The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers

Stuart A. GrossmanDepartments of Oncology and Neurosurgery, The Johns Hopkins Medical Institutions, and Nova Pharmaceutical Corporation, Baltimore, Maryland

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Carla ReinhardDepartments of Oncology and Neurosurgery, The Johns Hopkins Medical Institutions, and Nova Pharmaceutical Corporation, Baltimore, Maryland

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O. Michael ColvinDepartments of Oncology and Neurosurgery, The Johns Hopkins Medical Institutions, and Nova Pharmaceutical Corporation, Baltimore, Maryland

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Mark ChasinDepartments of Oncology and Neurosurgery, The Johns Hopkins Medical Institutions, and Nova Pharmaceutical Corporation, Baltimore, Maryland

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Robert BrundrettDepartments of Oncology and Neurosurgery, The Johns Hopkins Medical Institutions, and Nova Pharmaceutical Corporation, Baltimore, Maryland

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Rafael J. TamargoDepartments of Oncology and Neurosurgery, The Johns Hopkins Medical Institutions, and Nova Pharmaceutical Corporation, Baltimore, Maryland

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Henry BremDepartments of Oncology and Neurosurgery, The Johns Hopkins Medical Institutions, and Nova Pharmaceutical Corporation, Baltimore, Maryland

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✓ The local concentration and distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) within normal brain tissue were studied following surgical implantation of biodegradable polymer containing BCNU in New Zealand White rabbits. Cylindrical discs of poly(bis(p-carboxyphenoxy)-propane:sebacic acid) copolymer in a 20:80 formulation were made containing [3H]-inulin or [3H]-BCNU labeled in the methylene hydrogens of the chloroethyl groups. These were implanted in the brains of 56 New Zealand White rabbits. The animals were sacrificed 3, 7, 14, or 21 days later and the brains were rapidly removed, frozen, and prepared for quantitative autoradiography. Autoradiographs from coronal sections bisecting the polymer were analyzed to determine both the proportion of the brain section exposed to the tracer and the local drug concentrations as a function of distance from the polymer. Tritiated BCNU was also injected directly into the brains of eight additional rabbits, and local brain concentrations were studied over time.

The results of this study demonstrate that approximately 50% of the area of the brain sections was exposed to radiolabeled compound 3 days after BCNU-polymer implantation, 15% at 7 days, and less than 10% at 14 and 21 days. Polymer discs containing 600 µg BCNU generated 6 mM concentrations of BCNU in brain tissue 10 mm from the polymer at 3 and 7 days. Pharmacological studies demonstrated that approximately 25% of the tritium label was associated with intact BCNU 3 days following polymer implantation. Radiolabeled inulin delivered by polymer remained dispersed throughout the ipsilateral hemisphere for 14 days. Direct injection of [3H]-BCNU into brain parenchyma resulted in widely distributed tracer at 1 and 3 hours with rapid disappearance thereafter. It is concluded that local delivery of BCNU to brain tissue with this polymeric drug delivery system results in sustained high local concentrations of BCNU which may be of value in the treatment of patients with brain tumors.

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  • 1.

    Ali-Osman F, , Giblin J, & Dougherty D, et al: Application of in vivo and in vitro pharmacokinetics for physiologically relevant drug exposure in a human tumor clonogenic cell assay. Cancer Res 47:37183724, 1987 Ali-Osman F, Giblin J, Dougherty D, et al: Application of in vivo and in vitro pharmacokinetics for physiologically relevant drug exposure in a human tumor clonogenic cell assay. Cancer Res 47:3718–3724, 1987

    • Search Google Scholar
    • Export Citation
  • 2.

    Blasberg RG, & Groothuis DR: Chemotherapy of brain tumors: physiological and pharmacokinetic considerations. Semin Oncol 13:7082, 1986 Blasberg RG, Groothuis DR: Chemotherapy of brain tumors: physiological and pharmacokinetic considerations. Semin Oncol 13:70–82, 1986

    • Search Google Scholar
    • Export Citation
  • 3.

