Login Register Cart 0
Generic placeholder image

Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Utilization of Apatinib-Loaded Nanoparticles for the Treatment of Ocular Neovascularization

Author(s): Kathleen Halasz, Shannon J. Kelly, Muhammad Tajwar Iqbal, Yashwant Pathak and Vijaykumar Sutariya*

Volume 16, Issue 2, 2019

Page: [153 - 163] Pages: 11

DOI: 10.2174/1567201815666181017095708

Abstract

Background: The current treatment of ocular neovascularization requires frequent intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents that cause severe side effects.

Objective: The purpose of this study is to prepare and characterize a novel nanoscale delivery system of apatinib for ocular neovascularization.

Methods: The optimized formulation showed a particle size of 135.04 nm, polydispersity index (PDI) of 0.28 ± 0.07, encapsulation efficiency (EE) of 65.92%, zeta potential (ZP) of -23.70 ± 8.69 mV, and pH of 6.49 ± 0.20. In vitro release was carried out to demonstrate a 3.13-fold increase in the sustainability of apatinib-loaded nanoparticles versus free apatinib solution.

Result: Cell viability and VEGFA and VEGFR2 expression were analyzed in animal retinal pigment epithelial (ARPE-19) cells.

Conclusion: The results confirmed the hypothesis that apatinib nanoparticles decreased toxicity (1.36 ± 0.74 fold) and efficient VEGF inhibition (3.51 ± 0.02 fold) via VEGFR2 mediation.

Keywords: Apatinib, nanoparticles, neovascularization, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2).

