Integrin alpha V beta 3 targeted dendrimer‐rapamycin conjugate reduces fibroblast‐mediated prostate tumor progression and metastasis. Issue 10 (22nd June 2018)

• Record Type: Journal Article
• Authors: Hill, Elliott E.; Kim, Jin Koo; Jung, Younghun; Neeley, Chris K.; Pienta, Kenneth J.; Taichman, Russell S.; Nor, Jacques E.; Baker, James R.; Krebsbach, Paul H.
• Is Part Of: Journal of cellular biochemistry. Volume 119:Issue 10(2018)
• Page Start: 8074
• Page End: 8083
• Publication Date: 2018-06-22
• Subjects: dendrimer -- fibroblast -- integrin -- metastasis -- mTOR -- prostate cancer -- rapamycin -- VEGF; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.26727
• Languages: English
• ISSNs: 0730-2312

Abstract

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. Abstract : Here, we synthesized and characterized a novel dendrimer conjugate, G5‐FI‐RGD‐rapamycin. Multifunctional G5‐FI‐RGD‐rapamycin binds to PCa and fibroblasts via alpha V beta 3 integrin and significantly inhibits mTOR signaling and VEGF expression. These in vitro data were confirmed by in vivo data that G5‐FI‐RGD‐rapamycin inhibits fibroblast‐mediated PCa progression and metastasis.