PEGylated thermosensitive lipid-coated hollow gold nanoshells for effective combinational chemo-photothermal therapy of pancreatic cancer.

Pancreatic cancer has extremely poor prognosis with an 85% mortality rate that results from aggressive and asymptomatic growth, high metastatic potential, and rapid development of resistance to already ineffective chemotherapy. In this study, plasmonic hollow gold nanoshells (GNS) coated with PEGylated thermosensitive lipids were prepared as an efficient platform to ratiometrically co-deliver two drugs, bortezomib and gemcitabine (GNS-L/GB), for combinational chemotherapy and photothermal therapy of pancreatic cancer. Bortezomib was loaded within the lipid bilayers, while gemcitabine was loaded into the hydrophilic interior of the porous GNS via an ammonium sulfate-driven pH gradient method. Physicochemical characterizations and biological studies of GNS-L/GB were performed, with the latter using cytotoxicity assays, cellular uptake and apoptosis assays, live/dead assays, and western blot analysis of pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). The nanoshells showed remotely controllable drug release when exposed to near-infrared laser for site-specific delivery. GNS-L/GB showed synergistic cytotoxicity and improved internalization by cancer cells. High-powered near-infrared continuous wave laser (λ=808nm) effectively killed cancer cells via the photothermal effect of GNS-L/GB, irrespective of cell type in a power density-, time-, and GNS dose-dependent manner. These results suggest that this method can provide a novel approach to achieve synergistic combinational chemotherapy and photothermal therapy, even with resistant pancreatic cancer.

[1]  W. Chan,et al.  Synthesis and surface modification of highly monodispersed, spherical gold nanoparticles of 50-200 nm. , 2009, Journal of the American Chemical Society.

[2]  Jay V. Shah,et al.  Role of apoptosis and necrosis in cell death induced by nanoparticle-mediated photothermal therapy , 2015, Journal of Nanoparticle Research.

[3]  Jong Oh Kim,et al.  Nanoparticle-based combination drug delivery systems for synergistic cancer treatment , 2016, Journal of Pharmaceutical Investigation.

[4]  A. Athanassiou,et al.  Magnetite (Fe3O4)-filled carbon nanofibers as electro-conducting/superparamagnetic nanohybrids and their multifunctional polymer composites , 2015, Journal of Nanoparticle Research.

[5]  Joseph M. McLellan,et al.  Fabrication of cubic nanocages and nanoframes by dealloying Au/Ag alloy nanoboxes with an aqueous etchant based on Fe(NO3)3 or NH4OH. , 2007, Nano letters.

[6]  Massimo Fresta,et al.  Cytotoxic effects of Gemcitabine-loaded liposomes in human anaplastic thyroid carcinoma cells , 2004, BMC Cancer.

[7]  C. Pichot,et al.  New insights into self-organization of a model lipid mixture and quantification of its adsorption on spherical polymer particles. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[8]  P. Stauffer,et al.  Liposomes and hyperthermia in mice: increased tumor uptake and therapeutic efficacy of doxorubicin in sterically stabilized liposomes. , 1994, Cancer research.

[9]  Jan Schmidt,et al.  Bortezomib is ineffective in an orthotopic mouse model of pancreatic adenocarcinoma , 2008, Molecular Cancer Therapeutics.

[10]  S. Na'ara,et al.  Gemcitabine resistance in pancreatic ductal adenocarcinoma. , 2015, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[11]  Han‐Gon Choi,et al.  Combined phototherapy in anti-cancer treatment: therapeutics design and perspectives , 2016, Journal of Pharmaceutical Investigation.

[12]  Han‐Gon Choi,et al.  Development of Bioactive PEGylated Nanostructured Platforms for Sequential Delivery of Doxorubicin and Imatinib to Overcome Drug Resistance in Metastatic Tumors. , 2017, ACS applied materials & interfaces.

[13]  Younan Xia,et al.  Gold Nanocages for Biomedical Applications , 2007, Advanced materials.

[14]  I. Monaco,et al.  Surface modifications of gold nanorods for applications in nanomedicine , 2015 .

[15]  P. Jain,et al.  Calculated absorption and scattering properties of gold nanoparticles of different size, shape, and composition: applications in biological imaging and biomedicine. , 2006, The journal of physical chemistry. B.

[16]  R. Weissleder.  A clearer vision for in vivo imaging , 2001, Nature Biotechnology.

