Antitumor effects of polysorbate-80 coated gemcitabine polybutylcyanoacrylate nanoparticles in vitro and its pharmacodynamics in vivo on C6 glioma cells of a brain tumor model

Polybutylcyanoacrylate (PBCA) nanoparticles coated with polysorbate-80 have been extensively studied for delivery of drugs into the animal models; however, 1% polysorbate-80 coated gemcitabine PBCA nanoparticles (GCTB-PBCA-NPs) remain unknown. In this study, we investigated the inhibitory effects of brain targeted 1% polysorbate-80 coated GCTB-PBCA-NPs on C6 glioma cells in vitro and in vivo. GCTB-PBCA-NPs were prepared by emulsion polymerization and freeze drying. C6 glioma cells treated with 1% polysorbate-80 coated GCTB-PBCA-NPs showed poor growth with less cell density and increased detachment. Cell morphology was also greatly altered with nuclear vacuoles, ruptured cells and dead cells. Meanwhile, by flow cytometry, the numbers of cells treated with 1% polysorbate-80 coated GCTB-PBCA-NPs showed increase in G0/G1 phase and decreased in the S phase (P<0.01) compared with the blank control. CCK-8 assay also showed that GCTB could significantly inhibited cell proliferation in a concentration dependent manner. Finally, various preparations were injected (90 mg preparation per kg body weight) into the brain tumor model, which was produced after inoculating C6 glioma cells into Sprague Dawley (SD) rats for 14 days, it was shown that 1% polysorbate-80 coated GCTB-PBCA-NPs could significantly extend the survival time compared with the saline control (P<0.05). Taken together, 1% polysorbate-80 coated GCTB-PBCA-NPs can effectively inhibit the growth of C6 glioma cells in vitro and enhance antitumor activity on brain tumor in vivo.

[1]  William Couet,et al.  Indirect Evidence that Drug Brain Targeting Using Polysorbate 80-Coated Polybutylcyanoacrylate Nanoparticles Is Related to Toxicity , 1999, Pharmaceutical Research.

[2]  J. Renbarger,et al.  Plasma and cerebrospinal fluid pharmacokinetics of SU5416 after intravenous administration in nonhuman primates , 2003, Cancer Chemotherapy and Pharmacology.

[3]  D. A. Kharkevich,et al.  Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study. , 1998, Journal of microencapsulation.

[4]  D. R. van der Westhuyzen,et al.  Scavenger receptor class B, type I is expressed in porcine brain capillary endothelial cells and contributes to selective uptake of HDL‐associated vitamin E , 2001, Journal of neurochemistry.

[5]  R. Müller,et al.  'Stealth' corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. , 2000, Colloids and surfaces. B, Biointerfaces.

[6]  W. Pardridge,et al.  Drug and gene targeting to the brain via blood–brain barrier receptor-mediated transport systems , 2005 .

[7]  M. Egorin,et al.  Plasma and cerebrospinal fluid pharmacokinetics of gemcitabine after intravenous administration in nonhuman primates , 2001, Cancer Chemotherapy and Pharmacology.

[8]  M. Samanta,et al.  Targeted delivery of tacrine into the brain with polysorbate 80-coated poly(n-butylcyanoacrylate) nanoparticles. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[9]  Peter Ramge,et al.  Apolipoprotein-mediated Transport of Nanoparticle-bound Drugs Across the Blood-Brain Barrier , 2002, Journal of drug targeting.

[10]  Vladimir P Torchilin,et al.  Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. , 2006, Annual review of biomedical engineering.

[11]  Teruo Okano,et al.  Introduction of cisplatin into polymeric micelle , 1996 .

[12]  M. Alonso,et al.  Stealth PLA-PEG Nanoparticles as Protein Carriers for Nasal Administration , 1998, Pharmaceutical Research.

[13]  C. Birkinshaw,et al.  In vitro degradation of insulin-loaded poly (n-butylcyanoacrylate) nanoparticles. , 2004, Biomaterials.

[14]  M. Álvarez,et al.  Pt/TiO2 brain biocompatible nanoparticles: GBM treatment using the C6 model in Wistar rats. , 2008, Acta biomaterialia.

[15]  Nicolas de Tribolet,et al.  Outwitting the Blood-Brain Barrier for Therapeutic Purposes: Osmotic Opening and Other Means , 1998 .

[16]  J. Kreuter,et al.  Significant Transport of Doxorubicin into the Brain with Polysorbate 80-Coated Nanoparticles , 1999, Pharmaceutical Research.

[17]  Henry Brem,et al.  Targeted therapy for brain tumours , 2004, Nature Reviews Drug Discovery.

