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.
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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
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
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
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
Morrison PF, Laske DW, Bobo H, Oldfield EH, Dedrick RL: High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 266: R292-R305, 1994
Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30: 907–911, 1980
Saltzman WM, Radomsky ML: Drugs released from polymers: diffusion and elimination in brain tissue. Chem Eng Sci 46: 2420–2444, 1991
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
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
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
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
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
Deen WM: Hindered transport of large molecules in liquidfilled pores. AICHE J 33: 1409–1425, 1987
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
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
Krewson CE, Klarman ML, Saltzman WM: Distribution of nerve growth factor following direct delivery to brain interstitium. Brain Res 680: 196–206, 1995
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
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
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
Jain RK: Vascular and interstitial barriers to delivery or therapeutic agents in tumors. Cancer Metastasis Rev 9: 253–266, 1990
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
Reisseld B, Kalyanansundaram. Leong K: A mathematical model of polymeric controlled drug release and transport in the brain. J Controlled Release, in press
Baxter LT, Jain RK: Transport of fluid and macromolecules in tumors III. Role of binding and metabolism. Microvascular Res 41: 5–23, 1991
Dang W, Saltzman WM: Dextran retention in the rat brain following release from a polymer implant. Biotechnol Prog 8: 527–532, 1992
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
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
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
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
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
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
Langer R: Polymer implants for drug delivery in the brain. J Controlled Release 16: 53–60, 1991
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
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
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
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
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
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
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
Tamargo RJ, Bok RA, Brem H: Angiogenesis inhibition by minocycline. Cancer Res 51: 672–675, 1991
Lee A, Langer R: Shark cartilage contains inhibitors of angiogenesis. Science 221: 1185–1187, 1983
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
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
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
Winn SR, Wahlberg L, Tresco PA, Aebischer P: An encapsulated dopamine-releasing polymer alleviates experimental Parkinsonism in rats. Exp Neurol 105: 244–250, 1989
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
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
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
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
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
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
Sobarzo MR, M.S. Essay, Johns Hopkins University, 1989
Blasberg R, Patlak C, Fenstermacher J: Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther 195: 73–83, 1975
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
Rosenberg G, Kyner W, Estrada E: Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am J Physiol 238: F42-F49, 1980
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
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
Morrison P, Dedrick RL: Transport of cisplatin in rat brain following microinfusion: an analysis. J Pharm Sci 75: 120–128, 1986
Lee Sendelbecks, Urquhart J: Spatial distribution of dopamine, methotrexate and antipyrine during continuous intracerebral microperfusion. Brain Res 328: 251–258, 1985
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
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
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
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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
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DOI: https://doi.org/10.1007/BF01060215