    Bouvier G, , Penn RD, & Kroin JS, et al: Direct delivery of medication into a brain tumor through multiple chronically implanted catheters. Neurosurgery 20:286291, 1987 Bouvier G, Penn RD, Kroin JS, et al: Direct delivery of medication into a brain tumor through multiple chronically implanted catheters. Neurosurgery 20:286–291, 1987

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Brem H: Polymers to treat brain tumors. Biomaterials 11:699710, 1990 Brem H: Polymers to treat brain tumors. Biomaterials 11:699–710, 1990

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Brem H, , Kader A, & Epstein JI, et al: Biocompatibility of biodegradable, controlled-release polymer in the rabbit brain. Select Cancer Ther 5:5565, 1989 Brem H, Kader A, Epstein JI, et al: Biocompatibility of biodegradable, controlled-release polymer in the rabbit brain. Select Cancer Ther 5:55–65, 1989

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Brem H, , Mahaley MS Jr, & Vick NA, et al: Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 74:441446, 1991 Brem H, Mahaley MS Jr, Vick NA, et al: Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 74:441–446, 1991

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Brem H, , Tamargo RJ, & Olivi A: Delivery of drugs to the brain by use of a sustained-release polyanhydride polymer system. J Appl Toxicol (In press, 1992) Brem H, Tamargo RJ, Olivi A: Delivery of drugs to the brain by use of a sustained-release polyanhydride polymer system. J Appl Toxicol (In press, 1992)

    • Search Google Scholar
    • Export Citation
  • 8.

    Brown LR, , Wei CL, & Langer R: In vivo and in vitro release of macromolecules from polymeric drug delivery systems. J Pharmacol Sci 72:11811185, 1983 Brown LR, Wei CL, Langer R: In vivo and in vitro release of macromolecules from polymeric drug delivery systems. J Pharmacol Sci 72:1181–1185, 1983

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Cascino TL, , Byrne TN, & Deck MD, et al: Intra-arterial BCNU in the treatment of metastatic brain tumors. J Neurooncol 1:211218, 1983 Cascino TL, Byrne TN, Deck MD, et al: Intra-arterial BCNU in the treatment of metastatic brain tumors. J Neurooncol 1:211–218, 1983

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Chasin M, , Domb A, & Ron E, et al: Polyanhydrides as drug delivery systems, in Langer R, & Chasin M (eds): Biodegradable Polymers as Drug Delivery Systems. New York: Marcel Dekker, 1990, pp 4370 Chasin M, Domb A, Ron E, et al: Polyanhydrides as drug delivery systems, in Langer R, Chasin M (eds): Biodegradable Polymers as Drug Delivery Systems. New York: Marcel Dekker, 1990, pp 43–70

    • Search Google Scholar
    • Export Citation
  • 11.

    Chasin M, , Lewis D, & Langer R: Polyanhydrides for controlled drug delivery. Biopharm Manufact 1:3346, 1988 Chasin M, Lewis D, Langer R: Polyanhydrides for controlled drug delivery. Biopharm Manufact 1:33–46, 1988

    • Search Google Scholar
    • Export Citation
  • 12.

    Diemath HE: Lokale Anwendung von Zytostatika nach Exstirpation von Glioblastomen. Wien Klin Wochenschr 99:674676, 1987 Diemath HE: Lokale Anwendung von Zytostatika nach Exstirpation von Glioblastomen. Wien Klin Wochenschr 99:674–676, 1987

    • Search Google Scholar
    • Export Citation
  • 13.

    Fu YA, , Shihab Z, & Chen TT, et al: Clinical evaluation of the OCUSERT-pilocarpine system: a five year follow-up report. Glaucoma 3:3135, 1981 Fu YA, Shihab Z, Chen TT, et al: Clinical evaluation of the OCUSERT-pilocarpine system: a five year follow-up report. Glaucoma 3:31–35, 1981

    • Search Google Scholar
    • Export Citation
  • 14.

