Magnetic drug carrier with a smart pH-responsive polymer network shell for controlled delivery of doxorubicin

A smart magnetic targeting drug carrier (MCNC/PAA) comprising an approximately 100 nm sized magnetic colloid nanocrystal cluster (MCNC) core and a pH-responsive cross-linked poly(acrylic acid) (PAA) shell is reported. The abundant carboxyl groups in the shell enable the resultant MCNC/PAA to easily load a large amount of doxorubicin (DOX) (up to 44.6%) via the strong interaction between the DOX and the carboxyl group in a neutral solution. Interestingly, a synergistic pH-responsive effect derived from the entrapped DOX and PAA network was found to effectively manipulate the drug releasing behavior at 37 °C. It was found that the premature release was highly restricted at a pH of 7.4, and upon reduction in pH from 7.4 to 5.0 or 4.0, a large amount of drug was rapidly released. Compared with the synthesized MCNC/PNIPAM, MCNC/PHEMA and MCNC/PDMAPMA nanocarriers, the MCNC/PAA was preferably suited to drug delivery. In addition, the composite nanocarriers could be tracked by magnetic resonance imaging (MRI). The cytotoxicity assay of MCNC/PAA to normal cells indicated that the composite nanospheres were biocompatible and suitable as drug carriers. Meanwhile, the DOX-loaded composite nanospheres had more potent cytotoxicity than free DOX to HeLa cells. These results clearly imply that the MCNC/PAA nanocarrier is a promising platform that can be applied to construct a smart drug delivery system with magnetic targeting and pH-stimulation, as well as tracking by MRI.

[1]  Jia Guo,et al.  Thermo and pH dual responsive, polymer shell coated, magnetic mesoporous silica nanoparticles for controlled drug release , 2011 .

[2]  J. Fraser Stoddart,et al.  Mesostructured multifunctional nanoparticles for imaging and drug delivery , 2009 .

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

[4]  Jung Ho Yu,et al.  Designed Fabrication of a Multifunctional Polymer Nanomedical Platform for Simultaneous Cancer‐ Targeted Imaging and Magnetically Guided Drug Delivery , 2008 .

[5]  Jinkyu Lee,et al.  Multifunctional nanoparticles possessing a "magnetic motor effect" for drug or gene delivery. , 2005, Angewandte Chemie.

[6]  Taeghwan Hyeon,et al.  Multifunctional uniform nanoparticles composed of a magnetite nanocrystal core and a mesoporous silica shell for magnetic resonance and fluorescence imaging and for drug delivery. , 2008, Angewandte Chemie.

[7]  Zijian Guo,et al.  Superparamagnetic magnetite nanocrystal clusters as potential magnetic carriers for the delivery of platinum anticancer drugs , 2011 .

[8]  T. A. Hatton,et al.  Complexation and release of doxorubicin from its complexes with pluronic P85-b-poly(acrylic acid) block copolymers. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[9]  F. Zhang,et al.  Multi-functional thermosensitive composite microspheres with high magnetic susceptibility based on magnetite colloidal nanoparticle clusters. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[10]  C. Cai,et al.  Synthesis of magnetic, fluorescent and mesoporous core-shell-structured nanoparticles for imaging, targeting and photodynamic therapy , 2011 .

[11]  Chun Wang,et al.  Block copolymer micelles with acid-labile ortho ester side-chains: Synthesis, characterization, and enhanced drug delivery to human glioma cells. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[12]  Y. Hung,et al.  Monoclonal antibody-functionalized mesoporous silica nanoparticles (MSN) for selective targeting breast cancer cells , 2009 .

[13]  N. Melik-Nubarov,et al.  Doxorubicin-poly(acrylic acid) complexes: interaction with liposomes. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[14]  A. Elaissari,et al.  Highly temperature responsive core-shell magnetic particles: synthesis, characterization and colloidal properties. , 2011, Journal of colloid and interface science.

[15]  Taeghwan Hyeon,et al.  Multifunctional nanostructured materials for multimodal imaging, and simultaneous imaging and therapy. , 2009, Chemical Society reviews.

