Anti-angiogenic Drugs for the Treatment of Diabetic Retinopathy

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1 Vol. 35 No HPLC 26 Zhou Y Liu X Yang J et al. Analysis of caged xanthones J xanthone J Song J Z Yip Y K Han Q B et al. Rapid determination of polyprenylated xanthones in gamboge resin of Garcinia hanburyi by HPLC J. J Sep Sci Li S L Song J Z Han Q B et al. Improved high-performance liquid chromatographic method for simultaneous determination of 12 cytotoxic caged xanthones in gamboges a potential anticancer resin from Garcinia hanburyi J. Biomed Chromatogr from the resin of Garcinia hanburyi using ultra-performance liquid chromatography / electrospray ionization quadrupole time-of-flight tandem mass spectrometry J. Anal Chim Acta / J Han Q B Zhou Y Feng C et al. Bioassay guided discovery of apoptosis inducers from gamboge by high-speed counter-current chromatography and high-pressure liquid chromatography / electrospray ionization quadrupole timeof-flight mass spectrometry J. J Chromatogr B Analyt Technol Biomed Life Sci * C-β R A Anti-angiogenic Drugs for the Treatment of Diabetic Retinopathy ZHANG Fu-jing, GU Yue-qing ( Department of Biomedical Engineering,China Pharmaceutical University,Nanjing ,China) [Abstract] Diabetic retinopathy ( DR) is the main complication of diabetes, and has become one of the significant causes of blindness among the middle-aged and old people. Angiogenesis has been widely considered as the therapeutic target in DR. The anti-angiogenic drugs for the treatment of DR,including * Tel cpuyueqing@ 163. com

2 2011 Vol. 35 No anti-vascular endothelial cell growth factor ( VEGF) drugs, corticosteroid hormones, protein kinase C-β ( PKC-β) inhibitors and pigment epithelium derived factor ( PEDF) were introduced in this paper,so as to provide the ideas for the further development and the clinical use of these drugs. [Key words] diabetic retinopathy; age-related macular degeneration; anti-angiogenic; vascular endothelial cell growth factor DR DR diabetic retinopathy DR DR 3 age-related macular degeneration AMD DR nonproliferative DR NPDR AMD DR DR AMD NPDR 1 2 DR DR proliferative DR PDR VEGF 1 3 DR VEGF DR bevasiranib Cand5 - C DG- VEGF mrna VEGF PKC 1. 1 DR FDA AMD DME Ⅲ 2 28 RNA PEG PKC DR 1 C 294 H 342 F 13 N 107 Na 28 O 188 P 28 C 2 H 4 O n VEGF 165 VEGF 165 VEGFR-2 IC 50 diabetic macular edema DME DR VEGF DR pegaptanib sodium Macugen bevacizumab Avastin ranibizumab Lucentis VEGF Trap vascular endothelial cell growth factor VEGF pigment epithelium derived factor MP0112 VEGF VEGF VEGFR ~ 1. 4 nmol L nmol L - 1 C-β PKC-β 100 % 3 5'- 3'- PEDF DR 4

3 Vol. 35 No. 8 1 Figure 1 The structural diagram of pegaptanib IC ± 5 μg L FDA AMD 9 AMD AMD ETDRS 12 DME 172 P = μm P = DME VEGF mg 1 Haritoglou 9 36 DME % 10 % P = Jorge 10 DR 68 μm 4 μm P = % 5 97 DME mg 90 μl 0. 3 mg mg + 2 mg 0. 3 mg C C % 7 % VEGF K d 1. 1 nmol L - 1 VEGF mininal angle 1. 2 resolution MAR logmar ± A VEGF logmar ± ± IgG1κ DME

4 2011 Vol. 35 No mg mg Fab VEGF 0. 3 mg P = FDA AMD VEGF 20 ~ FDA VEGF VEGF 165 VEGF 121 VEGF 110 IC ± ± ± AMD PDR nmol L DME off-lable use VEGF Trap 3. 2 VEGF Trap Regeneron VEGF VEGF Trap 14 VEGFR-1 1 ~ 3 AMD IgG1 Fc FOCUS Ⅰ /Ⅱ photodynamic therapy PDT 9. 4 AMD 15 MARINA Ⅲ extra-cellular matrix ECM AMD Regeneron 16 AMD DME VEGF Trap VEGFR-1 PDR DME -2 VEGFR DME 10 IgG1 Fc ~ 0. 5 mg 1 3 VEGF Trap DME VEGF Trap-Eye VEGF Trap-Eye 0. 3 mg ETDRS ± ECM VEGF mg 7. 8 ± mg 50 % VEGF Trap ± placental growth factor PLGF ± μm 17 VEGF Trap-Eye AMD PDR National AMD Ⅰ Eye Institute NEI Ⅲ VEGF Trap-Eye PDR VEGF Trap VEGF VEGF 165 K d 0. 5 pmol L mg μm 1 % mg

