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

• DOI: 10.1002/jcb.26727
• Publication Date: 2018-01-30T10:03:03Z
• Authors: Elliott E. Hill; Jin Koo Kim; Younghun Jung; Chris K. Neeley; Kenneth J. Pienta; Russell S. Taichman; Jacques E. Nor; James R. Baker; Paul H. Krebsbach
• Keywords: Male; 0301 basic medicine; Aging; Medical Physiology; dendrimer; fibroblast; Mice; Nanotechnology; 2.1 Biological and endogenous factors; Cellular and Developmental Biology; Aetiology; Neoplasm Metastasis; Cells, Cultured; Cancer; Cyclic; Tumor; Cultured; Blotting; Prostate Cancer; Biological Sciences; prostate cancer; Flow Cytometry; VEGF; 3. Good health; 5.1 Pharmaceuticals; PC-3 Cells; mTOR; Development of treatments and therapeutic interventions; Western; Urologic Diseases; Biochemistry & Molecular Biology; Dendrimers; integrin; Science; Cells; Blotting, Western; 610; Bioengineering; Peptides, Cyclic; Cell Line; 03 medical and health sciences; Cell Line, Tumor; Health Sciences; Genetics; metastasis; Animals; Humans; Sirolimus; rapamycin; Molecular; Prostatic Neoplasms; Fibroblasts; Integrin alphaVbeta3; Biochemistry and cell biology; Biochemistry and Cell Biology; Peptides

AbstractTherapeutic 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.