Skip to main content
Log in

Distribution of drugs following controlled delivery to the brain interstitium

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Intracranial controlled release polymers have been used for drug delivery to the brain, bypassing the blood brain barrier (BBB). By understanding the rates and patterns of transport in the local tissues, it is possible to design delivery systems that provide the optimal spatial and temporal pattern of chemotherapy within the intracranial space. This paper reviews the kinetics of drug release from polymeric controlled release implants, and describes the fate of drug molecules following release into the brain interstitium. Potential improvements in drug delivery based on the understanding of the mechanisms of drug release, transport and elimination are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Granholm A, Biddle PT, Backman C, Ebendal T, Gerhardt G, Hoffer B, Mackerlova L, Olson L, Soderstrom S, Walus L, Friden P: Peripheral administration of nerve growth factor conjugated to an anti-transferrin receptor antibody increases cholinergic neuron survival in intraocular forebrain transplants. In: Flanagan TR, Emerich DF, Winn SR (eds) Providing Pharmacological Access to the Brain: Alternate Approaches. Academic Press, Inc, San Diego, 1994, pp 71–92

    Google Scholar 

  2. Robinson PJ: Osmotic opening of the blood-brain barrier and brain tumor chemotherapy. In: Flanagan TR, Emerich DF, Winn SR (eds) Providing Pharmacological Access to the Brain: Alternative Approaches. Academic Press, Inc, San Diego, 1994, pp 35–51

    Google Scholar 

  3. White JD, Schwartz MW: Using osmotic minipumps for intracranial delivery of amino acids and peptides. In: Flanagan TR, Emerich DF, Winn SR (eds) Providing Pharmacological Access to the Brain: Alternate Approaches. Academic Press, Inc, San Diego, 1994, pp 187–200

    Google Scholar 

  4. Hagg T: Continuous central nervous system infusion with Alzet osmotic pumps. In: Flanagan TR, Emerich DF, Winn SR (eds) Providing Pharmacological Access to the Brain: Alternate Approaches. Academic Press, Inc, San Diego, 1994, pp 201–213

    Google Scholar 

  5. Morrison PF, Laske DW, Bobo H, Oldfield EH, Dedrick RL: High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 266: R292-R305, 1994

    PubMed  Google Scholar 

  6. Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30: 907–911, 1980

    Google Scholar 

  7. Saltzman WM, Radomsky ML: Drugs released from polymers: diffusion and elimination in brain tissue. Chem Eng Sci 46: 2420–2444, 1991

    Google Scholar 

  8. Reinhard CS, Randomsky ML, Saltzman WM, Hilton J, Brem H: Polymeric controlled release of dexamethasone in normal rat brain. J Controlled Release 16: 331–340, 1991

    Google Scholar 

  9. Rhine WD, Hsieh DST, Langer R: Polymers for sustained macromolecule release: Procedures to fabricate reproducible delivery systems and control release kinetics. J Pharm Sci 69 (3): 265–270, 1980

    PubMed  Google Scholar 

  10. Saltzman WM: Antibodies for treating and preventing disease: The potential role of polymeric controlled release. Crit Rev Ther Drug Carrier Syst 10 (2): 111–142, 1993

    PubMed  Google Scholar 

  11. Saltzman WM, Sheppard NF, McHugh MA, Dause RB, Pratt JA, Dodrill AM: Controlled antibody release from a matrix of poly(ethylene-co-vinyl acetate) fractionated with a supercritical fluid. J Appl Polym Sci 48: 1493–1500, 1993

    Google Scholar 

  12. Leong KW, Brott BC, Langer R: Bioerodible polyanhydrides as drug carrier matrices I. Characteristics, degradation and release characteristics. J Biomed Mat Res 19: 941–955, 1985

    Google Scholar 

  13. Deen WM: Hindered transport of large molecules in liquidfilled pores. AICHE J 33: 1409–1425, 1987

    Google Scholar 

  14. Strasser JF, Fung L, Eller S, Grossman SA, Saltzman WM: Distribution of 1,3-bis(2-chloroethyl)-1-nitrosurea (BCNU) and tracers in the rabbit brain following interstitial delivery by biodegradable polymer implants. J Pharmacol Exp Ther, in press