    Garfield J, & Dyan AD: Postoperative intracavitary chemotherapy of malignant gliomas. A preliminary study using methotrexate. J Neurosurg 39:315322, 1973 Garfield J, Dyan AD: Postoperative intracavitary chemotherapy of malignant gliomas. A preliminary study using methotrexate. J Neurosurg 39:315–322, 1973

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Girgis M, & Shih-Chang W: Stereotactic Atlas of the Rabbit Brain. St Louis: WH Green, 1981 Girgis M, Shih-Chang W: Stereotactic Atlas of the Rabbit Brain. St Louis: WH Green, 1981

    • Search Google Scholar
    • Export Citation
  • 16.

    Goodson JM, , Holborow D, & Dunn RL, et al: Monolithic tetracycline-containing fibers for controlled delivery to periodontal pockets. J Periodontol 54:575579, 1983 Goodson JM, Holborow D, Dunn RL, et al: Monolithic tetracycline-containing fibers for controlled delivery to periodontal pockets. J Periodontol 54:575–579, 1983

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Goodson JM, , Offenbacher S, & Fair DH, et al: Periodontal disease treatment by local drug delivery. J Periodontol 56:265272, 1985 Goodson JM, Offenbacher S, Fair DH, et al: Periodontal disease treatment by local drug delivery. J Periodontol 56:265–272, 1985

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Greenberg HS, , Ensminger WD, & Chandler WF, et al: Intraarterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system. J Neurosurg 61:423429, 1984 Greenberg HS, Ensminger WD, Chandler WF, et al: Intraarterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system. J Neurosurg 61:423–429, 1984

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Gutin PH, , Leibel SA, & Wara WM, et al: Recurrent malignant gliomas: survival following interstitial brachytherapy with high-activity iodine-125 sources. J Neurosurg 67:864873, 1987 Gutin PH, Leibel SA, Wara WM, et al: Recurrent malignant gliomas: survival following interstitial brachytherapy with high-activity iodine-125 sources. J Neurosurg 67:864–873, 1987

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Heller J: Biodegradable polymers in controlled drug delivery. Crit Rev Ther Drug Carrier Sys 1:3990, 1984 Heller J: Biodegradable polymers in controlled drug delivery. Crit Rev Ther Drug Carrier Sys 1:39–90, 1984

    • Search Google Scholar
    • Export Citation
  • 21.

    Hochberg FH, , Parker LM, & Takvorian T, et al: High-dose BCNU with autologous bone marrow rescue for recurrent glioblastoma multiforme. J Neurosurg 54:455460, 1981 Hochberg FH, Parker LM, Takvorian T, et al: High-dose BCNU with autologous bone marrow rescue for recurrent glioblastoma multiforme. J Neurosurg 54:455–460, 1981

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Hochberg FH, & Pruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30:907911, 1980 Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30:907–911, 1980

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Hochberg FH, , Pruitt AA, & Beck DO, et al: The rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma, in Howell LS (ed): Intra-Arterial and Intracavitary Chemotherapy. Boston: Martinus Nijhoff, 1984, pp 97109 Hochberg FH, Pruitt AA, Beck DO, et al: The rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma, in Howell LS(ed): Intra-Arterial and Intracavitary Chemotherapy. Boston: Martinus Nijhoff, 1984, pp 97–109

    • Search Google Scholar
    • Export Citation
  • 24.

    Kelly PJ, , Daumas-Duport C, & Scheithauer BW, et al: Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo Clin Proc 62:450459, 1987 Kelly PJ, Daumas-Duport C, Scheithauer BW, et al: Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo Clin Proc 62:450–459, 1987

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Kornblith PL, & Walker M: Chemotherapy for malignant gliomas. J Neurosurg 68:117, 1988 Kornblith PL, Walker M: Chemotherapy for malignant gliomas. J Neurosurg 68:1–17, 1988

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Kroin JS, & Penn RD: Intracerebral chemotherapy: chronic microinfusion of cisplatin. Neurosurgery 10:349354, 1982 Kroin JS, Penn RD: Intracerebral chemotherapy: chronic microinfusion of cisplatin. Neurosurgery 10:349–354, 1982

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Laurencin CT, , Domb AJ, & Morris CD, et al: High dosage administration of polyanhydrides in vivo: studies of biocompatibility and toxicology. Proc Int Symp Control Rel Bioact Mater 14:140, 1987 (Abstract) Laurencin CT, Domb AJ, Morris CD, et al: High dosage administration of polyanhydrides in vivo: studies of biocompatibility and toxicology. Proc Int Symp Control Rel Bioact Mater 14:140, 1987 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 28.

