首页 » 文章 » 文章详细信息
Drug Delivery Volume 25 ,Issue 1 ,2018-01-01
Hyaluronic acid modified MPEG-b-PAE block copolymer aqueous micelles for efficient ophthalmic drug delivery of hydrophobic genistein
Research Article
Cong Li 1 Rui Chen 2 , 3 Mengzhen Xu 2 Jiyan Qiao 2 Liang Yan 4 Xin Dong Guo 1
Show affiliations
Received 2018-4-9, accepted for publication 2018-5-7, Published 2018-5-7

The ophthalmic drug delivery is a challenge in the clinical treatment of ocular diseases. The traditional drug administration usually shows apparent limitations, such as the low bioavailability from the reason of low penetration of the cornea and the short survival time of drug in the eyes. To overcome these shortcomings, we propose an amphiphilic polymer micelle modified with hyaluronic acid (HA) for high efficient ophthalmic delivery of genistein, a widely used hydrophobic drug for treatment of ocular angiogenesis. The MPEG-b-PAE copolymer was synthesized by the Michael addition reaction, and the final drug carrier MPEG-b-PAE-g-HA was obtained by the process of esterification. Then, genistein was packaged in this drug carrier, getting the final micelles with size of about 84.5 nm. The cell viability tests showed that the micelles take no obvious cytotoxicity to the human cornea epithelium cells. The functionalities of drug slow release and cornea penetration ability were demonstrated in a series ex vivo experiments. Further, the vascular inhibition test illustrated that the micelles could significantly inhibit the angiogenesis of human umbilical vein endothelial cells. These results indicate that the constructed polymer has high feasibility to be used as drug carrier in the treatment of ocular diseases.


neovascularization inhibition;cornea penetration;ocular delivery;genistein;Polymer micelles


© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Schematic illustration for the synthetic route of MPEG-b-PAE-g-HA copolymer.

(a) 1H NMR spectra of MPEG (black line), MPEG-A (red line) in d-CDCl3. (b) 1H NMR spectra of MPEG-b-PAE in d-CDCl3. (c) 1H NMR spectrum of MPEG-b-PAE-g-HA in D2O. (d) GPC spectrum of MPEG-b-PAE-g-HA.

(a) TEM image of genistein/MPEG-b-PAE-g-HA micelles. (b) Particle size and (c) Zeta potential results of genistein/MPEG-b-PAE-g-HA micelle detected by dynamic light scattering. (d) Ultraviolet spectrophotometer of genistein (blue line), blank micelle (red line) and the drug-loaded micelle (black line).

(a) In vitro drug release curves of drug-loading micelle and pure Genistein (n = 3). (b) In vitro cytotoxicity of the genistein/MPEG-b-PAE-g-HA micelles against HCECs after incubation for 24 h, 48 h, and 72 h (n = 5).

(a) In vitro corneal cumulative penetration profiles of genistein/MPEG-b-PAE-g-HA micelles and genistein eye drops. (b) The numbers of neovascular lumens of control groups and micelle treatment groups, n = 5. (c) Neovascular lumens formed by control HUVECs. (d) Vascular inhibition of genistein/MPEG-b-PAE-g-HA micelles on HUVECs.


1. Rui Chen.CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China;Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.chenr@nanoctr.cn
2. Xin Dong Guo.Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, China.xdguo@buct.edu.cn


Cong Li,Rui Chen,Mengzhen Xu,Jiyan Qiao,Liang Yan,Xin Dong Guo. Hyaluronic acid modified MPEG-b-PAE block copolymer aqueous micelles for efficient ophthalmic drug delivery of hydrophobic genistein. Drug Delivery ,Vol.25, Issue 1(2018)