  15. Dang W, Colvin OM, Brem H, Saltzman WM: Covalent coupling of methotrexate to dextran enhances the penetration of cytotoxicity into a tissue-like matrix. Cancer Res 54: 1729–1735, 1994

    PubMed  Google Scholar 

  16. Krewson CE, Klarman ML, Saltzman WM: Distribution of nerve growth factor following direct delivery to brain interstitium. Brain Res 680: 196–206, 1995

    PubMed  Google Scholar 

  17. Fung LK, Shin M, Brem H, Saltzman WM: Chemotherapeutic drugs released from polymer implants: Distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in the rat brain, submitted

  18. Fung LK, Shin M, Strasser J, Caviston T, Sipos EP, Tyler B, Brem H, Saltzman M: Transport of 1,3-bis(1,2-chloroethyl)-1-nitrosourea (BCNU) in the brain following controlled release by a polymer. Proceedings of the International Symposium on Controlled Release of Bioactive Materials 22: 65–66, 1995

    Google Scholar 

  19. Krewson CE, Saltzman WM: Targeting of proteins in the brain following release from a polymer. In: Lee VHL, Hashida M, Mizushima Y (eds) Trends and Future Perspectives in Peptide and Protein Drug Delivery. Harwood Academic Publishers, Amsterdam, pp 273–294, 1995

    Google Scholar 

  20. Jain RK: Vascular and interstitial barriers to delivery or therapeutic agents in tumors. Cancer Metastasis Rev 9: 253–266, 1990

    PubMed  Google Scholar 

  21. Brem H, Tamargo RJ, Olivi A, Pinn M, Weingart JD, Wharam M, Epstein JI: Biodegradable polymers for controlled delivery of chemotherapy with and without radiation therapy in the monkey brain. J Neurosurg 80: 283–290, 1994

    PubMed  Google Scholar 

  22. Reisseld B, Kalyanansundaram. Leong K: A mathematical model of polymeric controlled drug release and transport in the brain. J Controlled Release, in press

  23. Baxter LT, Jain RK: Transport of fluid and macromolecules in tumors III. Role of binding and metabolism. Microvascular Res 41: 5–23, 1991

    Google Scholar 

  24. Dang W, Saltzman WM: Dextran retention in the rat brain following release from a polymer implant. Biotechnol Prog 8: 527–532, 1992

    PubMed  Google Scholar 

  25. Veh RW, Havves H, Meyer K, Czekalla J, Grumbach IM, Pham HT: Neuropeptide conjugation to carrier proteins. In: Conn M (ed) Neuropeptide Analogs, Conjugates and Fragments. Academic Press, Inc, San Diego, 1993, pp 333–351

    Google Scholar 

  26. Neuwelt EA, Kroll RA: Osmotic blood-barrier modification: Increasing delivery of diagnostic and therapeutic agents to the brain. In: Thomas RF, Dwaine FE, Shelley RW (eds) Providing Pharmacological Access to the Brain: Alternate Approaches. Academic Press, Inc, San Diego, 1994, pp 52–67

    Google Scholar 

  27. Brem H: Controlled delivery to the brain. In: Gregoridadis G, Allison AC, Poste G (eds) Targeting of Drugs 2: Optimization Strategies, Plenum Publ Corp, New York, 1990, pp 155–163

    Google Scholar 

  28. Walter KA, Cahan MA, Gur A, Tyler B, Hilton J, Colvin OM, Burger PC, Domb A, Brem H: Interstitial taxol delivered from a biodegradable polymer implant against experimental malignant glioma. Cancer Res 54: 2207–2212, 1994

    PubMed  Google Scholar 

  29. Rama B, Mandel T, Jansen J, Dingeldein E, Mennel HD: The intraneoplastic chemotherapy in a rat brain tumor model utilizing methotrexate-polymethylmethacrylate-pellets. Acta Neurochir 87: 70–75, 1987

