Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac

International Journal of Nanomedicine Dovepress open access to scientific and medical research O r i g in a l R e s e a r c h International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 5.135.254.153 on 12-Jul-2018 For personal use only. Open Access Full Text Article Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nanodiamino-tetrac This article was published in the following Dove Press journal: International Journal of Nanomedicine 15 February 2017 Number of times this article has been viewed Thangirala Sudha 1 Dhruba J Bharali 1 Murat Yalcin 1,2 Noureldien HE Darwish 1,3 Melis Debreli Coskun 1,4 Kelly A Keating 1 Hung-Yun Lin 5,6 Paul J Davis 1,7 Shaker A Mousa 1 The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA; 2Department of Physiology, Veterinary Medicine Faculty, Uludag University, Gorukle, Bursa, Turkey; 3 Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 4 Department of Biology, Faculty of Arts and Sciences, Uludag University, Gorukle, Bursa, Turkey; 5PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, 6Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; 7 Department of Medicine, Albany Medical College, Albany, NY, USA 1 Correspondence: Shaker A Mousa The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY 12144, USA Tel +1 518 694 7397 Fax +1 518 694 7567 Email Introduction Generic cancer chemotherapeutic agents in use today act by a number of mechanisms.1–5 They destroy cell DNA, inhibit synthesis of nucleic acid components that make up DNA and RNA, disrupt gene transcription of specific RNAs, or they inhibit protein synthesis. Doxorubicin is an example of an anticancer agent that disorders gene transcription of specific RNAs,3 and paclitaxel is a protein synthesis inhibitor.4 These various drug effects are not limited to cancer cells, and thus the generic anticancer drugs act on nonmalignant cells to generate important side effects. Because of the side effect profiles of generic cancer chemotherapeutic agents, there is substantial interest in developing molecular mechanisms that direct these drugs specifically to cancer cells.6–11 Tetraiodothyroacetic acid (tetrac) is a ligand of a specific target on the extracellular domain of plasma membrane integrin αvβ3,12 an integrin generously expressed by cancer cells and by dividing endothelial cells of tumor-relevant blood vessels. We have covalently bonded tetrac via a short diaminopropane linker to a 150–200 nm poly(lactic-co-glycolic acid) (PLGA) nanoparticle (Nanotetrac, nano-diamino-tetrac [NDAT]), as shown in Figure 1. The nanoparticle of NDAT can encapsulate a chemotherapeutic drug payload13 to offer tumor-targeted drug delivery and the prospect of decreased systemic toxicity. The substantial progress made elsewhere in the development of targeted PLGA-based anticancer drug delivery systems has been reviewed by van der Meel et al14 and Iyer et al.15 Recently described cancer cell-targeting moieties 1305 submit your manuscript | www.dovepress.com International Journal of Nanomedicine 2017:12 1305–1315 Dovepress © 2017 Sudha et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/IJN.S123742 Powered by TCPDF (www.tcpdf.org) Abstract: The tetraiodothyroacetic acid (tetrac) component of nano-diamino-tetrac (NDAT) is chemically bonded via a linker to a poly(lactic-co-glycolic acid) nanoparticle that can encapsulate anticancer drugs. Tetrac targets the plasma membrane of cancer cells at a receptor on the extracellular domain of integrin αvβ3. In this study, we evaluate the efficiency of NDAT delivery of paclitaxel and doxorubicin to, respectively, pancreatic and breast cancer orthotopic nude mouse xenografts. Intra-tumoral drug concentrations were 5-fold (paclitaxel; P0.001) and 2.3-fold (doxorubicin; P0.01) higher than with conventional systemic drug administration. Tumor volume reductions reflected enhanced xenograft drug uptake. Cell viability was estimated by bioluminescent signaling in pancreatic tumors and confirmed an increased paclitaxel effect with drug delivery by NDAT. NDAT delivery of chemotherapy increases drug delivery to cancers and increases drug efficacy. Keywords: doxorubicin, integrin, nanoparticle, Nanotetrac, NDAT, paclitaxel, tetraiodothyroacetic acid, xenografts Dovepress Sudha et al , 2 + 2  International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 5.135.254.153 on 12-Jul-2018 For personal use only. 1+ +1 2 2 2 , , 2  2 2+ , Figure 1 Chemical structure of NDAT (Nanotetrac). Note: The chemical name is {4-[4-(3-(3-(poly-2-(2-hydroxyacetotoxy))propanamido) aminopropoxy)-3,5-diiodophenoxy]-3,5-diiodopheny} acetic acid. Abbreviations: NDAT, nano-diamino-tetrac; tetrac, tetraiodothyroacetic acid. bound to PLGA include folate antennae,16,17 DNA antibody,18 transferrin,19 chemokine-targeting peptide,20 modified epidermal growth factor (EGF),21 and arginine-glycine-aspartic acid (RGD) peptide.22 In a companion article,23 we report the use of this delivery system to enhance cisplatin uptake by tumor xenografts and to reduce cisplatin-induced neurotoxicity. In the current study, we examine the tumor xenograftspecific delivery of paclitaxel and doxorubicin by NDAT. Chemotherapy with these 2 agents has been of interest in hepatocellular carcinoma24 and lung cancer,25 and both agents, in contrast to cisplatin, are ligands of P-glycoprotein (P-gp). P-gp is a plasma membrane efflux pump that is a component of cancer cell chemoresistance and is subject to inhibition by tetrac.26,27 Methods Generation of free PLGA nanoparticles encapsulated with paclitaxel or doxorubicin The methodology was based on prior publications and involves a single solvent emulsion in the presence of the chemotherapeutic agent.13,28,29 The PLGA nanoparticles obtained were characterized in terms of size, surface charge, and loading as described in the following sections. Dynamic light scattering (DLS) The size distribution of the synthesized nanoparticles in aqueous dispersions was determined using a Malvern zeta sizer (Malvern Instrumentation Co, Westborough, MA, USA). Approximately 1 mL (...truncated)