[17]  Takuro Niidome,et al.  Surface modification of gold nanorods using layer-by-layer technique for cellular uptake , 2008 .

[18]  G. Xu,et al.  Gold nanorod enhanced two-photon excitation fluorescence of photosensitizers for two-photon imaging and photodynamic therapy. , 2014, ACS applied materials & interfaces.

[19]  S. Reed,et al.  Gold nanoparticles become stable to cyanide etch when coated with hybrid lipid bilayers. , 2008, Chemical communications.

[20]  A. Plant.  Supported Hybrid Bilayer Membranes as Rugged Cell Membrane Mimics , 1999 .

[21]  E. S. Day,et al.  Elucidating the fundamental mechanisms of cell death triggered by photothermal therapy. , 2015, ACS nano.

[22]  Yulian Wu,et al.  Enhancing Apoptosis and Overcoming Resistance of Gemcitabine in Pancreatic Cancer with Bortezomib: A Role of Death-Associated Protein Kinase-Related Apoptosis-Inducing Protein Kinase 1 , 2009, Tumori.

[23]  Y. Ning,et al.  Near-infrared light-responsive supramolecular nanovalve based on mesoporous silica-coated gold nanorods , 2014 .

[24]  A. Mikhailovsky,et al.  Scalable routes to gold nanoshells with tunable sizes and response to near-infrared pulsed-laser irradiation. , 2008, Small.

[25]  F. Gansauge,et al.  Treatment of Pancreatic Cancer: Challenge of the Facts , 2003, World Journal of Surgery.

[26]  R. Bold,et al.  Schedule-dependent molecular effects of the proteasome inhibitor bortezomib and gemcitabine in pancreatic cancer. , 2003, The Journal of surgical research.

[27]  Juewen Liu,et al.  Self-healable and reversible liposome leakage by citrate-capped gold nanoparticles: probing the initial adsorption/desorption induced lipid phase transition. , 2015, Nanoscale.

[28]  Younan Xia,et al.  On the polyol synthesis of silver nanostructures: glycolaldehyde as a reducing agent. , 2008, Nano letters.

[29]  J. Dagorn,et al.  p8 Is a New Target of Gemcitabine in Pancreatic Cancer Cells , 2006, Clinical Cancer Research.

[30]  Yan Zhang,et al.  Controllable synthesis of monodispersed silver nanoparticles as standards for quantitative assessment of their cytotoxicity. , 2012, Biomaterials.

[31]  S. Ku,et al.  Liquid crystalline nanoparticles encapsulating cisplatin and docetaxel combination for targeted therapy of breast cancer. , 2016, Biomaterials science.

[32]  Chun Li,et al.  Exceptionally high payload of doxorubicin in hollow gold nanospheres for near-infrared light-triggered drug release. , 2010, ACS nano.

[33]  K. Udekwu,et al.  Silver Nanoparticle Applications: In the Fabrication and Design of Medical and Biosensing Devices , 2015 .

[34]  Shawn D. Lin,et al.  A novel efficient Au–Ag alloy catalyst system: preparation, activity, and characterization , 2005 .

[35]  Stephan Link,et al.  Optical properties and ultrafast dynamics of metallic nanocrystals. , 2003, Annual review of physical chemistry.

[36]  T. Gocho,et al.  Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation , 2014, Molecular Cancer Therapeutics.

[37]  Dong Yun Lee,et al.  Photothermal therapy with gold nanoparticles as an anticancer medication , 2016, Journal of Pharmaceutical Investigation.

[38]  Younan Xia,et al.  Template-Engaged Replacement Reaction: A One-Step Approach to the Large-Scale Synthesis of Metal Nanostructures with Hollow Interiors , 2002 .

[39]  R. Bold,et al.  Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapy in the A549 non-small-cell lung cancer cell line , 2004, Cancer Chemotherapy and Pharmacology.

[40]  Zhonghua Wu,et al.  Cationic amphiphilic drugs self-assemble to the core–shell interface of PEGylated phospholipid micelles and stabilize micellar structure , 2013, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[41]  R. Bold,et al.  Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. , 2001, The Journal of surgical research.

[42]  Po-Jung Jimmy Huang,et al.  Dissociation and degradation of thiol-modified DNA on gold nanoparticles in aqueous and organic solvents. , 2011, Langmuir : the ACS journal of surfaces and colloids.