« Previous Next »
Graphical Abstract

[1]
Lee, J.E.; Kim, K.L.; Kim, D.; Yeo, Y.; Han, H.; Kim, M.G.; Kim, S.H.; Kim, H.; Jeong, J.H.; Suh, W. Apatinib-loaded nanoparticles suppress vascular endothelial growth factor-induced angiogenesis and experimental corneal neovascularization. Int. J. Nanomedicine, 2017, 12, 4813-4822.
[2]
Suh, W.; Nguyen, H.; Lee, J.; Jeong, J. Therapeutic effect of apatinib-loaded nanoparticles on diabetes-induced retinal vascular leakage. Int. J. Nanomedicine, 2016, 11, 3101-3109.
[3]
Hirani, A.; Pathak, Y. Introduction to nanotechnology with special reference to ophthalmic delivery. In: Nano-biomaterials for ophthalmic drug delivery; Springer: Switzerland, 2016; pp. 1-8.
[4]
Kimura, H.; Ogura, Y. Biodegradable polymers for ocular drug delivery. Ophthalmologica, 2001, 215, 143-155.
[5]
Riedman, D.; O’Colmain, B.; Muñoz, B.; Tomany, S.; McCarty, C.; de Jong, P.; Nemesure, B.; Mitchell, P.; Kempen, J. Prevalence of age-related macular degeneration in the United States. Arch. Ophthalmol., 2004, 122, 564-572.
[6]
Sasore, T.; Reynolds, A.; Kennedy, B. Targeting the PI3K/Akt/mTOR pathway in ocular neovascularization. Adv. Exp. Med. Biol., 2014, 801, 805-811.
[7]
Klaassen, I.; Van Noorden, C.; Schlingemann, R. Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions. Prog. Retin. Eye Res., 2013, 34, 19-48.
[8]
Campochiaro, P. Ocular neovascularization. J. Mol. Med., 2013, 91, 311-321.
[9]
Semenza, G. Hypoxia-inducible factors in physiology and medicine. Cell, 2012, 148, 399-408.
[10]
Halasz, K.; Kelly, S.; Sutariya, V. Hypoxia Inducible Factor-1 (HIF-1) as a target for ocular drug delivery. J. Biomol. Res. Ther., 2017, 6, e154.
[11]
Kelly, S.; Halasz, K.; Sutariya, V. HIF-1a Inhibitors for the treatment of posterior segment ocular diseases; Int. J. Nanomedicine Nanosurgery, 2017, p. 3.
[12]
Yoshida, T.; Zhang, H.; Iwase, T.; Shen, J.; Semenza, G.; Compochiaro, P. Digoxin inhibits retinal ischemia-induced HIF-1α expression and ocular neovascularization. FASEB J., 2010, 24(6), 1759-1767.
[13]
Cohen Stuart, M.A.; Mulder, J.W. Adsorbed polymers in aqueous media the relation between zeta potential, layer thickness and ionic strength. Colloids Surf., 1985, 15, 49-55.
[14]
Raghava, S.; Edelhauser, H.; Grossniklaus, H.; Ambati, B.; Kompella, U. Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV. Gene Ther., 2009, 16, 645-659.
[15]
Kompella, U.; Bandi, N.; Ayalasomayajula, S. Subconjunctival nano- and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Inves. Ophthalmol. Vis. Sci., 2003, 1192-1201.
[16]
Koch, S.; Claesson-Welsh, L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb. Perspect. Med., 2012, 2.
[17]
Aiello, L.; Avery, R.; Arrigg, P.; Keyt, B.; Jampel, H.; Shah, S.; Pasquale, L.; Thieme, H.; Iwamoto, M.; Park, J. Vascular endothelial growth factor in ocular fluid of ptients with diabetic retiopathy and other retinal disorders. N. Engl. J. Med., 1994, 331, 1480-1487.
[18]
van Wijngaarden, P.; Coster, D.; Williams, K. Inhibitors of ocular neovascularization promises and potential problems. JAMA, 2005, 293, 1509-1513.
[19]
Weis, S.; Cheresh, D. Pathophysiological consequences of VEGF-induced vascular permeability. Nature, 2005, 437, 496-504.
[20]
Zhang, Y.; Yang, M.; Portney, N.; Cui, D.; Budak, G.; Ozbay, E.; Ozkan, M.; Ozkan, C. Zeta potential: A surface electrical characteristics to probe the interaction of nanoparticles with normal and cancer human breast epithelial cells. Biomed. Microdev, 2008, 10, 321-328.
[21]
Dejana, E.; Tournier-Lasserva, E.; Weinstein, B. The control of vascular integrity by endothelial cell junctions: Molecular basis and pathological implications. Dev. Cell, 2009, 16, 209-221.
[22]
Sampat, K.; Garg, S. Complications of intravitreal injections. Curr. Opin. Ophthalmol., 2010, 21, 178-183.
[23]
Astete, C.; Sabliov, C. Synthesis of poly(DL-lactide-co-glycolide) nanoparticles with entrapped magnetite by emulsion evaporation method. Particulate. Sci. Tech., 2006, 24(3), 321-328.
[24]
De Campos, A.; Sánchez, A.; Alonso, M. Chitosan nanoparticles: A new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporine A. Int. J. Pharm., 2001, 244, 159-168.
[25]
Hirani, A.; Grover, A.; Lee, Y.; Pathak, Y.; Sutariya, V. Triamcinolone acetonide nanoparticles incorporated in thermoreversible gels for age-related macular degeneration. Pharm. Dev. Technol., 2014, 21, 61-67.