5 Vol. 35 No CLEAR-IT Bevasiranib Ⅱ AMD Bevasiranib OPKO VEGF VEGF Trap-Eye 5 mrna RNA sirna 0. 5 mg mg '-ACCUCACCAAGGCCAGCACdTdT-3' mg mg mg bevasiranib 1 AMD DME Ⅰ /Ⅱ μm 20 VEGF VEGF Trap-Eye AMD Regeneron Bayer DR FDA 2006 DA VINCI 219 DME Ⅱ 23 bevasiranib DR 5 VEGF Trap-Eye mg mg mg mg Regeneron VEGF ETDRS VEGF 2. 5 VEGF DR Trap-Eye 8. 5 ~ P < triarmcinolone VEGF Trap-Eye DME acetonide fluocinolone 1. 5 MP0112 MP0112 Molecular Partners designed ankyrin repeat proteins DARPins 21 VEGF ~ /10 1 /2 MP0112 VEGF 50 2 VEGF MP0112 Martidis 24 DME MP mg 3 Snellen Molecular Partners MP0112 DME Ⅰ /Ⅱa MP VEGF mrna VEGF bevasiranib Ⅲ OPKO RNA VEGF dexamethasone % 25 DME

6 2011 Vol. 35 No SurModics 36 ~ 54 h I-vation TA MK0140 Allergan Ozurdex mg STRIDE DME FDA I-vation TA 925 μg 6 13 % ETDRS Ozurdex DME Ⅱ Ozurdex 71 % ~ 9 Ozurdex DME Ⅲ 3 % 3 C-β 2. 2 PKC VEGF 28-1 ET-1 ET-1 Retisert 2005 PKC DR FDA DME ruboxistaurin mesylate Arxxant 1 Retisert DME PKC-β PKC Retisert PKC-β Ⅰ PKC-β Ⅱ DME Alimera IC 50 5 nmol L - 1 Ⅰ /Ⅱ 3. 5 mm mm 27 DR 3 PKC-DRS 252 Iluvien 25 DR FAME 956 DME 8 Ⅲ Iluvien mg qd 36 ~ mg % NPDR DR ETDRS 15 PKC-DRS2 685 DR

7 Vol. 35 No. 8 PEDF 32 mg qd GenVec PEDF E1 E3 E4 30 % DR AdGVPEDF. 11D AdGVPEDF. 11D ETDRS AMD P = PU 35 GenVec DR 2 PEDF Ad35 PKC-DRS2 PEDF DR 30 4 DR PEDF DR DR DR PEDF DR VEGF PEDF 2 PKC-β PEDF PEDF 31 PEDF VEGF 32 PEDF DR VEGF 1-1α HIF-1α VEGF 2 γ VEGFR-1 C VEGFR-1 C VEGFR-2 VEGFR-1 N VEGF VEGFR-2 VEGF-VEGFR 3 VEGF PI3K /Akt 33 PEDF DR Yoshida 36 PEDF 50 μg kg PEDF VEGF 5 -