    Leibel SA, & Sheline GE: Radiation therapy for neoplasms of the brain. J Neurosurg 66:122, 1987 Leibel SA, Sheline GE: Radiation therapy for neoplasms of the brain. J Neurosurg 66:1–22, 1987

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Leong KW, , Brott BC, & Langer R: Bioerodible polyanhydrides as drug-carrier matrices. 1: Characterization, degradation, and release characteristics. J Biomed Mater Res 19:941955, 1985 Leong KW, Brott BC, Langer R: Bioerodible polyanhydrides as drug-carrier matrices. 1: Characterization, degradation, and release characteristics. J Biomed Mater Res 19:941–955, 1985

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Madajewicz JS, , West CR, & Park HC, et al: Phase II study — intra-arterial BCNU therapy for metastatic brain tumors. Cancer 47:653657, 1981 Madajewicz JS, West CR, Park HC, et al: Phase II study — intra-arterial BCNU therapy for metastatic brain tumors. Cancer 47:653–657, 1981

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Mahaley MS, , Mettlin C, & Natarajan N, et al: National survey of patterns of care for brain-tumor patients. J Neurosurg 71:826836, 1989 Mahaley MS, Mettlin C, Natarajan N, et al: National survey of patterns of care for brain-tumor patients. J Neurosurg 71:826–836, 1989

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Neuwelt EA, , Frenkel EP, & Gumerlock MK, et al: Developments in the diagnosis and treatment of primary CNS lymphoma. Cancer 58:16091620, 1986 Neuwelt EA, Frenkel EP, Gumerlock MK, et al: Developments in the diagnosis and treatment of primary CNS lymphoma. Cancer 58:1609–1620, 1986

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Patchell RA, , Tibbs PA, & Walsh JW, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494500, 1990 Patchell RA, Tibbs PA, Walsh JW, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494–500, 1990

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Pitt CG, & Schingler A: The design of controlled drug delivery systems based on biodegradable polymers, in Hafez ESE, & van Os WAA (eds): Biodegradable Delivery Systems for Contraceptives. Lancaster, England: MTP Press Ltd. 1980, Vol 1, pp 1746 Pitt CG, Schingler A: The design of controlled drug delivery systems based on biodegradable polymers, in Hafez ESE, van Os WAA(eds): Biodegradable Delivery Systems for Contraceptives. Lancaster, England: MTP Press Ltd. 1980, Vol 1, pp 17–46

    • Search Google Scholar
    • Export Citation
  • 35.

    Prados M, , Leibel S, & Barnett CM, et al: Interstitial brachytherapy far metastatic brain tumors. Cancer 63:657660, 1989 Prados M, Leibel S, Barnett CM, et al: Interstitial brachytherapy far metastatic brain tumors. Cancer 63:657–660, 1989

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Rall DP, & Zubrod CG: Mechanism of drug absorption and excretion. Passage of drugs in and out of the central nervous system. Annu Rev Pharmacol 2:109128, 1962 Rall DP, Zubrod CG: Mechanism of drug absorption and excretion. Passage of drugs in and out of the central nervous system. Annu Rev Pharmacol 2:109–128, 1962

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Rubin RC, , Ommaya AK, & Henderson ES, et al: Cerebrospinal fluid perfusion for central nervous system neoplasms. Neurology 16:680692, 1966 Rubin RC, Ommaya AK, Henderson ES, et al: Cerebrospinal fluid perfusion for central nervous system neoplasms. Neurology 16:680–692, 1966

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Shapiro WR: Introduction: brain tumors. Semin Oncol 13:13, 1986 Shapiro WR: Introduction: brain tumors. Semin Oncol 13:1–3, 1986

    • Search Google Scholar
    • Export Citation
  • 39.

