Abstract
Chemotherapies for brain diseases have been hampered due to the inability of transport of drug across the blood-brain barrier (BBB). In order to overcome the barrier, p-hydroxybenzoic acid (p-HA), a small molecule of benzamide analogue, was used as a ligand for brain-targeted drug delivery. The p-HA was conjugated to PEG-DSPE to form p-HA-PEG-DSPE. Docetaxel-loaded polymeric micelles were prepared by a thin-film hydration method using methoxy-poly(ethylene glycol)-distearoylphosphatidylethanolamine (mPEG2000-DSPE) as a carrier and the p-HA-PEG-DSPE as a brain targeted material. The prepared micelles showed spherical with a mean diameter of (18±3) nm. Encapsulation efficiency and drug loading were (83.49±1.3)%, (7.7±1.2)% for unmodified micelles and (80.65±1.6)%, (7.47±1.8)% for p-HA-modified micelles, respectively. In vitro cellular uptake experiments showed that the p-HA-modified micelles increased BCECs cellular uptake by 1.2 times compared to the unmodified micelles. Ex vivo near-infrared fluorescence imaging showed that brain uptake of the p-HA-modified micelles was 1.3–1.8 times higher than that of the unmodified micelles. In vitro cytotoxicity assay against glioblastoma cell U87 MG showed that inhibition rate of the p-HA-modified micelles increased by 1.2 times compared to that of the unmodified micelles and 1.7 times compared to that of DTX. Survival time of nude mice bearing intracranial glioblastoma showed that the lifetime of saline group, Taxotere group, mPEG-DSPE/DTX micelles group and p-HA-PEG-DSPE/DTX micelles group was 22, 27, 32 and 45.8 d, representively, which indicated that anti-glioblastoma activity of DTX could be significantly enhanced by the p-HA-modified polymeric micelles. These results demonstrated that the p-HA-modified micelles could be a promising brain-targeted drug delivery system for hydrophobic drugs against glioblastoma.
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Stupp R, Hegi M E, Chakravarti, et al. A chemoradiotherapy in malignant glioma: Standard of care and future directions. J Clin Oncol, 2007, 25: 27–36
De Smedt S C, Demeester J, Hennink W E. Cationic polymer based gene delivery systems. Pharm Res, 2000, 17: 113–126
Pardridge W M. The blood-brain barrier: Bottleneck in brain drug development. NeuroRx, 2005, 2: 3–14
Risau W, Wolburg H. Development of the blood-brain barrier. Trends Neurosci, 1990, 13: 174–178
Wang P P, Frazier J, Brem H. Local drug delivery to the brain. Adv Drug Deliv Rev, 2002, 54: 987–1013
Béduneau A, Benoit J P. Brain targeting using novel lipid nanovectors. J Control Release, 2008, 126: 44–49
Jones A R, Shusta E V. Blood-brain barrier transport of therapeutics via receptor-mediation. Pharm Res, 2007, 24: 1759–1771
Huang R Q, Qu Y H, Jiang C, et al. Efficient gene delivery targeted to the brain using a transferrin-conjugated polyethyleneglycol-modified polyamidoamine dendrimer. FASEB J, 2007, 21: 1117–1125
Chen Y, Liu L. Modern methods for delivery of drugs across the blood-Brain barrier. Adv Drug Deliv Rev, 2012: 640–655
Ulbrich K, Hekmatara T, Herbert E, et al. Transferrin- and transferrinreceptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (BBB). Eur J Pharm Biopharm, 2009, 71: 251–256
Schulingkamp R J, Pagano T C, Hung D, et al. Insulin receptors and insulin action in the brain: Review and clinical implications. Neurosci Amp Biobehav Rev, 2000, 24: 855–872
Halatsch ME, Schmidt U, Behnke-Mursch J, et al. Epidermal growth factor receptor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumours. Cancer Treat Rev, 2006, 32: 74–89
Lucarelli M, Gennarelli M, Cardelli P, et al. Expression of receptors for native and chemically modified low-density lipoproteins in brain microvessels. FEBS Lett, 1997, 401: 53–58
Ngarmukos C, Baur E L, Kumagai A K. Co-localization of GLUT1 and GLUT4 in the blood-brain barrier of the rat ventromedial hypothalamus. Brain Res, 2001, 900: 1–8
Robert P H, Allain H. Clinical management of agitation in the elderly with tiapride. Euro Psychiatry, 2001, 1: 42–47
Takano A, Suhara T, Okubo Y, et al. The antipsychotic sultopride is overdosed—A PET study of druginduced receptor occupancy in comparison with sulpiride. Int J Neuropsychopharmacol, 2006, 9: 539–545
Levey A I, Hersch S M, Ciliax B J, et al. Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc Natl Acad Sci USA, 1993, 90: 8861–8865
Saji H D, Tanahashi K K, Yokoyama A, et al. Synthesis, in vitro binding profile and biodistribution of a 125I-labeled N-Benzyl pyrrolidinyl benzamide derivative: A potential radioligand for mapping dopamine D2 receptors. Bioorg Med Chem Lett, 2009, 6: 1797–1801
Wang T, Petrenko V A, Torchilin V P. Paclitaxel-loaded polymeric micelles modified with MCF-7 cell-specific phage protein: Enhanced binding to target cancer cells and increased cytotoxicity. Mol Pharm, 2010, 7: 1007–1014
Shao K, Huang R Q, Jiang C, et al. Angiopep-2 modified PE-PEG based polymeric micelles for amphotericin B delivery targeted to the brain. J Control Release, 2010, 147: 118–126
Torchilin V P. Targeted polymeric micelles for delivery of poorly soluble drugs. Cell Mol Life Sci, 2004, 61: 2549–2559
Torchilin V P. Targeted pharmaceutical nanocarriers for cancer therapy and imaging. Aaps J, 2007, 9: E128–E147
Zhan C Y, Li B, Lu W Y, et al. Micelle-based brain-targeted drug delivery enabled by a nicotine acetylcholine Receptor Ligand. Angew Chem Int Ed, 2011, 50: 5482–5485
Liu Y, Lu W Y. Recent advences in brain tumor-targeted nano-drug delivery system. Expert Opin Drug Deliv, 2012, 9: 671–686
Li J, Meng Q G, Lu W Y. Benzamide analogue-conjugated polyethylenimine for brain-targeting and gene delivery. J Drug Targeting, 2011, 19: 814–820
Han X, Liu J, Lu W Y. 9-NC-loaded folate-conjugated polymer micelles as tumor targeted drug delivery system: Preparation and evaluation in vitro. Int J Pharm, 2009, 372: 125–131
Otova B, Va R, Gut I, et al. Effects of paclitaxel, docetaxel and their combinations on subcutaneous lymphomas in inbred Sprague-Dawley/Cub rats. Eur J Pharm Sci, 2006, 29: 442–450
Zhan C Y, Gu B, Lu W Y, et al. Cyclic RGD conjugated poly (ethylene glycol)-co-poly(lactic acid) micelle enhances paclitaxel anti-glioblastoma effect. J Control Release, 2010, 143: 136–142
Yan Z Q, Lu W Y. LyP-1-conjugated PEGylated liposomes: A carrier system for targeted therapy of lymphatic metastatic tumor. J Control Release, 2012, 157: 118–125
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Zhang, Z., Wei, X., Zhang, X. et al. p-Hydroxybenzoic acid (p-HA) modified polymeric micelles for brain-targeted docetaxel delivery. Chin. Sci. Bull. 58, 2651–2656 (2013). https://doi.org/10.1007/s11434-013-5760-z
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DOI: https://doi.org/10.1007/s11434-013-5760-z