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Selective Photodynamic Therapy by Targeted Verteporfin Delivery Toexperimental Choroidal Neovascularization Mediated by a Homing

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Selective Photodynamic Therapy by Targeted Verteporfin Delivery Toexperimental Choroidal Neovascularization Mediated by a Homing LABORATORY SCIENCES Selective Photodynamic Therapy by Targeted Verteporfin Delivery to Experimental Choroidal Neovascularization Mediated by a Homing Peptide to Vascular Endothelial Growth Factor Receptor-2 Reem Z. Renno, MD; Yoshiko Terada, MD; Makhluf J. Haddadin, PhD; Norman A. Michaud, MS; Evangelos S. Gragoudas, MD; Joan W. Miller, MD Objective: To evaluate the feasibility, efficacy, and se- ter treatment. Photodynamic therapy using verteporfin- lectivity of photodynamic therapy (PDT) using targeted PVA at the same drug dose achieved closure in 18 of 20 delivery of verteporfin to choroidal neovascularization CNV. Histological examination after PDT of normal retina (CNV) in the rat laser-injury model of CNV. and choroid using targeted verteporfin and irradiation at 1 hour showed minimal effect on retinal pigment epithe- Methods: We performed PDT in rat eyes on experi- lium and no injury to photoreceptors, whereas PDT using mental CNV and normal retina and choroid using verte- verteporfin-PVA resulted in retinal pigment epithelium ne- porfin conjugates. A targeted verteporfin conjugate was crosis and mild damage to photoreceptors. made by conjugating verteporfin (after isolation from its liposomal formulation) to a modified polyvinyl alcohol Conclusions: Verteporfin bound to the targeting pep- (PVA) polymer (verteporfin-PVA) followed by linkage tide, ATWLPPR, retained its spectral and photosensitiz- to the peptide ATWLPPR known to bind the receptor for ing properties. Angiography demonstrated localization vascular endothelial growth factor, VEGFR2. The verte- of the targeted verteporfin 1 hour after injection. Pho- porfin-PVA conjugate served as a control. We per- todynamic therapy using targeted verteporfin and the con- formed fluorescent fundus angiography to determine the trol conjugate were more effective in causing CNV clo- optimal timing of light application for PDT using the con- sure than standard liposomal verteporfin. The targeted jugates. Closure of CNV was assessed angiographically verteporfin resulted in more selective treatment than the and graded in a masked standardized fashion. We used control conjugate or standard verteporfin. These results standardized histological grading to compare the effects suggest that targeted PDT strategies based on selective on normal retina and choroid. expression of receptors on CNV vasculature may im- prove current therapy. Results: The verteporfin-PVA conjugation ratio was on average 28:1. The conjugate retained typical emission/ Clinical Relevance: Targeted PDT for CNV is feasible excitation spectra and photosensitizing activity and was as and may offer a qualitative improvement in current treat- efficient as an equivalent amount of verteporfin. Peak in- ments for patients with age-related macular degenera- tensity of targeted verteporfin in CNV was detected angio- tion. This study provides the basis for further preclini- graphically at 1 hour after intravenous injection. Photody- cal studies of targeted PDT strategies and subsequent namic therapy using targeted verteporfin (3 or 4.5 mg/m2) clinical trials. with light application 1 hour after drug injection showed angiographic closure of all treated CNV (17/17) 1 day af- Arch Ophthalmol. 2004;122:1002-1011 HOTODYNAMIC THERAPY and retinal vessels at the time that light is (PDT) using verteporfin as a applied. Preclinical work on PDT with photosensitizer has been verteporfin (QLT PhotoTherapeutics Inc, demonstrated in large clini- Vancouver, British Columbia) has shown cal trials to be an effective treatment-related damage to the surround- new treatment for subfoveal choroidal neo- ing retina, choroid, and retinal pigment P 5-7 vascularization (CNV) secondary to age- epithelium (RPE). This collateral dam- related macular degeneration and other age is cumulative with repeated PDT.7,8 causes.1-4 The preferential occlusion of Modifications to PDT, including combi- CNV after PDT as currently practiced is nation with antiangiogenic therapy9,10 or Author affiliations are listed based on the differences in biodistribu- with targeted photosensitizer, may im- at the end of this article. tion of the photosensitizer between CNV prove selectivity and vision outcomes. (REPRINTED) ARCH OPHTHALMOL / VOL 122, JULY 2004 WWW.ARCHOPHTHALMOL.COM 1002 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Homing peptides are an emerging class of pharma- optical density, 250ϫ4.6 mm; a solvent system consisting of ceuticals that exploits differences between cell types by solution A (500 mL each of 1% [NH4]2SO4 and CH3CN and binding specific cell membrane receptors.11-13 The pep- 50 mL of CH3COOH) and solution B (500 mL of 1% [NH4]2 tide targeting of photosensitizers might enable specific SO4 and C4H8O and 50 mL of CH3COOH 50mL); a flow rate of and enhanced retention of photosensitizer to CNV and 1.7 mL/min; and a gradient of solutions A-B of 60%:40% for 5 minutes, then a starting gradient flow from 40% solution B to allow more selective PDT with minimal adverse effects. 