    Google Scholar 

  30. Tamargo RJ, Sills AK, Reinhard CS, Pinn ML, Long DM, Brem H: Interstitial delivery of dexamethasone in the brain for the reduction of peritumoral edema. J Neurosurg 74: 956–961, 1991

    PubMed  Google Scholar 

  31. Langer R: Polymer implants for drug delivery in the brain. J Controlled Release 16: 53–60, 1991

    Google Scholar 

  32. Boisdron-Celle M, Menei P, Benoit JP: Preparation of biodegradable 5-fluorouracil-loaded microspheres and study of their anticancer activity on animal model of glioma. Presented at the 9th International Symposium on Microencapsulation, Ankara, Turkey, September 13–15, 1993

  33. Kubo O, Himuro H, Inoue N, Tajika Y, Tajika T, Tohyama T, Sakairi M, Yoshida M, Kaetsu I, Kitamura K: Treatment of malignant brain tumors with slowly releasing anticancer drug-polymer composites (Abstract). No Shinkei Geka 14: 1189–1195, 1986

    PubMed  Google Scholar 

  34. Katakura R, Mori T, Mineura K, Suzuki J: A device for prolonged releasing of anticancer drug-bleomycin (Abstract). No Shinkei Geka 8: 1057–1062, 1980

    PubMed  Google Scholar 

  35. Buahin KG, Judy KD, Hartke C, Maniar M, Colvin OM, Brem H: Controlled release of 4-hydroxyperoxy-cyclophosphamide from the fatty acid dimer-sebacic acid copolymer. Polymer for Advanced Technologies 3: 311–316, 1992

    Google Scholar 

  36. Domb A, Bogdansky S, Olivi A, Judy K, Dureza C, Lenartz D, Pinn ML, Colvin OM, Brem H: Controlled delivery of water soluble and hydrolytically unstable anti-cancer drugs for polymeric implants. Polym Preprints 32: 219–220, 1991

    Google Scholar 

  37. Olivi A, Brem H: Interstitial chemotherapy with sustainedrelease polymer systems for the treatment of malignant gliomas. Recent Results in Cancer Res 135: 149–154, 1994

    Google Scholar 

  38. Tamargo RJ, Leong KW, Brem H: Inhibition of a growth of the 9L gliosarcoma by the local, sustained release of heparin and cortisone. J Neurooncol 9: 131–138, 1990

    PubMed  Google Scholar 

  39. Tamargo RJ, Bok RA, Brem H: Angiogenesis inhibition by minocycline. Cancer Res 51: 672–675, 1991

    PubMed  Google Scholar 

  40. Lee A, Langer R: Shark cartilage contains inhibitors of angiogenesis. Science 221: 1185–1187, 1983

    PubMed  Google Scholar 

  41. McRae-Degueurce A, Hjorth S, Dillon DL, Mason DW, Tice TR: Implantable microencapsulated dopamine (DA): A new approach for slow-release DA delivery into brain tissue. Neurosci Lett 92: 303–309, 1988

    PubMed  Google Scholar 

  42. Becker JB, Robinson TE, Barton P, Sintov A, Siden R, Levy RJ: Sustained behavioral recovery from unilateral nigrostriatal damage produced by the controlled release of dopamine from a silicone polymer pellet placed into the denervated striaturn. Brain Res 506: 60–64, 1990

    Google Scholar 

  43. During MJ, Sabel BA, Freese A, Saltzman WM, Duetch A, Roth RH, Langer R: Controlled release of dopamine from a polymeric brain implant:in vivo characterization. Ann Neurol 25: 351–356, 1989

    PubMed  Google Scholar 

  44. Winn SR, Wahlberg L, Tresco PA, Aebischer P: An encapsulated dopamine-releasing polymer alleviates experimental Parkinsonism in rats. Exp Neurol 105: 244–250, 1989

    PubMed  Google Scholar 

  45. Howard MA, Gross A, Grady MS, Langer RS, Mathiowitz E, Winn HR, Mayberg MR: Intracerebral drug delivery in rats with lesion-induced memory deficits. J Neurosurg 71: 105–112, 1989

