Development of a drug-eluting intraocular lens to deliver epidermal growth factor receptor inhibitor gefitinib for posterior capsule opacification prophylaxis
Restricted accessResearch articleFirst published online March, 2021
Development of a drug-eluting intraocular lens to deliver epidermal growth factor receptor inhibitor gefitinib for posterior capsule opacification prophylaxis
Different molecular targets, such as the epidermal growth factor receptor, have been identified for the prophylaxis of posterior capsule opacification. This led to the proposal of several drugs, yet drug delivery into the capsular bag remains challenging. The intraocular lens as a drug delivery device would provide a convenient method to allow drug release in the location needed. This is to evaluate the effect of a drug-eluting intraocular lens using an epidermal growth factor receptor inhibitor.
Methods:
Hydrophobic and hydrophilic intraocular lenses were coated with gefitinib using the dip coating technique. The cellular response on the modified intraocular lenses was tested in a human lens epithelial cell line (FHL-124) in an anterior segment model. Furthermore, modified intraocular lenses were implanted into human capsular bags ex vivo. Drug release was determined as well as the biocompatibility on human corneal endothelial cells. Unmodified intraocular lenses served as controls. In addition, immunofluorescence staining with fibronectin as a marker for fibrotic response was conducted.
Results:
Both coated hydrophilic and hydrophobic intraocular lenses could attenuate the cell growth of FHL-124 cells in the human capsular bag in comparison to the unmodified controls. Furthermore, gefitinib-soaked intraocular lenses showed a constant drug release over the first 10 days. No reduction in cell viability of corneal endothelial cells occurred. A decrease in fibronectin expression under gefitinib treatment could be observed.
Conclusion:
In vitro epidermal growth factor receptor seems to be a valuable target for the prevention of posterior capsule opacification. The gefitinib-eluting intraocular lens in this study could inhibit cell growth in non-toxic concentrations.
NibourgLMGelensEKuijerR, et al. Prevention of posterior capsular opacification. Exp Eye Res2015; 136: 100–115.
6.
AzzoliCGBakerSJrTeminS, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol2009; 27(36): 6251–6266.
7.
KobayashiKHagiwaraK. Epidermal growth factor receptor (EGFR) mutation and personalized therapy in advanced nonsmall cell lung cancer (NSCLC). Target Oncol2013; 8(1): 27–33.
8.
WormstoneIMTamiyaSAndersonI, et al. TGF-beta2-induced matrix modification and cell transdifferentiation in the human lens capsular bag. Invest Ophthalmol Vis Sci2002; 43(7): 2301–2308.
9.
WertheimerCLieglRKerntM, et al. EGFR-blockade with erlotinib reduces EGF and TGF-β2 expression and the actin-cytoskeleton which influences different aspects of cellular migration in lens epithelial cells. Curr Eye Res2014; 39(10): 1000–1012.
10.
ShuDYWojciechowskiMLovicuFJ. ERK1/2-mediated EGFR-signaling is required for TGFβ-induced lens epithelial-mesenchymal transition. Exp Eye Res2018; 178: 108–121.
11.
WertheimerCKassumehSPiravejNP, et al. The intraocular lens as a drug delivery device: in vitro screening of pharmacologic substances for the prophylaxis of posterior capsule opacification. Invest Ophthalmol Vis Sci2017; 58(14): 6408–6418.
12.
KassumehSAWertheimerCMvon StudnitzA, et al. Poly(lactic-co-glycolic) acid as a slow-release drug-carrying matrix for methotrexate coated onto intraocular lenses to conquer posterior capsule opacification. Curr Eye Res2018; 43(6): 702–708.
13.
Eibl-LindnerKHWertheimerCKampikA. Intraocular lens as a drug delivery device: state of the art and future perspective. Klin Monbl Augenheilkd2016; 233(2): 172–178.
14.
WormstoneIMTamiyaSEldredJA, et al. Characterisation of TGF-beta2 signalling and function in a human lens cell line. Exp Eye Res2004; 78(3): 705–714.
15.
BednarzJTeifelMFriedlP, et al. Immortalization of human corneal endothelial cells using electroporation protocol optimized for human corneal endothelial and human retinal pigment epithelial cells. Acta Ophthalmol Scand2000; 78(2): 130–136.
16.
GotohNPerdueNRMatsushimaH, et al. An in vitro model of posterior capsular opacity: SPARC and TGF-beta2 minimize epithelial-to-mesenchymal transition in lens epithelium. Invest Ophthalmol Vis Sci2007; 48(10): 4679–4687.
