Synthesis of pH-responsive chitosan nanocapsules for the controlled delivery of doxorubicin.

Well-defined chitosan nanocapsules (CSNCs) with tunable sizes were synthesized through the interfacial cross-linking of N-maleoyl-functionalized chitosan (MCS) in miniemulsions, and their application in the delivery of doxorubicin (Dox) was investigated. MCS was prepared by the amidation reaction of CS with maleic anhydride in water/DMSO at 65 °C for 20 h. Subsequently, thiol-ene cross-linking was conducted in oil-in-water miniemulsions at room temperature under UV irradiation for 1 h, using MCS as both a surfactant and precursor polymer, 1,4-butanediol bis(3-mercapto-propionate) as a cross-linker, and D-α-tocopheryl poly(ethylene glycol) 1000 succinate as a cosurfactant. With the increase in cosurfactant concentration in the reaction systems, the sizes of the resulting CSNCs decreased steadily. Dox-loaded CSNCs were readily prepared by in situ encapsulation of Dox during miniemulsion cross-linking. With acid-labile β-thiopropionate cross-linkages, the Dox-loaded CSNCs demonstrated a faster release rate under acidic conditions. Relative to free Dox, Dox-loaded CSNCs exhibited enhanced cytotoxicity toward MCF-7 breast cancer cells without any noticeable cytotoxicity from empty CSNCs. The effective delivery of Dox to MCF-7 breast cancer cells via Dox-loaded CSNCs was also observed.

[1]  K. Wooley,et al.  Poly(ethylene oxide)‐block‐Polyphosphoester‐graft‐Paclitaxel Conjugates with Acid‐Labile Linkages as a pH‐Sensitive and Functional Nanoscopic Platform for Paclitaxel Delivery , 2014, Advanced healthcare materials.

[2]  Chih-Kuang Chen,et al.  Biodegradable cationic polymeric nanocapsules for overcoming multidrug resistance and enabling drug-gene co-delivery to cancer cells. , 2014, Nanoscale.

[3]  J. Fei,et al.  Assembled Microcapsules by Doxorubicin and Polysaccharide as High Effective Anticancer Drug Carriers , 2013, Advanced healthcare materials.

[4]  Zhishen Ge,et al.  Functional block copolymer assemblies responsive to tumor and intracellular microenvironments for site-specific drug delivery and enhanced imaging performance. , 2013, Chemical Society reviews.

[5]  Chih-Kuang Chen,et al.  Well-defined degradable brush polymer-drug conjugates for sustained delivery of Paclitaxel. , 2013, Molecular pharmaceutics.

[6]  Ming Jiang,et al.  Synthesis of cationic polylactides with tunable charge densities as nanocarriers for effective gene delivery. , 2013, Molecular pharmaceutics.

[7]  Chih-Kuang Chen,et al.  Well‐Defined Degradable Cationic Polylactide as Nanocarrier for the Delivery of siRNA to Silence Angiogenesis in Prostate Cancer , 2012, Advanced healthcare materials.

[8]  Ruth Duncan,et al.  Endocytosis and intracellular trafficking as gateways for nanomedicine delivery: opportunities and challenges. , 2012, Molecular pharmaceutics.

[9]  A. Attia,et al.  Advanced Materials for Co‐Delivery of Drugs and Genes in Cancer Therapy , 2012, Advanced healthcare materials.

[10]  Joonyoung Park,et al.  Low molecular-weight chitosan as a pH-sensitive stealth coating for tumor-specific drug delivery. , 2012, Molecular pharmaceutics.

[11]  Karen L Wooley,et al.  Design of polymeric nanoparticles for biomedical delivery applications. , 2012, Chemical Society reviews.

[12]  G. Luo,et al.  A Novel Microfluidic Approach for Monodispersed Chitosan Microspheres with Controllable Structures , 2012, Advanced healthcare materials.

[13]  Chih-Kuang Chen,et al.  Well‐defined drug‐conjugated biodegradable nanoparticles by azide–alkyne click crosslinking in miniemulsion , 2012 .

[14]  Kurt E. Geckeler,et al.  Paclitaxel‐Loaded Polymer Nanoparticles for the Reversal of Multidrug Resistance in Breast Cancer Cells , 2011 .

[15]  R. Duncan,et al.  Nanomedicine(s) under the microscope. , 2011, Molecular pharmaceutics.

[16]  Chong Cheng,et al.  Polyelectrolyte nanocages via crystallized miniemulsion droplets. , 2011, Chemical communications.

[17]  Chih-Kuang Chen,et al.  Clicking Well‐Defined Biodegradable Nanoparticles and Nanocapsules by UV‐Induced Thiol‐Ene Cross‐Linking in Transparent Miniemulsions , 2011, Advanced materials.

[18]  Wei Wang,et al.  Monodisperse core-shell chitosan microcapsules for pH-responsive burst release of hydrophobic drugs , 2011 .

[19]  D. Hua,et al.  Smart Chitosan-Based Stimuli-Responsive Nanocarriers for the Controlled Delivery of Hydrophobic Pharmaceuticals , 2011 .

[20]  S. Edge,et al.  Breast cancer racial disparities: unanswered questions. , 2011, Cancer research.

[21]  Dong Wook Kim,et al.  Oleyl-chitosan nanoparticles based on a dual probe for optical/MR imaging in vivo. , 2011, Bioconjugate chemistry.

[22]  Xiaoming He,et al.  Synthesis and characterization of thermally responsive Pluronic F127-chitosan nanocapsules for controlled release and intracellular delivery of small molecules. , 2010, ACS nano.

[23]  Ying Zhang,et al.  Synthesis and characterization of amphiphilic glycidol-chitosan-deoxycholic acid nanoparticles as a drug carrier for doxorubicin. , 2010, Biomacromolecules.