[16]  Li Yuan,et al.  Preparation of pH-Responsive Mesoporous Silica Nanoparticles and Their Application in Controlled Drug Delivery , 2011 .

[17]  Jia Guo,et al.  Hydrophilic dual‐responsive magnetite/PMAA core/shell microspheres with high magnetic susceptibility and ph sensitivity via distillation‐precipitation polymerization , 2011 .

[18]  P. Cullis,et al.  Accumulation of doxorubicin and other lipophilic amines into large unilamellar vesicles in response to transmembrane pH gradients. , 1993, Biochimica et biophysica acta.

[19]  Xiaogang Liu,et al.  Emerging functional nanomaterials for therapeutics , 2011 .

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

[21]  Jan Grimm,et al.  Drug/dye-loaded, multifunctional iron oxide nanoparticles for combined targeted cancer therapy and dual optical/magnetic resonance imaging. , 2009, Small.

[22]  Jun Lin,et al.  Synthesis of Magnetic, Up‐Conversion Luminescent, and Mesoporous Core–Shell‐Structured Nanocomposites as Drug Carriers , 2010 .

[23]  P. Stayton,et al.  Thermosensitive liposomes modified with poly(N-isopropylacrylamide-co-propylacrylic acid) copolymers for triggered release of doxorubicin. , 2010, Biomacromolecules.

[24]  Hua Ai,et al.  Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems. , 2006, Nano letters.

[25]  Jun Lin,et al.  A magnetic, luminescent and mesoporous core-shell structured composite material as drug carrier. , 2009, Biomaterials.

[26]  A. Elaissari,et al.  Organic–Inorganic Hybrid Magnetic Latex , 2010 .

[27]  A. Elaissari,et al.  Stimuli-responsive magnetic particles for biomedical applications. , 2011, International journal of pharmaceutics.

[28]  M. Mahmoudi,et al.  Superparamagnetic colloidal nanocrystal clusters coated with polyethylene glycol fumarate: a possible novel theranostic agent. , 2011, Nanoscale.

[29]  D. Zhao,et al.  Mesoporous biocompatible and acid-degradable magnetic colloidal nanocrystal clusters with sustainable stability and high hydrophobic drug loading capacity. , 2011, ACS nano.

[30]  M. Mahmoudi,et al.  Superparamagnetic Iron Oxide Nanoparticles with Rigid Cross-linked Polyethylene Glycol Fumarate Coating for Application in Imaging and Drug Delivery , 2009 .

[31]  Dong Jun Lee,et al.  Multifunctional mesoporous silica nanocomposite nanoparticles for pH controlled drug release and dual modal imaging , 2011 .

[32]  R. Ozols,et al.  The anthracycline antineoplastic drugs. , 1981, The New England journal of medicine.

[33]  D. Papahadjopoulos,et al.  Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. , 1999, Pharmacological reviews.

[34]  Jimmy C. Yu,et al.  Synthesis of biocompatible, mesoporous Fe(3)O(4) nano/microspheres with large surface area for magnetic resonance imaging and therapeutic applications. , 2011, ACS applied materials & interfaces.

[35]  Hatem Fessi,et al.  Modified double emulsion process as a new route to prepare submicron biodegradable magnetic/polycaprolactone particles for in vivo theranostics , 2012 .

[36]  E. Sacher,et al.  pH-Triggered Doxorubicin Delivery Based on Hollow Nanoporous Silica Nanoparticles with Free-Standing Superparamagnetic Fe3O4 Cores , 2011 .

[37]  Monty Liong,et al.  Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. , 2008, ACS nano.

[38]  SYNTHESIS OF PEG-ENCAPSULATED SUPERPARAMAGNETIC COLLOIDAL NANOCRYSTALS CLUSTERS , 2010 .

[39]  A. Elaissari,et al.  Aminodextran containing magnetite nanoparticles for molecular biology applications: preparation and evaluation. , 2009, Journal of biomedical nanotechnology.

[40]  Yu Chen,et al.  Biocompatibility, MR imaging and targeted drug delivery of a rattle-type magnetic mesoporous silica nanosphere system conjugated with PEG and cancer-cell-specific ligands , 2011 .