8 2011 Vol. 35 No Jorge R Costa R A Calucci D et al. Intravitreal bevacizumab Avastin for persistent new vessels in diabetic -1 VEGFR-3 VEGF-VEGFR-2 retinopathy IBEPE study J. Retina Soheilian M Ramezani A Bijanzadeh B et al. Intravitreal bevacizumab Avastin injection alone or combined with triamcinolone versus macular photocoagulation as primary 1 Sun J Xu Y Sun S et al. Intermittent high glucose enhances cell proliferation and VEGF expression in retinal endothelial cells the role of mitochondrial reactive oxygen species J. Mol Cell Biochem / Campa C Harding S P. Anti-VEGF compounds in the treatment of neovascular age related macular degeneration J. Curr Drug Targets Eyetech Study Group. Preclinical and phase 1A clinical evaluation of an anti-vegf pegylated aptamer EYE001 for the treatment of exudative age-related macular degeneration J. Retina White R R Sullenger B A Rusconi C P. Developing aptamers into therapeutics J. J Clin Invest Cunningham E T Jr Adamis A P Altaweel M et al. A phase II randomized double-masked trial of pegaptanib an anti-vascular endothelial growth factor aptamer for diabetic macular edema J. Ophthalmology Singerman L J Masonson H Patel M et al. Pegaptanib sodium for neovascular age-related macular degeneration Third-year safety results of the VEGF inhibition study in ocular neovascularisation VISION trial J. Br J Ophthalmol Gerber H P Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies J. Cancer Res Michels S Rosenfeld P J Puliafito C A et al. Systemic bevacizumab Avastin therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study J. Ophthalmology Haritoglou C Kook D Neubauer A et al. Intravitreal bevacizumab Avastin therapy for persistent diffuse diabetic macular edema J. Retina treatment of diabetic macular edema J. Retina Bashshur Z F Haddad Z A Schakal A et al. Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration a one-year prospective study J. Am J Ophthalmol Lowe J Araujo J Palma M et al. RhuFab V2 inhibits VEGF-isoforms-stimulated HUVEC proliferation J. Invest Ophthalmol Vis Sci Konstantinidis L Mantel I Pournaras J A et al. Intravitreal ranibizumab Lucentis for the treatment of myopic choroidal neovascularization J. Graefes Arch Clin Exp Ophthalmol Heier J S Boyer D S Ciulla T A et al. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration year 1 results of the FOCUS Study J. Arch Ophthalmol Rosenfeld P J Brown D M Heier J S et al. Ranibizumab for neovascular age-related macular degeneration J. N Engl J Med Chun D W Heier J S Topping T M et al. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema J. Ophthalmology Holash J Davis S Papadopoulos N et al. VEGF-Trap A VEGF blocker with potent antitumor effects J. Proc Natl Acad Sci USA Nguyen Q D Shah S M Browning D J et al. A phase I study of intravitreal vascular endothelial growth factor trap-eye in patients with neovascular age-related macular degeneration J. Ophthalmology Heier J S Boyer D Nguyen Q D et al. The 1-year results of CLEAR-IT 2 a phase 2 study of vascular endothelial growth factor Trap-Eye dosed as-needed after 12-week fixed dosing J. Ophthalmology

9 Vol. 35 No Stumpp M T Binz H K Amstutz P. DARPins A new generation of protein therapeutics J. Drug Discov Today / Dejneka N S Wan S Bond O S et al. Ocular biodistribution of bevasiranib following a single intravitreal injection to rabbit eyes J. Mol Vis Ni Z Hui P. Emerging pharmacologic therapies for wet age-related macular degeneration J. Ophthalmologica Martidis A Duker J S Greenberg P B et al. Intravitreal triamcinolone for refractory diabetic macular edema J. Ophthalmology Yilmaz T Weaver C D Gallagher M J et al. Intravitreal triamcinolone acetonide injection for treatment of refractory diabetic macular edema a systematic review J. Ophthalmology Barnett P J. Mathematical modeling of triamcinolone acetonide drug release from the I-vation intravitreal implant a controlled release platform J. Conf Proc IEEE Eng Med Biol Soc Haller J A Kuppermann B D Blumenkranz M S et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema J. Arch Ophthalmol Amadio M Scapagnini G Lupo G et al. PKC betaii / HuR /VEGF A new molecular cascade in retinal pericytes for the regulation of VEGF gene expression J. Pharmacol Res Davis M D Sheetz M J Aiello L P et al. Effect of ruboxistaurin on the visual acuity decline associated with long-standing diabetic macular edema J. Invest Ophthalmol Vis Sci Sheetz M J Aiello L P Shahri N et al. Effect of ruboxistaurin rbx on visual acuity decline over a 6-year period with cessation and reinstitution of therapy Results of an open-label extension of the protein kinase C diabetic retinopathy study 2 PKC-DRS2 J. Retina Amano S Yamagishi S Inagaki Y et al. Pigment epitheliumderived factor inhibits oxidative stress-induced apoptosis and dysfunction of cultured retinal pericytes J. Microvasc Res / Ueda S Yamagishi S I Okuda S. Anti-vasopermeability effects of PEDF in retinal-renal disorders J. Curr Mol Med Elayappan B Ravinarayannan H Pasha S P et al. PEDF inhibits VEGF- and EPO- induced angiogenesis in retinal endothelial cells through interruption of PI3K / Akt phosphorylation J. Angiogenesis Wang B Atherton P Patel R et al. Antiangiogenic effects and transcriptional regulation of pigment epitheliumderived factor in diabetic retinopathy J. Microvasc Res GenVec Inc.. Study of AdGVPEDF. 11D in neovascular age-related macular degeneration AMD EB /OL http / /clinicaltrials. gov / ct2 /show /NCT term = GV &rank = Yoshida Y Yamagishi S Matsui T et al. Protective role of pigment epithelium-derived factor PEDF in early phase of experimental diabetic retinopathy J. Diabetes Metab Res Rev 殨 檿檿檿檿檿檿檿檿檿檿檿 殨 殨 檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿檿 殨