70% solution B in 20 minutes and staying at 70% solution B Vascular endothelial growth factor (VEGF) expres- for 5 minutes before returning to 40% solution B. Verteporfin- sion and binding of VEGF to its kinase domain receptor PVA eluted at 8 to 10 minutes, whereas unconjugated verte- (KDR/FLK1 or VEGFR-2) is an important mediator of porfin eluted at 18 to 19 minutes. The molecular weight of verte- angiogenesis, including retinal and choroidal neovascu- porfin-PVA was determined by mass spectrometry and found larization.14,15 Inhibition of VEGF and VEGFR-2 pre- to be approximately 28 kDa (verteporfin-PVA ratio, approxi- vents retinal and choroidal neovascularization.16-18 The mately 28:1). presence of KDR or VEGFR-2 has been demonstrated in Before binding to the homing peptide, thiol groups were normal vessels but shows increased expression in endo- introduced to verteporfin-PVA using 3-mercaptopropionic acid thelial cells of neovascular tissue and is thus a potential (Sigma-Aldrich Corp) in acetate buffer (pH, 5.5). Coupling of candidate for peptide-mediated targeting of CNV.19,20 The verteporfin-PVA to the targeting peptide (ATWLPPR; molecu- peptide ATWLPPR is reported to specifically bind lar weight, 840 Da synthesized to our specifications by Anaspec, San Diego, Calif) was performed using sulfo-m-maleimidoben- VEGFR-2 and completely inhibit binding of native VEGF, 21 zoyl-N-hydroxysulfosuccinimide ester as a heterobifunctional thereby preventing VEGF-induced angiogenesis in vivo. cross-linking reagent in carbonate buffer (pH, 8.5). Products We propose to use ATWLPPR as a homing peptide were separated by means of high-performance liquid chroma- bound to verteporfin to target verteporfin to CNV by bind- tography with the solvent system of solution A, 100% water, ing to VEGFR-2 on CNV. Because VEGFR-2 is overex- and 0.1% trifluoroacetic acid and solution B, 100% acetoni- pressed on neovascular endothelium, normal vessels trile and 0.1% trifluoroacetic acid (gradient starting at solu- should be relatively spared and retinal cells should be un- tions A-B, 80%:20% and going to 80% solution B in 45 minutes). affected after PDT using verteporfin targeted to VEGFR-2. The molecular weight of VEGFR-2–targeted verteporfin was de- Experiments were designed to evaluate the efficacy and termined by mass spectrometry and found to be approxi- selectivity of PDT with VEGFR2-targeted verteporfin in mately 30 kDa. For the remainder of this report, the photo- the rat laser-injury model of CNV. sensitizer dose will be expressed in verteporfin-equivalents (in milligrams divided by the square of the body surface in square meters) as determined by spectrofluorometry using a verte- porfin calibration curve. Briefly, a calibration curve correlat- METHODS ing concentration vs spectral emission of liposomal vertepor- fin was constructed. Spectral emission of a sample of ISOLATION OF FREE VERTEPORFIN VEGFR-2–targeted verteporfin was determined and used to ex- FROM ITS LIPOSOMAL FORMULATION trapolate from the calibration curve its verteporfin content. We recovered verteporfin at a concentration of 2 mg/mL in li- All intermediates (free verteporfin, verteporfin-PVA, and posomal formulation from material prepared for clinical treat- VEGFR-2–targeted verteporfin) were found to have the same ments; leftovers were refrigerated and processed within 2 weeks excitation and emission spectra as the liposomal verteporfin for- to ensure activity.22 Liposomal verteporfin was acidified using mulation as determined by spectrofluorometry and to pre- a 6M hydrochloric acid solution, and separation of organic serve an equivalent in vitro photosensitizing activity (tested in (verteporfin) and aqueous (liposome) layers was achieved us- human umbilical vein endothelial cells) as determined by the tetrazolium salt MMT assay.25 ing dichloromethane (CH2Cl2). After concentrating the solu- tion by means of evaporation, verteporfin was further purified by means of gravity chromatography on silica gel using an elut- EXPERIMENTAL CNV MODEL ing solvent consisting of a 3:1 ratio of CH2Cl2 to methanol. The verteporfin solution was evaporated to dryness and redis- The rat laser-injury model of CNV was modified from earlier re- 26-28 solved in dimethyl sulfoxide. ports and used in our laboratory for PDT. Adult male pig- mented rats (Brown-Norway; Charles River Laboratories, Wil- SYNTHESIS OF mington, Mass) were used in the study, and all procedures were VEGFR-2–TARGETED VERTEPORFIN
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