1. Integrin alpha V beta 3 targeted dendrimer‐rapamycin conjugate reduces fibroblast‐mediated prostate tumor progression and metastasis
- Author
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Hill, Elliott E, Kim, Jin Koo, Jung, Younghun, Neeley, Chris K, Pienta, Kenneth J, Taichman, Russell S, Nor, Jacques E, Baker, James R, and Krebsbach, Paul H
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Bioengineering ,Cancer ,Urologic Diseases ,Nanotechnology ,Aging ,Prostate Cancer ,5.1 Pharmaceuticals ,Aetiology ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,Animals ,Blotting ,Western ,Cell Line ,Tumor ,Cells ,Cultured ,Dendrimers ,Fibroblasts ,Flow Cytometry ,Humans ,Integrin alphaVbeta3 ,Male ,Mice ,Neoplasm Metastasis ,PC-3 Cells ,Peptides ,Cyclic ,Prostatic Neoplasms ,Sirolimus ,dendrimer ,fibroblast ,integrin ,metastasis ,mTOR ,prostate cancer ,rapamycin ,VEGF ,Medical Physiology ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - 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.
- Published
- 2018