A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats

Laboratory investigation

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Object

Paclitaxel, a cellular proliferation inhibitor/radiation sensitizer, while effective against gliomas in vitro, has poor CNS penetration and dose-limiting toxicities when administered systemically. OncoGel (paclitaxel in Re-Gel) provides controlled local paclitaxel release when placed into the CNS. The authors evaluated the safety and efficacy of OncoGel in rats with intracranial 9L gliosarcoma.

Methods

Safety studies included intracranial delivery of increasing volumes of ReGel and OncoGel containing 1.5 (OncoGel 1.5) or 6.3 (OncoGel 6.3) mg/ml paclitaxel. An in vivo radiolabeled biodistribution study was performed in 18 Fischer-344 rats to determine intracerebral distribution. Efficacy studies compared overall survival for controls, ReGel only, radiation therapy only, OncoGel 6.3, or OncoGel 6.3 in combination with radiation therapy. ReGel and OncoGel 6.3 were delivered either simultaneously with tumor implantation (Day 0) or 5 days later (Day 5). Radiation therapy was given on Day 5.

Results

Control and ReGel animals died of tumor within 17 days. Survival significantly increased in the Onco-Gel 6.3 group on Day 0 (median 31 days; p = 0.0001), in the OncoGel 6.3 group on Day 5 (median 17 days; p = 0.02), and in the radiation therapy–only group (median 26 days; p = 0.0001) compared with controls. Animals receiving both OncoGel and radiation therapy had the longest median survival: 83 days in the group with radiation therapy combined with OncoGel 6.3 on Day 0, and 32 days in the group combined with OncoGel 6.3 on Day 5 (p = 0.0001 vs controls). After 120 days, 37.5% of the animals in the OncoGel Day 0 group, 37.5% of animals in the OncoGel 6.3 Day 0 in combination with radiation therapy group, and 12.5% of the animals in the OncoGel 6.3 on Day 5 in combination with radiation therapy group were alive. In the biodistribution study, measurable radioactivity was observed throughout the ipsilateral hemisphere up to 3 weeks after the OncoGel injection, with the most radioactivity detected 3 hours after injection. The highest dose of radioactivity observed in the contralateral hemisphere was at the Day 3 time point.

Conclusions

OncoGel containing 6.3 mg/ml of paclitaxel is safe for intracranial injection in rats and effective when administered on Day 0. When combined with radiation therapy, the combination was more effective than either therapy alone and should be studied clinically for the treatment of malignant glioma.

Article Information

Address correspondence to: Betty Tyler, B.A., The Johns Hopkins University School of Medicine, Department of Neurosurgery, 1550 Orleans Street, CRB-2 2M41, Baltimore, Maryland 21231. email: btyler@jhmi.edu.

Please include this information when citing this paper: published online December 11, 2009; DOI: 10.3171/2009.11.JNS08162.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Kaplan-Meier survival curves of animals intracranially injected with various volumes and concentrations of ReGel and OncoGel in the safety studies. Intracranial injections of 25 μl of either ReGel (2 rats; solid diamonds) or OncoGel 6.3 (2 rats; open squares) resulted in no deaths. Injections of 50 μl of ReGel (6 rats; open diamonds) or OncoGel 6.3 (9 rats; solid circles) produced deaths in 33 and 22%, respectively. Animals injected intracranially with 75 μl of ReGel (2 rats; solid triangles) or OncoGel 6.3 (2 rats; solid squares) showed deaths in 100 and 50%, respectively. Animals injected intracranially with 100 μl of either OncoGel 6.3 (3 rats; open circles) or ReGel (3 rats; ×) showed deaths in 100 and 67%, respectively. Based on these data, 10- and 35- μl injections were used for the subsequent efficacy studies.

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    Bar graphs comparing intracerebral distribution of paclitaxel (Taxol) in the rat ipsilateral (injection) hemisphere (upper) and contralateral hemisphere (lower) using OncoGel. The x-axis is the distance from the injection site. Positive numbers represent anterior distances and negative numbers represent posterior distances. Each bar represents 3 animals.

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    Intracranial efficacy of OncoGel 6.3 with and without radiation therapy for the treatment of experimental malignant glioma. Fischer-344 rats were implanted with 9L glioma tumor. Controls (8 rats; black solid triangles) received no further treatment and had a median survival of 13 days. All treatment and placebo injections were delivered in 35 μl. Animals receiving ReGel on either Day 0 (8 rats; open diamonds) or Day 5 (5 rats; open triangles) had median survivals of 14 and 17 days, respectively. Animals that received OncoGel 6.3 on Day 5 (8 rats; ×) had a median survival of 17 days. Animals receiving 20 Gy radiation therapy only (7 rats; blue solid circles) had a median survival of 26 days with a mortality of 100%. An injection of OncoGel on Day 5 with radiation therapy (8 rats; green open circles) resulted in a median survival of 32 days with 12.5% long-term survivors. Animals receiving either OncoGel 6.3 on Day 0 alone (8 rats; black solid squares) or on Day 0 in combination with radiation therapy (8 rats; red open squares) had median survival times of 31 and 83 days, respectively, with 37.5% long-term survivors in both groups.