[26]
Malavade, S. Overview of the Ophthalmic System. In: Nano-Biomaterials For Ophthalmic Drug Delivery; Springer: Switzerland, 2016; pp. 9-36.
[27]
de la Fuente, M.; Ravina, M.; Paolicelli, P.; Sanchez, A.; Seijo, B.; Alonso, M. Chitosan-based nanostructures: A delivery platform for ocular therapeutics. Adv. Drug Deliv. Rev., 2010, 62, 100-117.
[28]
Weng, Y.; Liu, J.; Jin, S.; Guo, W.; Liang, X.; Hu, Z. Nanotechnology-based strategies for treatment of ocular disease. Acta Pharm. Sin. B, 2017, 7, 281-291.
[29]
Koo, H.; Moon, H.; Han, H.; Na, J.; Huh, M.; Park, J.; Woo, S.; Park, K.; Kwon, I.; Kim, K.; Kim, H. The movement of self-assembled amphiphilic polymeric nanoparticles in the vitreous and retina after intravitreal injection. Biomaterials, 2012, 33, 3485-3493.
[30]
Huang, J.; Presley, J.; Chimento, M.; Curcio, C.; Johnson, M. Age-related changes in human macular bruch’s membrane as seen by quick-freeze/deep-etch. Exp. Eye Res., 2007, 85, 202-218.
[31]
Agnihotri, S.; Mallikarjuna, N.; Aminabhavi, T. Recent advances on chitosan-based micro- and nanoparticles in drug delivery. J. Control. Release, 2004, 100, 5-28.
[32]
Govender, T.; Stolnik, S.; Garnett, M.; Illum, L.; Davis, S. PLGA nanoparticles prepared by nanoprecipitation: Drug loading and release studies of a water soluble drug. J. Control. Release, 1999, 57, 171-185.
[33]
Dubes, A.; Parrot-Lopez, H.; Abdelwahed, W.; Degobert, G.; Fessi, H.; Shahgaldian, P.; Coleman, A. Scanning electron micropscopy and atomic force micropscopy imaging of solid lipid nanoparticles derived from amphiphilic cyclodextrins. Eur. J. Pharm. Biopharma., 2003, 55, 279-282.
[34]
Khoshneviszadeh, R. A comparison of explanation methods of encapsulation efficacy of hydroquinone in a liposomal system. J. Paramed. Sci., 2016, 7, 23-28.
[35]
Kumari, A.; Yadav, S.; Yadav, S. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf. B Biointerfaces, 2010, 75, 1-18.
[36]
Murdock, R.; Braydish-Stolle, L.; Schrand, A.; Schalger, J.; Hussain, S. Characterization of nanomaterial dispersion in solution prior to in vitro exposure using dynamic light scattering technique. Tox. Sci., 2008, 101, 239-253.
[37]
Albanese, A.; Tang, P.; Chan, W. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu. Rev. Biomed. Eng., 2012, 14, 1-16.
[38]
Rajapaksa, T.; Bennett, K.; Hamer, M.; Lytle, C.; Rodgers, V.; Lo, D. Intranasal M cell uptake of nanoparticles is independently influenced by targeting ligands and buffer ionic strength. J. Biol. Chem., 2010, 285, 23739-23746.
[39]
Sniegowski, M.; Erlanger, M.; Velez-Montoya, R.; Olson, J. Difference in ocular surface temperature by infrared thermography in phakic and pseudophakic patients. Clin. Ophthalmol., 2015, 9, 461-466.
[40]
Tkáčová, M.; Živčák, J.; Foffová, P. A Reference for Human Eye Surface Temperature Measurements in Diagnostic Process of Ophthalmologic Diseases.In Proceedings of MEASUREMENT the 8th International Conference; Smolenice Castle, SlovakiaApril 27-30, 2011
[41]
Shen, J.; Burgess, D. In vitro dissolution testing strategies for nanoparticulate drug delivery systems: Recent developments and challenges. Drug Deliv. Transl. Res., 2013, 3, 409-415.
[42]
van Meerloo, J.; Kaspers, G.; Cloos, J. Cell sensitivity assays: The MTT assay. Cancer Cell Culture, 2011, 731, 237-245.
[43]
Kelly, S.; Hirani, A.; Shahidadpury, V.; Solanki, A.; Halasz, K.; Varghese Gupta, S.; Madow, B.; Sutariya, V. Aflibercept nanoformulation inhibits VEGF expression in ocular in vitro model: A preliminary report. Biomedicines, 2018, 6(3), 92.
[44]
Duh, E.; Yang, H.; Haller, J.; De Juan, E.; Humayun, M.; Gehlbach, P.; Melia, M.; Pieramici, D.; Harlan, J.; Campochiaro, P.; Zack, D. Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor: Implications for ocular angiogenesis. Am. J. Ophthalmol., 2004, 137, 668-674.
[45]
Sakurai, E.; Ozeki, H.; Junou, N.; Ogura, Y. Effect of particle size of polymeric nanospheres on intravitreal kinetics. Ophthalmic Res., 2001, 33, 31-36.
[46]
Schwalfenberg, G.K. The alkaline diet: Is there evidence that an alkaline pH diet benefits health? J. Environ. Public Health, 2012, 2012, 727630.
[47]
Jo, D.; Kim, J.; Lee, T.; Kim, J. Size, surface charge, and shape determine therapeutic effects of nanoparticles on brain and retinal diseases. Nanomedicine , 2015, 11, 1603-1611.
