Transferrin-conjugated magnetic silica PLGA nanoparticles loaded with doxorubicin and paclitaxel for brain glioma treatment.

The effective treatment of malignant brain glioma is hindered by the poor transport across the blood-brain barrier (BBB) and the low penetration across the blood-tumor barrier (BTB). In this study, transferrin-conjugated magnetic silica PLGA nanoparticles (MNP-MSN-PLGA-Tf NPs) were formulated to overcome these barriers. These NPs were loaded with doxorubicin (DOX) and paclitaxel (PTX), and their anti-proliferative effect was evaluated in vitro and in vivo. The in vitro cytotoxicity of drug-loaded NPs was evaluated in U-87 cells. The delivery and the subsequent cellular uptake of drug-loaded NPs could be enhanced by the presence of magnetic field and the usage of Tf as targeting ligand, respectively. In particular, cells treated with DOX-PTX-NPs-Tf with magnetic field showed the highest cytotoxicity as compared to those treated with DOX-PTX-NPs-Tf, DOX-PTX-NPs, DOX-PTX-NPs-Tf with free Tf. The in vivo therapeutic efficacy of drug-loaded NPs was evaluated in intracranial U-87 MG-luc2 xenograft of BALB/c nude mice. In particular, the DOX-PTX-NPs-Tf treatment exhibited the strongest anti-glioma activity as compared to the PTX-NPs-Tf, DOX-NPs-Tf or DOX-PTX-NPs treatment. Mice did not show acute toxicity after administrating with blank MNP-MSN-PLGA-Tf NPs. Overall, MNP-MSN-PLGA-Tf NPs are promising carriers for the delivery of dual drugs for effective treatment of brain glioma.

[1]  Yan Li,et al.  A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas. , 2012, Biomaterials.

[2]  Iwao Ojima.  Modern molecular approaches to drug design and discovery. , 2008, Accounts of chemical research.

[3]  Xin-guo Jiang,et al.  Enhanced intracellular delivery and chemotherapy for glioma rats by transferrin-conjugated biodegradable polymersomes loaded with doxorubicin. , 2011, Bioconjugate chemistry.

[4]  Juan L. Vivero-Escoto,et al.  Mesoporous silica nanoparticles for intracellular controlled drug delivery. , 2010, Small.

[5]  Xiaoling Fang,et al.  Anti-glioblastoma efficacy and safety of paclitaxel-loading Angiopep-conjugated dual targeting PEG-PCL nanoparticles. , 2012, Biomaterials.

[6]  X. Jing,et al.  Transferrin-conjugated micelles: enhanced accumulation and antitumor effect for transferrin-receptor-overexpressing cancer models. , 2012, Molecular pharmaceutics.

[7]  Mauro Ferrari,et al.  Mesoporous Silicon‐PLGA Composite Microspheres for the Double Controlled Release of Biomolecules for Orthopedic Tissue Engineering , 2012 .

[8]  S. Sahoo,et al.  Targeted nutlin-3a loaded nanoparticles inhibiting p53-MDM2 interaction: novel strategy for breast cancer therapy. , 2011, Nanomedicine.

[9]  K. Muraszko,et al.  Efficacy of transferrin receptor-targeted immunotoxins in brain tumor cell lines and pediatric brain tumors. , 1993, Cancer research.

[10]  A. Schilling,et al.  Biologically and chemically optimized composites of carbonated apatite and polyglycolide as bone substitution materials. , 2001, Journal of biomedical materials research.

[11]  Huiqing Yuan,et al.  Autophagy inhibition promotes paclitaxel-induced apoptosis in cancer cells. , 2011, Cancer letters.

[12]  Antony K. Chen,et al.  Superparamagnetic Iron Oxide Nanoparticle Probes for Molecular Imaging , 2006, Annals of Biomedical Engineering.

[13]  Xiaoli Wei,et al.  Co-delivery of TRAIL gene enhances the anti-glioblastoma effect of paclitaxel in vitro and in vivo. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[14]  Lin Zheng,et al.  The use of submicron/nanoscale PLGA implants to deliver paclitaxel with enhanced pharmacokinetics and therapeutic efficacy in intracranial glioblastoma in mice. , 2010, Biomaterials.

[15]  Changbong Hyeon,et al.  Efficient functional delivery of siRNA using mesoporous silica nanoparticles with ultralarge pores. , 2012, Small.