References

  • 1

    Bagley CABookland MJPindrik JAOzmen TGokaslan ZLWitham TF: Local delivery of OncoGel delays paresis in rat metastatic spinal tumor model. J Neurosurg Spine 2:1941982007

    • Search Google Scholar
    • Export Citation
  • 2

    Brem HPiantadosi SBurger PCWalker MSelker RVick NA: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 345:100810121995

    • Search Google Scholar
    • Export Citation
  • 3

    Cahan MAWalter KAColvin OMBrem H: Cytotoxicity of taxol in vitro against human and rat malignant brain tumors. Cancer Chemother Pharmacol 33:4414441994

    • Search Google Scholar
    • Export Citation
  • 4

    Eiseman JLEddington NDLeslie JMacAuley CSentz DLZuhowski M: Plasma pharmacokinetics and tissue distribution of paclitaxel in CD2F1 mice. Cancer Chemother Pharmacol 34:4654711994

    • Search Google Scholar
    • Export Citation
  • 5

    Fellner SBauer BMiller DSSchaffrik MFankhänel MSpruss T: Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo. J Clin Invest 110:130913182002

    • Search Google Scholar
    • Export Citation
  • 6

    Fung LKEwend MGSills ASipos EPThompson RWatts M: Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res 58:6726841998

    • Search Google Scholar
    • Export Citation
  • 7

    Heimans JJVermorken JBWolbers JGEeltink CMMeijer OWTaphoorn MJ: Paclitaxel (Taxol) concentrations in brain tumor tissue. Ann Oncol 5:9519531994

    • Search Google Scholar
    • Export Citation
  • 8

    Hochberg FHPruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30:9079111980

  • 9

    Jeong BBae YHKim SW: In situ gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions and degradation thereof. J Biomed Mater Res 50:1711772000

    • Search Google Scholar
    • Export Citation
  • 10

    Li KWDang WTyler BMTroiano GTihan TBrem H: Polilactofate microspheres for Paclitaxel delivery to central nervous system malignancies. Clin Cancer Res 9:344134472003

    • Search Google Scholar
    • Export Citation
  • 11

    Lidar ZMardor YJonas TPfeffer RFaibel MNass D: Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg 100:4724792004

    • Search Google Scholar
    • Export Citation
  • 12

    Linghu EMatthes KMino-Kenudson MBrugge WR: Feasibility of endoscopic ultrasound-guided OncoGel (ReGel/paclitaxel) injection into the pancreas in pigs. Endoscopy 37:114011422005

    • Search Google Scholar
    • Export Citation
  • 13

    Marupudi NIHan JELi KWRenard VMTyler BMBrem H: Paclitaxel: a review of adverse toxicities and novel delivery strategies. Expert Opin Drug Saf 6:6096212007

    • Search Google Scholar
    • Export Citation
  • 14

    Matthes KMino-Kenudson MSahani DVHolalkere NFowers KDRathi R: EUS-guided injection of paclitaxel (OncoGel) provides therapeutic drug concentrations in the porcine pancreas (with video). Gastrointest Endosc 65:4484532007

    • Search Google Scholar
    • Export Citation
  • 15

    Pradilla GWang PPGabikian PLi KMagee CAWalter KA: Local intracerebral administration of Paclitaxel with the paclimer delivery system: toxicity study in a canine model. J Neurooncol 76:1311382006

    • Search Google Scholar
    • Export Citation
  • 16

    Samlowski WEMcGregor JRJurek MBaudys MZentner GMFowers KD: ReGel polymer-based delivery of interleukin-2 as a cancer treatment. J Immunother 29:5245352006

    • Search Google Scholar
    • Export Citation
  • 17

    Valtonen STimonen UToivanen PKalimo HKivipelto LHeiskanen O: Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 41:44491997

    • Search Google Scholar
    • Export Citation
  • 18

    Walter KACahan MAGur ATyler BHilton JColvin OM: Interstitial taxol delivered from a biodegradable polymer implant against experimental malignant glioma. Cancer Res 54:220722121994

    • Search Google Scholar
    • Export Citation
  • 19

    Westphal MRam ZRiddle VHilt DBortey E: Executive Committee of the Gliadel Study Group: Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien) 148:2692752006

    • Search Google Scholar
    • Export Citation
  • 20

    Zentner GMRathi RShih CMcRea JCSep MHOh M: Biodegradable block copolymers for delivery of proteins and water-insoluble drugs. J Control Release 72:2032152001

    • Search Google Scholar
    • Export Citation

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