[24]  Omid C Farokhzad,et al.  pH-Responsive nanoparticles for drug delivery. , 2010, Molecular pharmaceutics.

[25]  R. Auzély-Velty,et al.  Contact‐Killing Polyelectrolyte Microcapsules Based on Chitosan Derivatives , 2010 .

[26]  C. Reinhart-King,et al.  Synthesis, characterization and cytotoxicity of photo-crosslinked maleic chitosan-polyethylene glycol diacrylate hybrid hydrogels. , 2010, Acta biomaterialia.

[27]  Jun Li,et al.  Functionalization of Chitosan via Atom Transfer Radical Polymerization for Gene Delivery , 2010 .

[28]  Robert Langer,et al.  Nanotechnology in drug delivery and tissue engineering: from discovery to applications. , 2010, Nano letters.

[29]  Joseph M. DeSimone,et al.  Strategies in the design of nanoparticles for therapeutic applications , 2010, Nature Reviews Drug Discovery.

[30]  W. Hennink,et al.  Tailorable thiolated trimethyl chitosans for covalently stabilized nanoparticles. , 2010, Biomacromolecules.

[31]  F. Liu,et al.  Paclitaxel nanocrystals for overcoming multidrug resistance in cancer. , 2010, Molecular pharmaceutics.

[32]  D. Benoit,et al.  pH-responsive polymeric sirna carriers sensitize multidrug resistant ovarian cancer cells to doxorubicin via knockdown of polo-like kinase 1. , 2010, Molecular pharmaceutics.

[33]  M. Kasaai.  Determination of the degree of N-acetylation for chitin and chitosan by various NMR spectroscopy techniques: A review , 2010 .

[34]  Gu Chunhua,et al.  Micellar carrier based on methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) block copolymers bearing ketone groups on the polyester block for doxorubicin delivery , 2010, Journal of materials science. Materials in medicine.

[35]  M. Nowakowska,et al.  Robust “one-component” chitosan-based ultrathin films fabricated using layer-by-layer technique , 2009 .

[36]  S. Harding,et al.  Macromolecular conformation of chitosan in dilute solution: A new global hydrodynamic approach , 2009 .

[37]  R. Riguera,et al.  Surpassing the use of copper in the click functionalization of polymeric nanostructures: a strain-promoted approach. , 2009, Journal of the American Chemical Society.

[38]  Lichen Yin,et al.  Biodegradable nanoparticles based on linoleic acid and poly(beta-malic acid) double grafted chitosan derivatives as carriers of anticancer drugs. , 2009, Biomacromolecules.

[39]  Kato L. Killops,et al.  Development of Thermal and Photochemical Strategies for Thiol−Ene Click Polymer Functionalization , 2008 .

[40]  E. Terentjev,et al.  Emulsification and stabilization mechanisms of o/w emulsions in the presence of chitosan. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[41]  M. Prabaharan,et al.  Stimuli-responsive chitosan-graft-poly(N-vinylcaprolactam) as a promising material for controlled hydrophobic drug delivery. , 2008, Macromolecular bioscience.

[42]  Xian‐Zheng Zhang,et al.  Low molecular weight polyethylenimine grafted N-maleated chitosan for gene delivery: properties and in vitro transfection studies. , 2008, Biomacromolecules.

[43]  Eric Pridgen,et al.  Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles , 2008, Molecular pharmaceutics.

[44]  Wei Wei,et al.  Monodisperse Chitosan Microspheres with Interesting Structures for Protein Drug Delivery , 2008 .

[45]  Yu-Hsin Lin,et al.  Oral delivery of peptide drugs using nanoparticles self-assembled by poly(gamma-glutamic acid) and a chitosan derivative functionalized by trimethylation. , 2008, Bioconjugate chemistry.

[46]  Elena E. Dormidontova,et al.  Doxorubicin and β-Lapachone Release and Interaction with Micellar Core Materials: Experiment and Modeling , 2007 .

[47]  Yong Hu,et al.  Hollow chitosan/poly(acrylic acid) nanospheres as drug carriers. , 2007, Biomacromolecules.

[48]  D. Schmaljohann.  Thermo- and pH-responsive polymers in drug delivery. , 2006, Advanced drug delivery reviews.

[49]  R. Schubert,et al.  Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient. , 2006, Biochimica et biophysica acta.

[50]  E. Zeiger,et al.  Genetic toxicity and carcinogenicity studies of glutaraldehyde--a review. , 2005, Mutation research.

[51]  Xianghong Peng,et al.  Surface fabrication of hollow microspheres from N-methylated chitosan cross-linked with glutaraldehyde. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[52]  A. Domb,et al.  Chitosan chemistry and pharmaceutical perspectives. , 2004, Chemical reviews.

[53]  Tejraj M Aminabhavi,et al.  Recent advances on chitosan-based micro- and nanoparticles in drug delivery. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[54]  Peter Vaupel,et al.  Tumor microenvironmental physiology and its implications for radiation oncology. , 2004, Seminars in radiation oncology.

[55]  Y. Hu,et al.  Core‐Template‐Free Strategy for Preparing Hollow Nanospheres , 2004 .

[56]  K. Kataoka,et al.  pH-responsive oligodeoxynucleotide (ODN)-poly(ethylene glycol) conjugate through acid-labile beta-thiopropionate linkage: preparation and polyion complex micelle formation. , 2003, Biomacromolecules.

[57]  M. Antonietti,et al.  Synthesis of chitosan-stabilized polymer dispersions, capsules, and chitosan grafting products via miniemulsion. , 2002, Biomacromolecules.

[58]  K. Janes,et al.  Chitosan nanoparticles as delivery systems for doxorubicin. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[59]  D. Gewirtz,et al.  Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. , 1994, Molecular pharmacology.