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

Betty Tyler, Kirk D. Fowers, Khan W. Li, Violette Renard Recinos, Justin M. Caplan, Alia Hdeib, Rachel Grossman, Luca Basaldella, Kimon Bekelis, Gustavo Pradilla, Federico Legnani, Henry Brem

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)210-217
Number of pages8
JournalJournal of Neurosurgery
Volume113
Issue number2
DOIs
Publication statusPublished - Aug 2010

Fingerprint

Paclitaxel
Brain Neoplasms
Radiotherapy
Hot Temperature
Gels
Radioactivity
Glioma
Injections
Gliosarcoma
Radiation-Sensitizing Agents
Safety
Inbred F344 Rats
Neoplasms
Cell Proliferation
Therapeutics

Keywords

  • 9L gliosarcoma
  • OncoGel
  • Paclitaxel
  • Radioactivity
  • Radiotherapy
  • Rat

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats : Laboratory investigation. / Tyler, Betty; Fowers, Kirk D.; Li, Khan W.; Recinos, Violette Renard; Caplan, Justin M.; Hdeib, Alia; Grossman, Rachel; Basaldella, Luca; Bekelis, Kimon; Pradilla, Gustavo; Legnani, Federico; Brem, Henry.

In: Journal of Neurosurgery, Vol. 113, No. 2, 08.2010, p. 210-217.

Research output: Contribution to journalArticle

Tyler, B, Fowers, KD, Li, KW, Recinos, VR, Caplan, JM, Hdeib, A, Grossman, R, Basaldella, L, Bekelis, K, Pradilla, G, Legnani, F & Brem, H 2010, 'A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats: Laboratory investigation', Journal of Neurosurgery, vol. 113, no. 2, pp. 210-217. https://doi.org/10.3171/2009.11.JNS08162
Tyler, Betty ; Fowers, Kirk D. ; Li, Khan W. ; Recinos, Violette Renard ; Caplan, Justin M. ; Hdeib, Alia ; Grossman, Rachel ; Basaldella, Luca ; Bekelis, Kimon ; Pradilla, Gustavo ; Legnani, Federico ; Brem, Henry. / A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats : Laboratory investigation. In: Journal of Neurosurgery. 2010 ; Vol. 113, No. 2. pp. 210-217.
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T1 - A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats

T2 - Laboratory investigation

AU - Tyler, Betty

AU - Fowers, Kirk D.

AU - Li, Khan W.

AU - Recinos, Violette Renard

AU - Caplan, Justin M.

AU - Hdeib, Alia

AU - Grossman, Rachel

AU - Basaldella, Luca

AU - Bekelis, Kimon

AU - Pradilla, Gustavo

AU - Legnani, Federico

AU - Brem, Henry

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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.

KW - 9L gliosarcoma

KW - OncoGel

KW - Paclitaxel

KW - Radioactivity

KW - Radiotherapy

KW - Rat

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