cells Review Nano-Strategies Targeting the Integrin αvβ3 Network for Cancer Therapy Tsai-Mu Cheng 1,2 , Wong-Jin Chang 1 , Hsiu-Yi Chu 1 , Roberto De Luca 3 , Jens Z. Pedersen 4 , Sandra Incerpi 5 , Zi-Lin Li 6,7 , Ya-Jung Shih 6,7 , Hung-Yun Lin 7,8,9,10,11, *, Kuan Wang 6 and Jacqueline Whang-Peng 7,8   Citation: Cheng, T.-M.; Chang, W.-J.; Chu, H.-Y.; De Luca, R.; Pedersen, J.Z.; Incerpi, S.; Li, Z.-L.; Shih, Y.-J.; Lin, H.-Y.; Wang, K.; et al. Nano-Strategies Targeting the Integrin αvβ3 Network for Cancer Therapy. Cells 2021, 10, 1684. https:// doi.org/10.3390/cells10071684 Academic Editor: Sergio Comincini Received: 27 May 2021 Accepted: 30 June 2021 Published: 3 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Graduate Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; tmcheng@tmu.edu.tw (T.-M.C.); wjchang@tmu.edu.tw (W.-J.C.); chuxiuyi@tmu.edu.tw (H.-Y.C.) 2 Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan 3 Department of Neurology, Center for Life Science, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; rdeluca@bidmc.harvard.edu 4 Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy; j.z.pedersen@gmail.com 5 Department of Sciences, University “Roma Tre”, 00154 Rome, Italy; sandra.incerpi@uniroma3.it 6 Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan; lizilin919@tmu.edu.tw (Z.-L.L.); shihyj@tmu.edu.tw (Y.-J.S.); wangk007@gmail.com (K.W.) 7 Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; jqwpeng@nhri.org.tw 8 Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan 9 Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan 10 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan 11 Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY 12144, USA * Correspondence: linhy@tmu.edu.tw; Tel.: +886-2-27361661 (ext. 7680) Abstract: Integrin αvβ3, a cell surface receptor, participates in signaling transduction pathways in cancer cell proliferation and metastasis. Several ligands bind to integrin αvβ3 to regulate proliferation and metastasis in cancer cells. Crosstalk between the integrin and other signal transduction pathways also plays an important role in modulating cancer proliferation. Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) activates the downstream integrin FAK to stimulate biological activities including cancer proliferation and metastasis. Blockage of signals related to integrin αvβ3 was shown to be a promising target for cancer therapies. 3,3 ′ ,5,5 ′ -tetraiodothyroacetic acid (tetrac) completely binds to the integrin with the thyroid hormone to suppress cancer proliferation. The (E)-stilbene analog, resveratrol, also binds to integrin αvβ3 to inhibit cancer growth. Recently, nanotechnologies have been used in the biomedical field for detection and therapeutic purposes. In the current review, we show and evaluate the potentiation of the nanomaterial carrier RGD peptide, derivatives of PLGA-tetrac (NDAT), and nanoresveratrol targeting integrin αvβ3 in cancer therapies. Keywords: integrin αvβ3; drug-delivery system; nanomaterial; NDAT; resveratrol; RGD 1. Introduction Malignancy-related deaths still rank at the top among causes of death. Although recent declines in mortality have occurred, lung cancer is still the number one malignancy- related death, and for years it’s mortality has exceeded that of breast, prostate, colorectal, and brain cancers combined. The decline in the mortality rate from lung cancer accelerated from 2013 to 2017. However, reductions in the death rates from female breast and colorectal cancers have slowed and in prostate cancer has even halted over the past decade. The death rate of breast cancer patients peaked in 2020. In summary, slowing the momentum of mortality from some cancers by early detection is essential for other notable increasingly Cells 2021, 10, 1684. https://doi.org/10.3390/cells10071684 https://www.mdpi.com/journal/cells