication into a brain tumor through multiple chronically implanted catheters.Neurosurgery, 20:286.CrossRefGoogle Scholar
  4. Brem, H., Ahn, H., Tamargo, R.J., Pinn, M.L. and Chasin, M., 1988, A biodegradable polymer for intracranial drug delivery: A radiological study in primates. American Association of Neurological Surgeons, Toronto, p. 349.Google Scholar
  5. Brem, H., Kader, A., Epstein, J.I., Tamargo, R., Domb, A., Langer, R. and Leong, K., 1989, Biocompatibility of bioerodible controlled release polymers in the rabbit brain.Selective Cancer Therapeutics. 5:55.CrossRefGoogle Scholar
  6. Brem, H., Tamargo, R.J. and Olivi, A., 1990, Delivery of drugs to the brain by use of a sustained release polymer system, to: “New Technologies and Concepts for Reducing Drug Toxicity”, H. Salem, ed., Telford Press, Caldwell, N.J., in press.Google Scholar
  7. Brem, H., Tamargo, R.J., Pinn, M. and Chasin, M., 1989, Biocompatibility of a BCNU-loaded biodegradable polymer: A toxicity study in primates. American Association of Neurological Surgeons, Toronto, p. 381.Google Scholar
  8. Chasin, M., Domb, A., Ron, E., Mathiowitz, E., Leong, K., Laurencin, C., Brem, H. and Langer, R., 1990, Polyanhydrides as drug delivery systems, to “Biodegradable Polymers as Drug Delivery Systems”, R. Langer and M. Chasin, eds.. Marcel Dekker toe.. New York, in pressGoogle Scholar
  9. Fishman, R.A., 1987, Is there a therapeutic role for osmotic breaching of the blood-brain barrier?Ann. Neurol., 22:298.CrossRefGoogle Scholar
  10. Garfield, J., Chir, M. and Dayan, A.D., 1973, Postoperative intracavitary chemotherapy of malignant gliomas,J.Neurosurg., 39:315.CrossRefGoogle Scholar
  11. Gimbrone, M.A., Cotran, R.S., Leapman, S.B. and Folkman, J., 1974, Tumorgrowth and neovascularization: An experimental model using the rabbit cornea,J.N.C.I., 52:413.Google Scholar
  12. Greenberg, H.S., Ensminger, W.D., Chandler, W.F., Layton, P.B., Junck, L., Knake, J. and Vine, A.D., 1984, Intra-arterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system,J.Neurosurg., 61:423.CrossRefGoogle Scholar
  13. Greig, N.H., 1987, Optimizing drug delivery to brain tumors,Cancer Treat.Rev., 14:1.CrossRefGoogle Scholar
  14. Harbaugh, R.E., Saunders, R.L. and Reeder, R., 1988, Use of implantable pumps for central nervous system drug infusions to treat neurological disease.Neurosurgery, 23:693.CrossRefGoogle Scholar
  15. Hochberg, F.H. and Pruitt, A., 1980, Assumptions in the radiotherapy of glioblastoma.Neurology, 30:907.CrossRefGoogle Scholar
  16. Hanker, J.S. and Giammara, B.L., 1988, Biomaterials and biomedical devices.Science, 242:885.CrossRefGoogle Scholar
  17. Langer, R., 1983, Implantable controlled release systems,Pharmac.Ther., 21:35.CrossRefGoogle Scholar
  18. Langer, R., Brem, H. and Tapper, D., 1981, Biocompatibility of polymeric delivery systems for macromolecules,J.Biomed.Mat.Res., 15:267.CrossRefGoogle Scholar
  19. Langer, R. and Folkman, J., 1976, Polymers for the sustained release of proteins and other macromolecules.Nature, 263:797.CrossRefGoogle Scholar
  20. Langer, R. and Wise, D., eds., 1986, “Medical Applications of Controlled Release”, Vols. I and II, CRC Press, Boca Raton, Florida.Google Scholar
  21. Leong, K.W., D’Amore, P., Marietta, M. and Langer, R., 1986, Bioerodible polyanhydrides as drug-carrier matrices. II. Biocompatibility and chemical reactivity,J.Biomed.Mat.Res., 20:51.CrossRefGoogle Scholar
  22. Levin, V.A., Patlak, C.S. and Landahl, H.D., 1980, Heuristic modeling of drug delivery to malignant brain tumors.J.Pharmocokinetics and Biopharmaceutics, 8:257.CrossRefGoogle Scholar
  23. Loo, T.L. and Dion, R.L., 1965, Colorimetric method for the determination of l,3-Bis(2-chloroethyl)-l-nitrosourea,J.Pharm.Sei., 54:809.CrossRefGoogle Scholar
  24. Neuwelt, E.A., Howieson, J., Frenkel, E.P., Specht, H.D., Weigel, R., Buchan, C.G. and Hill, S.A., 1986, Therapeutic efficacy of multiagent chemotherapy with drug delivery enhancement by blood-brain barrier modification in glioblastoma,Neurosurgenry, 19:573.CrossRefGoogle Scholar
  25. Ringkjob, R., 1968, Treatment of intracranial gliomas and metastatic carcinomas by local application of cytostatic agents.Acta Neurol.Scand., 44:318.CrossRefGoogle Scholar
  26. Rosenblum, M.L., Bowie, D.L. and Walker, M.D., 1973, Diffusionin vitroandin vivoof 1- (2-chloroethyl) -3- (trans-4-methylcyclohexyl)-1-nitro- sourea from silicone rubber capsules: A potentially new mode of chemotherapy administration.Cancer Res., 33:906.Google Scholar
  27. Rubin, R.C., Ommaya, A.K., Henderson, E.S., Bering, E.A. and Rail, D.P., 1966, Cerebrospinal fluid perfusion for central nervous system neoplasms.Neurology, 16:680.CrossRefGoogle Scholar
  28. Tamargo, R.J., Epstein, J.I., Reinhard, C.S., Chasin, M. and Brem, H., 1989, Brain biocompatibility of a biodegradable controlled release polymer in rats,J.Biomed.Mat.Res., 23:253.CrossRefGoogle Scholar
  29. Tamargo, R.J., Epstein, J.I., Reinhard, C.S., Chasin, M. and Brem, H., 1988, Brain biocompatibility of a biodegradable polymer capable of sustained release of macromolecules, American Association of Neurological Surgeons, Toronto, p. 399.Google Scholar
  30. Tamargo, R.J., Mtyseros, J.S. and Brem, H., 1988, Growth inhibition of the 9L gliosarcoma by the local sustained release of BCNU: a canparison of systemic versus regional chemotherapy, American Association of Neurological Surgeons, Toronto, p. 212.Google Scholar
  31. Wamke, P.C., Blasberg, R.G. and Groothuis, D.R., 1987, The effect of hyperosmotic blood-brain barrier disruption on blood-to-tissue transport in ENU-induced gliomas,Ann.Neurol. 22:300.CrossRefGoogle Scholar
  32. Weiss, S.R. and Raskind, R., 1969, Treatment of malignant brain tumors by local methotrexate.International Smrg., 51:149.Google Scholar
  33. Yang, M.B., Tamargo, R.J. and Brem, H., 1989, Controlled delivery of 1,3- Bis(2-chloroethyl)-l-nitrosourea fron ethylene-vinyl acetate copolymer,Cancer Res., 49:5103.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Henry Brem
    • 1
    • 2
  1. 1.Department of Neurological SurgeryJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Ophthalmology and OncologyJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations