1a.Department of Pharmacy; 1b.The Open Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; 2.The Affiliated Hospital of Jiangxi College of Traditional Chinese Medicine, Nanchang 330006, China;
3.College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China
Abstract��
To construct receptor-mediated lactoferrin-modified curcumin-loaded nanostructured lipid carriers(Lf-Cur-NLCs)and investigate its in vitro physicochemical properties and in vivo brain targeting efficiency. METHODS Cur-NLCs were prepared by melt-emulsification method, and then lactoferrin(Lf)was adsorbed onto the surface of Cur-NLCs via electrostatic interaction to form Lf-Cur-NLCs. Lf-Cur-NLCs with different concentrations of Lf were characterized in terms of shape, diameter, Zeta potential, serum stability and in vitro release of Lf-Cur-NLCs in saline containing 1% Tween 80. Additionally, Lf-NLCs labeled with NIRD-15, a fluorescent imaging agent, were prepared with Lf at concentrations of 0.5, 1.5 and 2.0 mg�mL-1(marked for Lf1-NLC, Lf3-NLC, and Lf4-NLC, respectively). After iv injection in mice, living animal imaging system was used to observe the fluorescence intensity of NIRD-15 in the living animals and isolated organs to evaluate the brain targeting of Lf-NLCs. RESULTS Cur-NLCs were spherical with average particle size of(187.5?4.7)nm and Zeta potential of(-23.7?2.9)mV. The average diameter of Lf-Cur-NLCs with spherical shape was between 167.8-299.9 nm. The Zeta potential was between-26.87--13.03 mV. When the concentration of Lf was 2.0 mg�mL-1 and the incubated time was 6 h, the adsorption of Lf at the surface of the Cur-NLCs was saturated. Lf-Cur-NLCs were stable in serum, and the release of Cur from Lf-Cur-NLCs was slowed down. Compared with NLCs, there was a strong fluorescence in the brain after iv injection of Lf-NLCs, indicating that Lf-NLCs were more effective than NLCs in brain targeting, while Lf3-NLCs were the most effective one. CONCLUSION Lf-NLCs are constructed successfully for brain targeting via electrostatic adsorption. The established process avoids chemical synthesis in the targeting drug delivery system design. However, the ability of brain targeting of the carriers is related with the amount of Lf.
XIAO Yan-Yu-a,
b,
CHEN Xi-a etc
.Preparation of Lactoferrin-Modified Nanostructured Lipid Carriers and Evaluation of its Brain Targeting Efficiency[J] Chinese Pharmaceutical Journal, 2013,V48(20): 1755-1760
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[1]
SINGLA A K, GARG A, AGGARWAL D. Paclitaxel and its formulation. Int J Pham,2002, 235(1-2):179-192.[2] WANG L, ZHANG M, ZHANG N,et al. Synergistic enhancement of cancer therapy using a combination of docetaxel and photothermal ablation induced by single-walled carbon nanotubes. Int J Nanomedicine,2011, 6:2641-2652.[3] KAWAGUCHI M, YAMAZAKI J, OHNO J,et al. Preparation and binding study of a complex made of DNA-treated single-walled carbon nanotubes and antibody for specific delivery of a "molecular heater" platform. Int J Nanomedicine,2012, 7: 4363-4372.[4] YUAN J, GAO H, CHING C B. Comparative protein profile of human hepatoma HepG2 cells treated with graphene and single-walled carbon nanotubes: An iTRAQ-coupled 2D LC-MS/MS proteome analysis. Toxicol Lett, 2011,207(3):213-221.[5] GARDE S V, FORT��A J, GE M, et al.Binding and internalization of NGR- peptide-targeted liposomal doxorubicin(TVT-DOX)in CD13-expressing cells and its antitumor effects.Anticancer drugs, 2007,18(10): 1189-1200[6] CHEN L, QU M Z, WANG G X, et al. Study on carbon canoutubes/bisphenol a polycarbonate composites produced by solution mixing. J Function Materials,2005,1(36):139-141.[7] BOSE S, MUKHERJEE M, DAS C K,et al. Effect of modified MWCNT and polyphosphazene elastomer on the properties of PES/LCP blend system. J Nanosci Nanotechnol, 2009,9(11):6569-6578.[8] DU F, WU K, YANG Y,et al. Synthesis and electrochemical probing of water-soluble poly(sodium 4-styrenesulfonate-co-acrylic acid)-grafted multiwalled carbon nanotubes.Nanotechnology, 2008,19(8):085716. [9] WEEDEN C, HARTLIEB K J, LIM L Y. Preparation and physicochemical characterization of a novel paclitaxel-loaded amphiphilic aminocalixarene nanoparticle platform for anticancer chemotherapy. J Pharm Pharmacol, 2012,64(10):1403-1411. KOLLIPARA S, BENDE G, MOVVA S,et al.Application of rotatable central composite design in the preparation and optimization of poly(lactic-co-glycolic acid)nanoparticles for controlled delivery of paclitaxel. Drug Dev Ind Pharm, 2010, 36(11):1377-1387. LIU D, LI S B, BAO J, et al. Preparation, in vitro release and pharmacokinetics of paclitaxel lipid nanoparticles for intravenous injection. Chin Pharm J,2009,44( 17):1320-1326. LIU Z, DAVIS C, CAI W,et al. Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy. Proc Natl Acad Sci USA, 2008, 105(5): 1410-1415. WANG L, SHI J, ZHANG H,et al.Synergistic anticancer effect of RNAi and photothermal therapy mediated by functionalized single-walled carbon nanotubes. Biomaterials,2013, 34(1):262-274.
