Integrin alpha V beta 3 targeted dendrimer-rapamycin conjugate reduces fibroblast-mediated prostate tumor progression and metastasis

Elliott E. Hill, Jin Koo Kim, Younghun Jung, Chris K. Neeley, Kenneth Pienta, Russell S. Taichman, Jacques E. Nor, James R. Baker, Paul H. Krebsbach

Research output: Contribution to journalArticle

Abstract

Therapeutic strategies targeting both cancer cells and associated cells in the tumor microenvironment offer significant promise in cancer therapy. We previously reported that generation 5 (G5) dendrimers conjugated with cyclic-RGD peptides target cells expressing integrin alpha V beta 3. In this study, we report a novel dendrimer conjugate modified to deliver the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. In vitro analyses demonstrated that this drug conjugate, G5-FI-RGD-rapamycin, binds to prostate cancer (PCa) cells and fibroblasts to inhibit mTOR signaling and VEGF expression. In addition, G5-FI-RGD-rapamycin inhibits mTOR signaling in cancer cells more efficiently under proinflammatory conditions compared to free rapamycin. In vivo studies established that G5-FI-RGD-rapamycin significantly inhibits fibroblast-mediated PCa progression and metastasis. Thus, our results suggest the potential of new rapamycin-conjugated multifunctional nanoparticles for PCa therapy.

Original languageEnglish (US)
Pages (from-to)8074-8083
Number of pages10
JournalJournal of Cellular Biochemistry
Volume119
Issue number10
DOIs
StatePublished - Nov 1 2018

Fingerprint

Integrin alphaV
Dendrimers
Sirolimus
Fibroblasts
Tumors
Prostate
Neoplasm Metastasis
Neoplasms
Cells
Prostatic Neoplasms
Cyclic Peptides
Tumor Microenvironment
Nanoparticles
Vascular Endothelial Growth Factor A

Keywords

  • dendrimer
  • fibroblast
  • integrin
  • metastasis
  • mTOR
  • prostate cancer
  • rapamycin
  • VEGF

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Integrin alpha V beta 3 targeted dendrimer-rapamycin conjugate reduces fibroblast-mediated prostate tumor progression and metastasis. / Hill, Elliott E.; Kim, Jin Koo; Jung, Younghun; Neeley, Chris K.; Pienta, Kenneth; Taichman, Russell S.; Nor, Jacques E.; Baker, James R.; Krebsbach, Paul H.

In: Journal of Cellular Biochemistry, Vol. 119, No. 10, 01.11.2018, p. 8074-8083.

Research output: Contribution to journalArticle

Hill, Elliott E. ; Kim, Jin Koo ; Jung, Younghun ; Neeley, Chris K. ; Pienta, Kenneth ; Taichman, Russell S. ; Nor, Jacques E. ; Baker, James R. ; Krebsbach, Paul H. / Integrin alpha V beta 3 targeted dendrimer-rapamycin conjugate reduces fibroblast-mediated prostate tumor progression and metastasis. In: Journal of Cellular Biochemistry. 2018 ; Vol. 119, No. 10. pp. 8074-8083.
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abstract = "Therapeutic strategies targeting both cancer cells and associated cells in the tumor microenvironment offer significant promise in cancer therapy. We previously reported that generation 5 (G5) dendrimers conjugated with cyclic-RGD peptides target cells expressing integrin alpha V beta 3. In this study, we report a novel dendrimer conjugate modified to deliver the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. In vitro analyses demonstrated that this drug conjugate, G5-FI-RGD-rapamycin, binds to prostate cancer (PCa) cells and fibroblasts to inhibit mTOR signaling and VEGF expression. In addition, G5-FI-RGD-rapamycin inhibits mTOR signaling in cancer cells more efficiently under proinflammatory conditions compared to free rapamycin. In vivo studies established that G5-FI-RGD-rapamycin significantly inhibits fibroblast-mediated PCa progression and metastasis. Thus, our results suggest the potential of new rapamycin-conjugated multifunctional nanoparticles for PCa therapy.",
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AU - Pienta, Kenneth

AU - Taichman, Russell S.

AU - Nor, Jacques E.

AU - Baker, James R.

AU - Krebsbach, Paul H.

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