[16]  Xin-guo Jiang,et al.  Aptamer-functionalized PEG-PLGA nanoparticles for enhanced anti-glioma drug delivery. , 2011, Biomaterials.

[17]  P. De Bonis,et al.  Glioblastoma therapy: going beyond Hercules Columns , 2010, Expert review of neurotherapeutics.

[18]  Rongrong Hua,et al.  Lactoferrin-conjugated biodegradable polymersome holding doxorubicin and tetrandrine for chemotherapy of glioma rats. , 2010, Molecular pharmaceutics.

[19]  K. Rice,et al.  Metabolically Stabilized Long-Circulating PEGylated Polyacridine Peptide Polyplexes Mediate Hydrodynamically Stimulated Gene Expression in Liver , 2010, Gene Therapy.

[20]  Y. Kuo,et al.  Targeting nevirapine delivery across human brain microvascular endothelial cells using transferrin-grafted poly(lactide-co-glycolide) nanoparticles. , 2011, Nanomedicine.

[21]  H. Gu,et al.  Synthesis and characterization of pore size-tunable magnetic mesoporous silica nanoparticles. , 2011, Journal of colloid and interface science.

[22]  Xiaojun Cai,et al.  Mesoporous silica nanoparticles capped with disulfide-linked PEG gatekeepers for glutathione-mediated controlled release. , 2012, ACS applied materials & interfaces.

[23]  Takako Sasaki,et al.  Inhibition of brain tumor growth by intravenous poly(β-l-malic acid) nanobioconjugate with pH-dependent drug release , 2010, Proceedings of the National Academy of Sciences.

[24]  E. Shusta,et al.  Blood–Brain Barrier Transport of Therapeutics via Receptor-Mediation , 2007, Pharmaceutical Research.

[25]  B. Shapiro,et al.  A Two-Magnet System to Push Therapeutic Nanoparticles. , 2010, AIP conference proceedings.

[26]  P. Russo,et al.  Synthesis and rapid characterization of amine-functionalized silica. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[27]  Xiaoling Fang,et al.  Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles as dual-targeting drug delivery system for brain glioma. , 2011, Biomaterials.

[28]  Linyin Feng,et al.  Transferrin-modified c[RGDfK]-paclitaxel loaded hybrid micelle for sequential blood-brain barrier penetration and glioma targeting therapy. , 2012, Molecular pharmaceutics.

[29]  Jing Wang,et al.  Mesoporous Silica‐Coated Gold Nanorods as a Light‐Mediated Multifunctional Theranostic Platform for Cancer Treatment , 2012, Advanced materials.

[30]  H. Gu,et al.  Magnetic field enhanced cell uptake efficiency of magnetic silica mesoporous nanoparticles. , 2012, Nanoscale.

[31]  A. Cereseto,et al.  Mechanism of Paclitaxel Activity in Kaposi’s Sarcoma1 , 2000, The Journal of Immunology.

[32]  P. Thorpe.  Vascular Targeting Agents as Cancer Therapeutics , 2004, Clinical Cancer Research.

[33]  Shanshan Huang,et al.  Magnetic Mesoporous Silica Spheres for Drug Targeting and Controlled Release , 2009 .

[34]  T. Yen,et al.  The characteristics, biodistribution, magnetic resonance imaging and biodegradability of superparamagnetic core-shell nanoparticles. , 2010, Biomaterials.

[35]  K. Landfester,et al.  Magnetic Polystyrene Nanoparticles with a High Magnetite Content Obtained by Miniemulsion Processes , 2003 .

[36]  M. Kruk,et al.  "Click" grafting of high loading of polymers and monosaccharides on surface of ordered mesoporous silica. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[37]  Yasuto Hoshikawa,et al.  Mesoporous Silica Nanoparticles with Remarkable Stability and Dispersibility for Antireflective Coatings , 2010 .

[38]  Le Yu,et al.  Facile synthesis and magnetic property of iron oxide/MCM-41 mesoporous silica nanospheres for targeted drug delivery , 2012 .

[39]  P. Parren,et al.  An integrated science-based approach to drug development. , 2008, Current Opinion in Immunology.

[40]  Sungho Jin,et al.  Magnetic targeting of nanoparticles across the intact blood-brain barrier. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[41]  Yan Zhang,et al.  Dual-targeting daunorubicin liposomes improve the therapeutic efficacy of brain glioma in animals. , 2010, Journal of controlled release : official journal of the Controlled Release Society.