[2]
SCHWARTZBAUM J A, FISHER J L, ALDAPE K D, et al. Epidemiology and molecular pathology of glioma . Nat Clin Pract Neurol, 2006, 2(9):494-503.[2] CHEN H, LI J. Progress on receptor mediated tumor targeting therapy of cancer . Pharm Clin Res (ҩѧ���ٴ��о�), 2008, 16(4): 288-292.[3] CHEN H, TANG L, QIN Y, et al. Lactoferrin-modified procationic liposomes as a novel drug carrier for brain delivery . Eur J Pharm Sci, 2010, 40(2): 94-102.[4] HU K, LI J, SHEN Y, et al. Lactoferrin-conjugated PEG-PLA nanoparticles with improved brain delivery: In vitro and in vivo evaluations . J Controlled Release, 2009, 134(1):55-61.[5] HUANG R, KE W, LIU Y, et al. The use of lactoferrin as a ligand for targeting the polyamidoamine-based gene delivery system to the brain . Biomaterials, 2008, 29(2):238-246.[6] NAGAI S, KURIMOTO M, WASHIYAMA K, et al. Inhibition of cellular proliferation and induction of apoptosis by curcumin in human malignant astrocytoma cell lines . J Neurooncol, 2005, 74(2):105-111.[7] GAO X, DEEB D, JIANG H, et al. Curcumin differentially sensitizes malignant glioma cells to TRAIL/Apo2L-mediated apoptosis through activation of procaspases and release of cytochrome c from mitochondria . J Exp Ther Oncol, 2005, 5(1):39-48.[8] BELKAID A, COPLAND I B, MASSILLON D, et al. Silencing of the human microsomal glucose-6-phosphate translocase induces glioma cell death: Potential new anticancer target for curcumin .FEBS Lett, 2006, 580(15):3746-3752. [9] KARMAKAR S, BANIK N L, PATEL S J, et al. Curcumin activated both receptor-mediated and mitochondria-mediated proteolytic pathways for apoptosis in human glioblastoma T98G cells .Neurosci Lett, 2006, 407(1):53-58. AOKI H, TAKADA Y, KONDO S, et al. Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: Role of Akt and extracellular signal-regulated kinase signaling pathways .Mol Pharmacol, 2007, 72(1):29-39. LIU E, WU J, CAO W, et al. Curcumin induces G2/M cell cycle arrest in a p53-dependent manner and upregulates ING4 expression in human glioma . J Neurooncol, 2007, 85(3):263-270. LI D M, WAN C L, LI J C. Development of small living animal lmaging technology . Chin J Biomed Eng (�й�����ҽѧ����ѧ��), 2009, 28(6): 916-921. ZHOU T, HAN Y, GONG W, et al. Applications of in vivo optical imaging technology in biomedicine . Chin J Stereology Mage Anal(�й�����ѧ��ͼ�����), 2007,12(1):69-74. SUZUKI Y A, LOPEZ V, LONNERDAL B. Mammalian lactoferrin receptors: Structure and function . Cell Mol Life Sci, 2005, 62(22):2560-2575. SUZUKI Y A, SHIN K, LONNERDAL B. Molecular cloning and functional expression of a human intestinal lactoferrin receptor .Biochemistry, 2001, 40(51):15771-15779.
2013, Vol. 48 