[48]
Jiang, K.; Oberdorster, G.; Biswas, P. Characterization of size, surface charge, and agllomeration state of nanoparticle dispersions for toxicological studies. J. Nano Res., 2009, 11, 77-89.
[49]
Skoog, D.; Holler, J.; Crouch, S. Principles of Instrumental Analysis, 6th ed; Thomson Brooks/Cole: Canada, 2007.
[50]
Thanki Paragkumar, N.; Dellacheria, E.; Six, J. Surface characterstics of PLA and PLGA films. Appl. Surf. Sci., 2006, 253, 2758-2764.
[51]
Awotwe-Otoo, D.; Zidan, A.; Rahman, Z.; Habib, M. Evaluation of anticancer drug-loaded nanoparticle characteristics by nondestructive methodologies. AAPS PharmSciTech, 2012, 13, 611-622.
[52]
Carroll, R.; Bhatia, D.; Geldenhuys, W.; Bhatia, R.; Miladore, N.; Bishayee, A.; Sutariya, V. Brain-targeted delivery of tempol-loaded nanoparticles for neurological disorders. J. Drug Target., 2010, 18, 665-674.
[53]
Xu, Q.; Kambhampati, S.P.; Kannan, R.M. Nanotechnology approaches for ocular drug delivery. Middle East Afr. J. Ophthalmol., 2013, 1, 26-37.
[54]
Govender, T.; Stolnik, S.; Garnett, M.; Illum, L.; Davis, S. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. J. Control. Release, 1999, 57, 171-185.
[55]
Rao Prasad, J.; Geckeler, K. Polymer nanoparticles: Preparation techniques and size-controll parameters. Progess. Polym. Sci., 2011, 36, 887-913.
[56]
Tosi, G.; Bortot, B.; Ruozi, B.; Dolcetta, D.; Vandelli, M.; Forni, F.; Severini, G. Potential use of polymeric nanoparticles for drug delivery across the blood brain barrier. Curr. Med. Chem., 2013, 20, 2212-2225.
[57]
Esmaeili, F.; Ghahremani, M.; Esmaeili, B.; Khoshayand, M.; Atybabi, F.; Dinarvand, R. PLGA Nanoparticles of different surface properties: preparation and evluation of htier body distribution. Int. J. Pharm., 2008, 349, 249-255.
[58]
Zhu, M.; Nia, G.; Meng, H.; Xia, T.; Nel, A.; Zhao, Y. Physicochemical properties determine nanomaterial cellular uptake, transport, and fate. Acc. Chem. Res., 2013, 46, 622-631.
[59]
Carneiro-da-Cunha, M.; Cerqueira, M.; Souza, B.; Teixeira, J.; Vincentre, A. Influence of concentration, ionic strength and pH on zeta potential and mean hydrodynamic diameter of edible polysaccharide solutions envisaged for multianolayered films production. Carbohydr. Polym., 2011, 85, 522-528.
[60]
The Eyetech Study Group Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase II study results. In: The American Academy of Ophthalmology Annual Meeting, New Orleans, Louisiana, November, 2001; The Eyetech Study Group. Ophthalmology, 2003, 110, 979-986.
[61]
Lin, P.; Lin, S.; Wang, P.; Rajagopalan, S. Techniques for physicochemical characterization of nanomaterials. Biotech. Adv., 2014, 32, 711-726.
[62]
Zhang, Y.; Yang, M.; Portney, N.; Cui, D.; Budak, G.; Ozbay, E.; Ozkan, M.; Ozkan, C. Zeta potential: A surface electrical characteristics to probe the interaction of nanoparticles with normal and cancer human breast epithelial cells. Biomed. Microdev, 2008, 10, 321-328.
[63]
Hamm, L.; Nakhoul, N.; Hering-Smith, K. Acid-base homeostasis. Clin. J. Am. Soc. Nephrol., 2015, 10, 2232-2242.
[64]
Simon, L.; Sabliov, C. The effect of nanoparticle properties, detection method, delivery route and animal model on poly(lactic-co-glycolic) acid annoparticles biodistribution in mice and rats. Drug Metab. Rev., 2014, 46, 128-141.
[65]
Bourges, J.; Gautier, S.; Delie, F.; Bejjani, R.; Jeanny, J.; Gurny, R.; BenEzra, D.; Behar-Cohen, F. Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Inv. Ophthalmol. Vis. Sci., 2003, 44, 3562-3569.
[66]
Ho, A.; Scott, I.; Kim, S.; Brown, G.; Brown, M.; Ip, M.; Recchia, F. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: A report by the American Academy of Ophthalmology. Ophthalmology, 2012, 119, 2179-2188.
[67]
Olsson, A.; Dimberg, A.; Kreuger, J.; Claesson-Welsh, L. VEGF receptor signaling - In control of vascular function. Nat. Rev. Mol. Cell Biol., 2006, 7, 359-371.
[68]
Willoughby, C.; Ponzin, D.; Ferrari, S.; Lobo, A.; Landau, K.; Omidi, Y. Anatomy and physiology of the human eye: Effects of mucopolysaccharidoses disease on structure and function – a review. Clin. Exp. Ophthalmol., 2010, 38(1), 2-11.

Rights & Permissions Print Cite
Article Metrics
41
19
1
2
© 2024 Bentham Science Publishers | Privacy Policy