Microfluidic Encapsulation of Prickly Zinc‐Doped Copper Oxide Nanoparticles with VD1142 Modified Spermine Acetalated Dextran for Efficient Cancer Therapy

Structural features of nanoparticles have recently been explored for different types of applications. To explore specific particles as nanomedicine and physically destroy cancer is interesting, which might avoid many obstacles in cancer treatment, for example, drug resistance. However, one key element and technical challenge of those systems is to selectively target them to cancer cells. As a proof-of-concept, Prickly zinc-doped copper oxide (Zn-CuO) nanoparticles (Prickly NPs) have been synthesized, and subsequently encapsulated in a pH-responsive polymer; and the surface has been modified with a novel synthesized ligand, 3-(cyclooctylamino)-2,5,6-trifluoro-4-[(2-hydroxyethyl)sulfonyl] benzenesulfonamide (VD1142). The Prickly NPs exhibit very effective cancer cell antiproliferative capability. Moreover, the polymer encapsulation shields the Prickly NPs from unspecific nanopiercing and, most importantly, VD1142 endows the engineered NPs to specifically target to the carbonic anhydrase IX, a transmembrane protein overexpressed in a wide variety of cancer tumors. Intracellularly, the Prickly NPs disintegrate into small pieces that upon endosomal escape cause severe damage to the endoplasmic reticulum and mitochondria of the cells. The engineered Prickly NP is promising in efficient and targeted cancer treatment and it opens new avenue in nanomedication.

[1]  K. Mihara,et al.  A novel insertion pathway of mitochondrial outer membrane proteins with multiple transmembrane segments , 2007, The Journal of cell biology.

[2]  W. Sly,et al.  Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. , 2001, The American journal of pathology.

[3]  S. Dhar,et al.  Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics , 2012, Proceedings of the National Academy of Sciences.

[4]  Mark B. Carter,et al.  The Targeted Delivery of Multicomponent Cargos to Cancer Cells via Nanoporous Particle-Supported Lipid Bilayers , 2011, Nature materials.

[5]  Jorge S Reis-Filho,et al.  Genetic heterogeneity and cancer drug resistance. , 2012, The Lancet. Oncology.

[6]  J. Pastorek,et al.  Monoclonal antibodies generated in carbonic anhydrase IX-deficient mice recognize different domains of tumour-associated hypoxia-induced carbonic anhydrase IX. , 2003, Journal of immunological methods.

[7]  Jianming Pan,et al.  Spatio‐Design of Multidimensional Prickly Zn‐Doped CuO Nanoparticle for Efficient Bacterial Killing , 2016 .

[8]  P. Pinton,et al.  Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis , 2008, Oncogene.

[9]  S. Gražulis,et al.  Functionalization of Fluorinated Benzenesulfonamides and Their Inhibitory Properties toward Carbonic Anhydrases , 2015, ChemMedChem.

[10]  Hongwei Zhang,et al.  Silica Nanopollens Enhance Adhesion for Long-Term Bacterial Inhibition. , 2016, Journal of the American Chemical Society.

[11]  D. Ferrari,et al.  Activation and caspase-mediated inhibition of PARP: a molecular switch between fibroblast necrosis and apoptosis in death receptor signaling. , 2002, Molecular biology of the cell.

[12]  Xiukun Lin,et al.  Zinc-Doped Copper Oxide Nanocomposites Inhibit the Growth of Human Cancer Cells through Reactive Oxygen Species-Mediated NF-κB Activations. , 2016, ACS applied materials & interfaces.

[13]  J. Ladbury,et al.  Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX. , 2014, Journal of medicinal chemistry.

[14]  Richard W Tothill,et al.  Navigating the challenge of tumor heterogeneity in cancer therapy. , 2014, Cancer discovery.

[15]  Josep Galceran,et al.  Dissolution Kinetics and Solubility of ZnO Nanoparticles Followed by AGNES , 2012 .

[16]  Jarno Salonen,et al.  Inhibition of Multidrug Resistance of Cancer Cells by Co‐Delivery of DNA Nanostructures and Drugs Using Porous Silicon Nanoparticles@Giant Liposomes , 2015 .

[17]  Lennart Möller,et al.  Intracellular uptake and toxicity of Ag and CuO nanoparticles: a comparison between nanoparticles and their corresponding metal ions. , 2013, Small.

[18]  Junying Yuan,et al.  Human ICE/CED-3 Protease Nomenclature , 1996, Cell.

[19]  C. Supuran Structure-based drug discovery of carbonic anhydrase inhibitors , 2012, Journal of enzyme inhibition and medicinal chemistry.

[20]  E. Dudek,et al.  Calreticulin, a therapeutic target? , 2016, Expert opinion on therapeutic targets.

[21]  Xuedong Liu,et al.  PINK1 Triggers Autocatalytic Activation of Parkin to Specify Cell Fate Decisions , 2014, Current Biology.

[22]  F. Liu,et al.  Solvent‐Polarity‐Induced Active Layer Morphology Control in Crystalline Diketopyrrolopyrrole‐Based Low Band Gap Polymer Photovoltaics , 2014 .

[23]  Wenhao Chen,et al.  High electrochemical performance and lithiation–delithiation phase evolution in CuO thin films for Li-ion storage , 2015 .

[24]  Yoo-Shin Kim,et al.  Intraoperative diagnostics and elimination of residual microtumours with plasmonic nanobubbles. , 2016, Nature nanotechnology.

[25]  A. Scaloni,et al.  Biochemical Characterization of CA IX, One of the Most Active Carbonic Anhydrase Isozymes* , 2008, Journal of Biological Chemistry.

[26]  F. Niesen,et al.  The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability , 2007, Nature Protocols.