    Shapiro WR, , Green SB, & Burger PC, et al: A randomized comparison of intra-arterial vs. intravenous BCNU for patients with malignant glioma: interim analysis demonstrating lack of efficacy for IA BCNU. Proc Am Soc Clin Oncol 6:69, 1987 (Abstract) Shapiro WR, Green SB, Burger PC, et al: A randomized comparison of intra-arterial vs. intravenous BCNU for patients with malignant glioma: interim analysis demonstrating lack of efficacy for IA BCNU. Proc Am Soc Clin Oncol 6:69, 1987 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 40.

    Solero CL, , Monfardini S, & Brambilla C, et al: Controlled study with BCNU vs CCNU as adjuvant chemotherapy following surgery plus radiotherapy for glioblastoma multiforme. Cancer Clin Trials 2:4348, 1979 Solero CL, Monfardini S, Brambilla C, et al: Controlled study with BCNU vs CCNU as adjuvant chemotherapy following surgery plus radiotherapy for glioblastoma multiforme. Cancer Clin Trials 2:43–48, 1979

    • Search Google Scholar
    • Export Citation
  • 41.

    Soskolne A, , Golomb G, & Friedman M, et al: New sustained release dosage form of chlorhexidine for dental use. II. Use in periodontal therapy. J Periodontal Res 18:330336, 1983 Soskolne A, Golomb G, Friedman M, et al: New sustained release dosage form of chlorhexidine for dental use. II. Use in periodontal therapy. J Periodontal Res 18:330–336, 1983

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42.

    Stewart DJ, , Benjamin RS, & Zimmerman S, et al: Clinical pharmacology of intraarterial cis-diaminedichloroplatinum (II). Cancer Res 42:20592062, 1982 Stewart DJ, Benjamin RS, Zimmerman S, et al: Clinical pharmacology of intraarterial cis-diaminedichloroplatinum (II). Cancer Res 42:2059–2062, 1982

    • Search Google Scholar
    • Export Citation
  • 43.

    Tamargo RJ, , Epstein JI, & Reinhard CS, et al: Brain biocompatibility of a biodegradable, controlled-release polymer in rats. J Biomed Mater Res 23:253266, 1989 Tamargo RJ, Epstein JI, Reinhard CS, et al: Brain biocompatibility of a biodegradable, controlled-release polymer in rats. J Biomed Mater Res 23:253–266, 1989

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44.

    Tamargo RJ, , Epstein JI, & Yang MB, et al: Interstitial vs systemic chemotherapy of the intracranial 9L gliosarcoma: controlled-release polymers for local therapy. J Neurosurg 70:311A, 1989 Tamargo RJ, Epstein JI, Yang MB, et al: Interstitial vs systemic chemotherapy of the intracranial 9L gliosarcoma: controlled-release polymers for local therapy. J Neurosurg 70:311A, 1989

    • Search Google Scholar
    • Export Citation
  • 45.

    Walker MD, , Alexander E Jr, & Hunt WE, et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49:333343, 1978 Walker MD, Alexander E Jr, Hunt WE, et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49:333–343, 1978

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46.

    Walker MD, , Green SB, & Byar DP, et al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303:13231329, 1980 Walker MD, Green SB, Byar DP, et al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303:1323–1329, 1980

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47.

    Wara WM: Radiation therapy for brain tumors. Cancer 55:22912295, 1985 Wara WM: Radiation therapy for brain tumors. Cancer 55:2291–2295, 1985

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48.

    Weiss SR, & Raskind R: Treatment of malignant brain tumors by local methotrexate. A preliminary report. Int Surg 51:149155, 1969 Weiss SR, Raskind R: Treatment of malignant brain tumors by local methotrexate. A preliminary report. Int Surg 51:149–155, 1969

    • Search Google Scholar
    • Export Citation
  • 49.

    Yang MB, , Tamargo RJ, & Brem H: Controlled delivery of 1,3,-bis(2-chloroethyl)-1-nitrosourea from ethylene-vinyl acetate copolymer. Cancer Res 49:51035107, 1989 Yang MB, Tamargo RJ, Brem H: Controlled delivery of 1,3,-bis(2-chloroethyl)-1-nitrosourea from ethylene-vinyl acetate copolymer. Cancer Res 49:5103–5107, 1989

    • Search Google Scholar
    • Export Citation

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