Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors

Justin S Hanes, A. Sills, Z. Zhao, K. W. Suh, Betty Mae Tyler, F. DiMeco, D. J. Brat, M. A. Choti, K. W. Leong, E. M. Pardoll, Henry Brem

Research output: Contribution to journalArticle

Abstract

Purpose. The purpose of our study was to develop an injectable polymeric system for the long-term localized delivery of bioactive interleukin-2 for antitumor immunotherapy. Methods. IL-2 was encapsulated into gelatin and chondroitin-6-sulfate using an aqueous-based complex coacervation. CTLL-2 cells were used to measure the bioactivity of released IL-2 and radiolabeled IL-2 was used for release studies in the rat brain and mouse liver. Antitumor efficacy studies were carried out in primary (9L gliosarcoma) and metastatic (B16-F10 melanoma) brain tumor models in rats and mice, respectively, as well as a murine liver tumor model (CT26 carcinoma). Survivors of the metastatic brain tumor challenge were rechallenged with tumor in the opposite lobe of the brain to confirm that antitumor immunologic memory had developed. Results. Bioactive IL-2 was released for over 2 weeks in vitro and in vivo IL-2 release showed significant IL-2 levels for up to 21 days. Polymeric IL-2 microspheres injected intratumorally were statistically more effective in protecting animals challenged with fatal tumor doses in the brain and the liver than placebo or autologous tumor cells genetically engineered to secrete IL-2. Immunologic memory was induced following IL-2 microsphere therapy in the B16-F10 brain tumor model that was capable of protecting 42% of animals from a subsequent intracranial tumor challenge, suggesting that tumor destruction was mediated by the immune system. Conclusions. Local IL-2 therapy using novel polymeric carriers, aimed at stimulating long-lasting antitumor immunity, may provide an improved method of treating a variety of cancers.

Original languageEnglish (US)
Pages (from-to)899-906
Number of pages8
JournalPharmaceutical Research
Volume18
Issue number7
DOIs
StatePublished - 2001

Fingerprint

Biodegradable polymers
Brain Neoplasms
Liver
Interleukin-2
Tumors
Brain
Polymers
Animals
Neoplasms
Immunologic Memory
Microspheres
Rats
Gliosarcoma
Data storage equipment
Experimental Melanomas
Chondroitin Sulfates
Immune system
Gelatin
Bioactivity
Immunotherapy

Keywords

  • Brain cancer
  • Controlled release
  • Immunotherapy
  • Interleukin-2
  • Liver cancer
  • Polymer microspheres

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors. / Hanes, Justin S; Sills, A.; Zhao, Z.; Suh, K. W.; Tyler, Betty Mae; DiMeco, F.; Brat, D. J.; Choti, M. A.; Leong, K. W.; Pardoll, E. M.; Brem, Henry.

In: Pharmaceutical Research, Vol. 18, No. 7, 2001, p. 899-906.

Research output: Contribution to journalArticle

Hanes, Justin S ; Sills, A. ; Zhao, Z. ; Suh, K. W. ; Tyler, Betty Mae ; DiMeco, F. ; Brat, D. J. ; Choti, M. A. ; Leong, K. W. ; Pardoll, E. M. ; Brem, Henry. / Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors. In: Pharmaceutical Research. 2001 ; Vol. 18, No. 7. pp. 899-906.
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T1 - Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors

AU - Hanes, Justin S

AU - Sills, A.

AU - Zhao, Z.

AU - Suh, K. W.

AU - Tyler, Betty Mae

AU - DiMeco, F.

AU - Brat, D. J.

AU - Choti, M. A.

AU - Leong, K. W.

AU - Pardoll, E. M.

AU - Brem, Henry

PY - 2001

Y1 - 2001

N2 - Purpose. The purpose of our study was to develop an injectable polymeric system for the long-term localized delivery of bioactive interleukin-2 for antitumor immunotherapy. Methods. IL-2 was encapsulated into gelatin and chondroitin-6-sulfate using an aqueous-based complex coacervation. CTLL-2 cells were used to measure the bioactivity of released IL-2 and radiolabeled IL-2 was used for release studies in the rat brain and mouse liver. Antitumor efficacy studies were carried out in primary (9L gliosarcoma) and metastatic (B16-F10 melanoma) brain tumor models in rats and mice, respectively, as well as a murine liver tumor model (CT26 carcinoma). Survivors of the metastatic brain tumor challenge were rechallenged with tumor in the opposite lobe of the brain to confirm that antitumor immunologic memory had developed. Results. Bioactive IL-2 was released for over 2 weeks in vitro and in vivo IL-2 release showed significant IL-2 levels for up to 21 days. Polymeric IL-2 microspheres injected intratumorally were statistically more effective in protecting animals challenged with fatal tumor doses in the brain and the liver than placebo or autologous tumor cells genetically engineered to secrete IL-2. Immunologic memory was induced following IL-2 microsphere therapy in the B16-F10 brain tumor model that was capable of protecting 42% of animals from a subsequent intracranial tumor challenge, suggesting that tumor destruction was mediated by the immune system. Conclusions. Local IL-2 therapy using novel polymeric carriers, aimed at stimulating long-lasting antitumor immunity, may provide an improved method of treating a variety of cancers.

AB - Purpose. The purpose of our study was to develop an injectable polymeric system for the long-term localized delivery of bioactive interleukin-2 for antitumor immunotherapy. Methods. IL-2 was encapsulated into gelatin and chondroitin-6-sulfate using an aqueous-based complex coacervation. CTLL-2 cells were used to measure the bioactivity of released IL-2 and radiolabeled IL-2 was used for release studies in the rat brain and mouse liver. Antitumor efficacy studies were carried out in primary (9L gliosarcoma) and metastatic (B16-F10 melanoma) brain tumor models in rats and mice, respectively, as well as a murine liver tumor model (CT26 carcinoma). Survivors of the metastatic brain tumor challenge were rechallenged with tumor in the opposite lobe of the brain to confirm that antitumor immunologic memory had developed. Results. Bioactive IL-2 was released for over 2 weeks in vitro and in vivo IL-2 release showed significant IL-2 levels for up to 21 days. Polymeric IL-2 microspheres injected intratumorally were statistically more effective in protecting animals challenged with fatal tumor doses in the brain and the liver than placebo or autologous tumor cells genetically engineered to secrete IL-2. Immunologic memory was induced following IL-2 microsphere therapy in the B16-F10 brain tumor model that was capable of protecting 42% of animals from a subsequent intracranial tumor challenge, suggesting that tumor destruction was mediated by the immune system. Conclusions. Local IL-2 therapy using novel polymeric carriers, aimed at stimulating long-lasting antitumor immunity, may provide an improved method of treating a variety of cancers.

KW - Brain cancer

KW - Controlled release

KW - Immunotherapy

KW - Interleukin-2

KW - Liver cancer

KW - Polymer microspheres

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