[18]  P. Desai,et al.  Pharmacokinetics of gemcitabine in tumor and non-tumor extracellular fluid of brain: an in vivo assessment in rats employing intracerebral microdialysis , 2007, Cancer Chemotherapy and Pharmacology.

[19]  A. Jemal,et al.  Cancer Statistics, 2007 , 2007, CA: a cancer journal for clinicians.

[20]  L. Maffei,et al.  Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Schmidt,et al.  Cancer therapy-associated CNS neuropathology: an update and review of the literature , 2006, Acta Neuropathologica.

[22]  R. Velichkova,et al.  Poly(butylcyanoacrylate) nanoparticles for topical delivery of 5-fluorouracil. , 2003, International journal of pharmaceutics.

[23]  R. Weissleder,et al.  A long-circulating co-polymer in "passive targeting" to solid tumors. , 1997, Journal of drug targeting.

[24]  J. Huwyler,et al.  Receptor mediated delivery of daunomycin using immunoliposomes: pharmacokinetics and tissue distribution in the rat. , 1997, The Journal of pharmacology and experimental therapeutics.

[25]  D. Lambert.  Rationale and applications of lipids as prodrug carriers. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[26]  N. Bodor,et al.  Improved Delivery Through Biological Membranes. XLV. Synthesis, Physical-Chemical Evaluation, and Brain Uptake Studies of 2-Chloroethyl Nitrosourea Delivery Systems , 1992, Pharmaceutical Research.

[27]  J. Connor,et al.  Interleukin-13 receptor–targeted nanovesicles are a potential therapy for glioblastoma multiforme , 2006, Molecular Cancer Therapeutics.

[28]  M. Y. Kim,et al.  Enhanced brain targeting efficiency of intranasally administered plasmid DNA: an alternative route for brain gene therapy , 2006, Journal of Molecular Medicine.

[29]  Robert Langer,et al.  Small-scale systems for in vivo drug delivery , 2003, Nature Biotechnology.

[30]  Hartwig Wolburg,et al.  Tight junctions of the blood-brain barrier: development, composition and regulation. , 2002, Vascular pharmacology.

[31]  D. Bazile,et al.  Stealth Me.PEG-PLA nanoparticles avoid uptake by the mononuclear phagocytes system. , 1995, Journal of pharmaceutical sciences.

[32]  E. Neuwelt,et al.  Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. , 1998, Neurosurgery.

[33]  Buchwald,et al.  Recent advances in the brain targeting of neuropharmaceuticals by chemical delivery systems. , 1999, Advanced drug delivery reviews.

[34]  P. Couvreur,et al.  Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells , 2007, Cellular and Molecular Life Sciences.

[35]  Thomas Jay Webster,et al.  Nanomedicine for implants: a review of studies and necessary experimental tools. , 2007, Biomaterials.

[36]  Raoul Kopelman,et al.  Brain cancer diagnosis and therapy with nanoplatforms. , 2006, Advanced drug delivery reviews.

[37]  Jee H Jung,et al.  Cytotoxicity of psammaplin A from a two-sponge association may correlate with the inhibition of DNA replication , 2004, BMC Cancer.

[38]  D. Yee,et al.  Pharmacodynamic characterization of gemcitabine cytotoxicity in an in vitro cell culture bioreactor system , 2007, Cancer Chemotherapy and Pharmacology.

[39]  C. Springer,et al.  Antibody-directed enzyme prodrug therapy: pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial , 1997, Cancer Chemotherapy and Pharmacology.

[40]  D. Wedekind,et al.  Tumor gene therapy made easy: allogeneic major histocompatibility complex in the C6 rat glioma model. , 1999, Human gene therapy.

[41]  J. Kreuter,et al.  Nanoparticulate systems for brain delivery of drugs. , 2001, Advanced drug delivery reviews.

[42]  Jarkko Rautioa,et al.  Drug delivery systems for brain tumor therapy. , 2004, Current pharmaceutical design.

[43]  C. Springer,et al.  The emerging fields of suicide gene therapy and virotherapy. , 2002, Trends in molecular medicine.

[44]  D. A. Kharkevich,et al.  Delivery of Loperamide Across the Blood-Brain Barrier with Polysorbate 80-Coated Polybutylcyanoacrylate Nanoparticles , 1997, Pharmaceutical Research.

[45]  P. Couvreur,et al.  Nanoparticles in cancer therapy and diagnosis. , 2002, Advanced drug delivery reviews.

[46]  J. Panda,et al.  The present and future of nanotechnology in human health care. , 2007, Nanomedicine : nanotechnology, biology, and medicine.

[47]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.