[27]  Joel A. Cohen,et al.  Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy , 2009, Proceedings of the National Academy of Sciences.

[28]  R. Khalifah,et al.  The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C. , 1971, The Journal of biological chemistry.

[29]  Shai Shaham,et al.  Death without caspases, caspases without death. , 2004, Trends in cell biology.

[30]  P. Cullis,et al.  Drug Delivery Systems: Entering the Mainstream , 2004, Science.

[31]  Piotras Cimmperman,et al.  A quantitative model of thermal stabilization and destabilization of proteins by ligands. , 2008, Biophysical journal.

[32]  Hélder A. Santos,et al.  A Versatile and Robust Microfluidic Platform Toward High Throughput Synthesis of Homogeneous Nanoparticles with Tunable Properties , 2015, Advanced materials.

[33]  Kyle E Broaders,et al.  Acetal-derivatized dextran: an acid-responsive biodegradable material for therapeutic applications. , 2008, Journal of the American Chemical Society.

[34]  Raimo Hartmann,et al.  Surface Functionalization of Nanoparticles with Polyethylene Glycol: Effects on Protein Adsorption and Cellular Uptake. , 2015, ACS nano.

[35]  Youngjoo Lee,et al.  Cobalt Chloride-Induced Estrogen Receptor α Down-Regulation Involves Hypoxia-Inducible Factor-1α in MCF-7 Human Breast Cancer Cells , 2005 .

[36]  S. Gražulis,et al.  4-Substituted-2,3,5,6-tetrafluorobenzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, XII, and XIII. , 2013, Bioorganic & medicinal chemistry.

[37]  Dong Wang,et al.  Erythrocyte Membrane-Enveloped Polymeric Nanoparticles as Nanovaccine for Induction of Antitumor Immunity against Melanoma. , 2015, ACS nano.

[38]  R. McKenna,et al.  Hypoxia-induced carbonic anhydrase IX facilitates lactate flux in human breast cancer cells by non-catalytic function , 2015, Scientific Reports.

[39]  N. McGranahan,et al.  The causes and consequences of genetic heterogeneity in cancer evolution , 2013, Nature.

[40]  Yachong Guo,et al.  Graphene Induces Formation of Pores That Kill Spherical and Rod-Shaped Bacteria. , 2015, ACS nano.

[41]  H. Santos,et al.  Improved stability and biocompatibility of nanostructured silicon drug carrier for intravenous administration. , 2015, Acta biomaterialia.

[42]  Victor S. Lobanov,et al.  High-Density Miniaturized Thermal Shift Assays as a General Strategy for Drug Discovery , 2001 .

[43]  Daumantas Matulis,et al.  Thermodynamic stability of carbonic anhydrase: measurements of binding affinity and stoichiometry using ThermoFluor. , 2005, Biochemistry.

[44]  C. Supuran,et al.  Carbonic anhydrase IX: Biochemical and crystallographic characterization of a novel antitumor target. , 2010, Biochimica et biophysica acta.

[45]  T. Mok,et al.  Population-based differences in treatment outcome following anticancer drug therapies. , 2010, The Lancet. Oncology.

[46]  M. Eshraghi,et al.  Apoptosis and cancer: mutations within caspase genes , 2009, Journal of Medical Genetics.

[47]  R. Gillies,et al.  Carbonic anhydrase IX as an imaging and therapeutic target for tumors and metastases. , 2014, Sub-cellular biochemistry.

[48]  M. Ferrari Cancer nanotechnology: opportunities and challenges , 2005, Nature Reviews Cancer.

[49]  P. Johnston,et al.  Cancer drug resistance: an evolving paradigm , 2013, Nature Reviews Cancer.

[50]  Y. Cheng,et al.  Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. , 1973, Biochemical pharmacology.

[51]  C. Supuran,et al.  Inhibition and binding studies of carbonic anhydrase isozymes I, II and IX with benzimidazo[1,2-c][1,2,3]thiadiazole-7-sulphonamides , 2010, Journal of enzyme inhibition and medicinal chemistry.

[52]  R. Youle,et al.  Mitochondrial dynamics and apoptosis. , 2008, Genes & development.

[53]  Jarno Salonen,et al.  Fabrication of a Multifunctional Nano‐in‐micro Drug Delivery Platform by Microfluidic Templated Encapsulation of Porous Silicon in Polymer Matrix , 2014, Advanced materials.

[54]  M. Plummer,et al.  Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. , 2012, The Lancet. Oncology.

[55]  Joel A. Cohen,et al.  Acid-degradable cationic dextran particles for the delivery of siRNA therapeutics. , 2011, Bioconjugate chemistry.

[56]  Vesa-Pekka Lehto,et al.  Microfluidic assembly of monodisperse multistage pH-responsive polymer/porous silicon composites for precisely controlled multi-drug delivery. , 2014, Small.

[57]  J. Pastorek,et al.  Carbonic anhydrase IX: regulation and role in cancer. , 2014, Sub-cellular biochemistry.

[58]  Young Jik Kwon,et al.  "Combo" nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy. , 2016, Advanced drug delivery reviews.

[59]  Ge Lin,et al.  Rapid endosomal escape of prickly nanodiamonds: implications for gene delivery , 2015, Scientific Reports.

[60]  Jarno Salonen,et al.  Microfluidic assisted one-step fabrication of porous silicon@acetalated dextran nanocomposites for precisely controlled combination chemotherapy. , 2015, Biomaterials.

[61]  A. Gedanken,et al.  A Zn‐Doped CuO Nanocomposite Shows Enhanced Antibiofilm and Antibacterial Activities Against Streptococcus Mutans Compared to Nanosized CuO , 2014 .