    PubMed  Google Scholar 

  46. Mayberg MR, Gross AS, Mathiowitz E, Langer R: Sustained release of acetylcholine in rat hippocampus using a polyanhydride drug-delivery system. Polymer for Advanced Technologies 3: 331–336, 1992

    Google Scholar 

  47. Yamamoto S, Yoshimine T, Fujita T, Luroda R, Irie T, Fujioka K, Hayakawa T: Protective effect of NGF atelocollagen mini-pellet on the hippocampal delayed neuronal death in gerbils. Neurosci Lett 141: 161–165, 1992

    PubMed  Google Scholar 

  48. Camarata PJ, Suryanarayanan R, Turner D, Parker RG, Ebner TJ: Sustained release of nerve growth factor from biodegradable polymer microspheres. Neurosurgery 30: 313–319, 1992

    PubMed  Google Scholar 

  49. Salehi-Had S, Saltzman WM: Controlled intracranial delivery of antibodies in the rat. In: Cleland JL, Langer R (eds) Protein Formulation and Delivery, ACS Symposium Series 567, 1994, pp 278–291

  50. Maysinger D, Jalsenjak V, Stolnik S, Garofalo L, Cuello AC, Jalsenjak I: Microencapsulated monosialoganglioside GM1: Physical properties andin vivo effect. J Microencapsul 6: 35–42, 1989

    PubMed  Google Scholar 

  51. Sobarzo MR, M.S. Essay, Johns Hopkins University, 1989

  52. Blasberg R, Patlak C, Fenstermacher J: Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther 195: 73–83, 1975

    PubMed  Google Scholar 

  53. Anderson KD, Alderson RF, Altar CA, DiStefano PS, Corcoran TI, Lindsay RM, Wiegand SJ: Distribution of exogenous BDNF and NGF delivered into the brain. Society for Neuroscience Abstracts 19: 662, 1993

    Google Scholar 

  54. Rosenberg G, Kyner W, Estrada E: Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am J Physiol 238: F42-F49, 1980

    PubMed  Google Scholar 

  55. Curran RE, Mosher MB, Owens ES, Fenstermacher JD: Cerebrospinal fluid production rates determined by simultaneous albumin and inulin perfusion. Exp Neurol 29: 546–553, 1970

    PubMed  Google Scholar 

  56. Lum JT, Nguyen T, Felpel LP: Drug distribution in solid tissue of the brain following chronic local perfusion utilizing implanted osmotic minipumps. J Pharmacol Methods 12: 141–147, 1984

    PubMed  Google Scholar 

  57. Morrison P, Dedrick RL: Transport of cisplatin in rat brain following microinfusion: an analysis. J Pharm Sci 75: 120–128, 1986

    PubMed  Google Scholar 

  58. Lee Sendelbecks, Urquhart J: Spatial distribution of dopamine, methotrexate and antipyrine during continuous intracerebral microperfusion. Brain Res 328: 251–258, 1985

    PubMed  Google Scholar 

  59. Kasamatsu T, Itakura T, Jonsson G: Intracortical spread of exogenous catecholamines: effective concentration for modifying cortical plasticity. J Pharmacol Exp Ther 217: 841–850, 1981

    PubMed  Google Scholar 

  60. Dykstra KH, Hsiao JK, Morrison PF, Bungay PM, Mefford IN, Scully MM, Dedrick RL: Quantitative examination of tissue concentration profiles associated with microdialysis. J Neurochem 58: 931–940, 1992

    PubMed  Google Scholar 

  61. Dykstra KH, Arya A, Arriola DM, Bungay PM, Morrison PF, Dedrick RL: Microdialysis study of zidovudine (AZT) transport in rat brain. J Pharmacol Exp Ther 267: 1227–1236, 1993

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mak, M., Fung, L., Strasser, J.F. et al. Distribution of drugs following controlled delivery to the brain interstitium. J Neuro-Oncol 26, 91–102 (1995). https://doi.org/10.1007/BF01060215

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01060215

Key words

Navigation