[1] RS Verhoeven, A Garcia et al.. (2018). Nonclinical development of ENV905 (Difluprednate) ophthalmic implant for the treatment of inflammation and pain associated with ocular surgery. J Ocul Pharmacol Ther 34:161–9.
[2] SJ Bakri, AF. Omar (2012). Evolution of vitreomacular traction following the use of the dexamethasone intravitreal implant (Ozurdex) in the treatment of macular edema secondary to central retinal vein occlusion. J Ocul Pharmacol Ther 28:547–9.
[3] AS Ibrahim, MM El-Shishtawy et al. (2010). Genistein attenuates retinal inflammation associated with diabetes by targeting of microglial activation. Mol Vis 16:2033–42.
[4] T Lajunen, R Nurmi et al.. (2016). Light activated liposomes: functionality and prospects in ocular drug delivery. J Control Release 244:157–66.
[5] R Hennig, A. Goepferich (2015). Nanoparticles for the treatment of ocular neovascularizations. Eur J Pharm Biopharm 95:294–306.
[6] JR Villanueva, MG Navarro et al. (2016). Dendrimers as a promising tool in ocular therapeutics: latest advances and perspectives. Int J Pharm 511:359–66.
[7] C Lim, DW Kim et al.. (2016). Preparation and characterization of a lutein loading nanoemulsion system for ophthalmic eye drops. J Drug Deliv Sci Technol 36:168–74.
[8] X Li, Z Zhang et al.. (2012). Diclofenac/biodegradable polymer micelles for ocular applications. Nanoscale 4:4667–73.
[9] B Balzus, FF Sahle et al.. (2017). Formulation and ex vivo evaluation of polymeric nanoparticles for controlled delivery of corticosteroids to the skin and the corneal epithelium. Eur J Pharm Biopharm 115:122–30.
[10] RD Jager, WF Mieler et al. (2008). Age-related macular degeneration. N Engl J Med 358:2606–17.
[11] AC Amrite, UB. Kompella (2005). Size-dependent disposition of nanoparticles and microparticles following subconjunctival administration. J Pharm Pharmacol 57:1555–63.
[12] Z Ioanna, S Christian et al.. (2018). Plasma levels of hypoxia-regulated factors in patients with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 256:325–32.
[13] OP Varghese, W Sun et al. (2009). In situ cross-linkable high molecular weight hyaluronan-bisphosphonate conjugate for localized delivery and cell-specific targeting: a hydrogel linked prodrug approach. J Am Chem Soc 131:8781–3.
[14] B Yavuz, SB Pehlivan et al.. (2016). In vivo tissue distribution and efficacy studies for cyclosporin A loaded nano-decorated subconjunctival implants. Drug Deliv 23:3279–84.
[15] L Xu, YY Wang et al. (2016). Effects of topical antibiotic prophylaxis on wound healing after flapless implant surgery: a pilot study. J Periodontol 87:275–80.
[16] PN Upadhayay, M Kumar et al. (2016). Norfloxacin loaded pH triggered nanoparticulate in-situ gel for extraocular bacterial infections: optimization, ocular irritancy and corneal toxicity. Iran J Pharm Res 15:3–22.
[17] EJ Oh, K Park et al.. (2010). Target specific and long-acting delivery of protein, peptide, and nucleotide therapeutics using hyaluronic acid derivatives. J Control Release 141:2–12.
[18] AN Witmer, GFJM Vrensen et al.. (2003). Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res 22:1–29.
[19] SR Singh, HE Grossniklaus et al.. (2009). Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV. Gene Ther 16:645–59.
[20] JJ Kang-Mieler, CR Osswald et al. (2014). Advances in ocular drug delivery: emphasis on the posterior segment. Expert Opin Drug Deliv 11:1647–60.
[21] Z Liu, Y Jiao et al.. (2008). Polysaccharides-based nanoparticles as drug delivery systems. Adv Drug Deliv Rev 60:1650–62.
[22] F Rafie, Y Javadzadeh et al.. (2010). In vivo evaluation of novel nanoparticles containing dexamethasone for ocular drug delivery on rabbit eye. Curr Eye Res 35:1081–9.
[23] G Gao, Y Li et al.. (2001). Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization. FEBS Lett 489:270–6.
[24] TM Allen, PR. Cullis (2013). Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev 65:36–48.
[25] SM Xu, ZJ Liang et al.. (2018). A systematic study on the prevention and treatment of retinopathy of prematurity in China. BMC Ophthalmol 18:44.
[26] Q Luo, J Zhao et al. (2011). Nanostructured lipid carrier (NLC) coated with chitosan oligosaccharides and its potential use in ocular drug delivery system. Int J Pharm 403:185–91.
[27] HS Chuang, YJ Chen et al. (2018). Enhanced diffusometric immunosensing with grafted gold nanoparticles for detection of diabetic retinopathy biomarker tumor necrosis factor-α. Biosens Bioelectron 101:75–83.
[28] VS Sangwan, PA Pearson et al. (2015). Use of the fluocinolone acetonide intravitreal implant for the treatment of noninfectious posterior uveitis: 3-year results of a randomized clinical trial in a predominantly Asian population. Ophthalmol Ther 4:1–19.
[29] FE Kane, J Burdan et al. (2008). Iluvien: a new sustained delivery technology for posterior eye disease. Expert Opin Drug Deliv 5:1039–46.
[30] E Sanchez-Lopez, MA Egea et al.. (2018). Memantine-loaded PEGylated biodegradable nanoparticles for the treatment of glaucoma. Small 14. doi: 10.1002/smll.201701808.
[31] MA Moustafa, YSR Elnaggar et al.. (2017). Hyalugel-integrated liposomes as a novel ocular nanosized delivery system of fluconazole with promising prolonged effect. Int J Pharm 534:14–24.
[32] R Bisht, JK Jaiswal et al.. (2017). Preparation and evaluation of PLGA nanoparticle-loaded biodegradable light-responsive injectable implants as a promising platform for intravitreal drug delivery. J Drug Deliv Sci Technol 40:142–56.
[33] Y Kureishi, Z Luo et al.. (2000). The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6:1004–10.
[34] M Farnoodian, SJ Wang et al.. (2017). Negative regulators of angiogenesis: important targets for treatment of exudative AMD. Clin Sci 131:1763–80.
[35] B Wang, Y Zou et al.. (2005). Genistein inhibited retinal neovascularization and expression of vascular endothelial growth factor and hypoxia inducible factor 1 alpha in a mouse model of oxygen-induced retinopathy. J Ocul Pharmacol Ther 21:107.
[36] S Liu, L Jones et al. (2012). Nanomaterials for ocular drug delivery. Macromol Biosci 12:608–20.