17.
LiuCSWormstoneIMDuncanG, et al. A study of human lens cell growth in vitro. A model for posterior capsule opacification. Invest Ophthalmol Vis Sci1996; 37(5): 906–914.
18.
ScudieroDAShoemakerRHPaullKD, et al. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res1988; 48(17): 4827–4833.
19.
SpitzerMSYoeruekESierraA, et al. Comparative antiproliferative and cytotoxic profile of bevacizumab (Avastin), pegaptanib (Macugen) and ranibizumab (Lucentis) on different ocular cells. Graefes Arch Clin Exp Ophthalmol2007; 245(12): 1837–1842.
20.
WertheimerCSiedleckiJKookD, et al. EGFR inhibitor Gefitinib attenuates posterior capsule opacification in vitro and in the ex vivo human capsular bag model. Graefes Arch Clin Exp Ophthalmol2015; 253(3): 409–417.
21.
WertheimerCKueresASiedleckiJ, et al. The intraocular lens as a drug delivery device for an epidermal growth factor-Receptor inhibitor for prophylaxis of posterior capsule opacification. Acta Ophthalmol2018; 96(7): e874–e882.
22.
KampmeierJBaldysiak-FigielAde Jong-HesseY, et al. Effect of growth factors on proliferation and expression of growth factor receptors in a human lens epithelial cell line. J Cataract Refract Surg2006; 32(3): 510–514.
23.
MaddalaRReddyVNEpsteinDL, et al. Growth factor induced activation of Rho and Rac GTPases and actin cytoskeletal reorganization in human lens epithelial cells. Mol Vis2003; 9: 329–336.
24.
HongoMItoiMYamamuraY, et al. Distribution of epidermal growth factor receptors in rabbit lens epithelial cells. Invest Ophthalmol Vis Sci1993; 34(2): 401–404.
25.
BhuyanDKReddyPGBhuyanKC. Growth factor receptor gene and protein expressions in the human lens. Mech Ageing Dev2000; 113(3): 205–218.
26.
ShigemitsuTIshiguroKShimizuY, et al. Immunocytochemical features of lens after cataract tissue—signalling molecules (growth factors, cytokines, other signalling molecules), cytoskeleton proteins, cellular and extracellular matrix proteins. Int Ophthalmol1999; 23(3): 137–144.
WojciechowskiMCMahmutovicLShuDY, et al. ERK1/2 signaling is required for the initiation but not progression of TGFβ-induced lens epithelial to mesenchymal transition (EMT). Exp Eye Res2017; 159: 98–113.
29.
TiwariARamJLuthra-GuptasarmaM. Targeting the fibronectin type III repeats in tenascin-C inhibits epithelial-mesenchymal transition in the context of posterior capsular opacification. Invest Ophthalmol Vis Sci2014; 56(1): 272–283.
30.
SpaltonDJRussellSLEvans-GowingR, et al. Effect of total lens epithelial cell destruction on intraocular lens fixation in the human capsular bag. J Cataract Refract Surg2014; 40(2): 306–312.
31.
RodriguesGALutzDShenJ, et al. Topical drug delivery to the posterior segment of the eye: addressing the challenge of preclinical to clinical translation. Pharm Res2018; 35(12): 245.
32.
Eibl-LindnerKHLieglRWertheimerC, et al. Intraocular lens as a drug delivery device. Ophthalmologe2013; 110(10): 990–994.
33.
DickBGreinerKMagdowskiG, et al. Long-term stability of heparin-coated PMMA intraocular lenses. Results of an in vitro study. Ophthalmologe1997; 94(12): 920–924.
34.
LarssonRSelenGFormgrenB, et al. Long-term stability of heparin-surface-modified intraocular lenses in vivo. J Cataract Refract Surg1992; 18(3): 247–251.
35.
BorkarDSLacoutureMEBastiS. Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: a five-year review. Support Care Cancer2013; 21(4): 1167–1174.
36.
TodokoroDItakuraHIbeT, et al. Anterior uveitis caused by ocular side effects of afatinib: a case report. Case Rep Ophthalmol2016; 7(1): 74–78.
37.
ClearyGSpaltonDJZhangJJ, et al. In vitro lens capsule model for investigation of posterior capsule opacification. J Cataract Refract Surg2010; 36(8): 1249–1252.
38.
EldredJAZhengJChenS, et al. An in vitro human lens capsular bag model adopting a graded culture regime to assess putative impact of IOLs on PCO formation. Invest Ophthalmol Vis Sci2019; 60(1): 113–122.
