Multivalent nanoparticles bind the retinal and choroidal vasculature

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• 作者：Robert Hennig^a ; Andreas Ohlmann^b ; Janina Staffel^c ; Klaus Pollinger^a ; Alexandra Haunberger^a ; Miriam Breunig^a ; Frank Schweda^c ; Ernst R. Tamm^b ; Achim Goepferich^a ; ^{achim.goepferich@chemie.uni-regensburg.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：EXP3174 (PubChem CID ; 108185) ; Angiotensin II (PubChem CID ; 172198)
• 刊名：Journal of Controlled Release
• 出版年：2015
• 出版时间：28 December 2015
• 年：2015
• 卷：220
• 期：part_PA
• 页码：265-274
• 全文大小：1674 K

文摘

The angiotensin II receptor type 1 (AT₁R), which is expressed in blood vessels of the posterior eye, is of paramount significance in the pathogenesis of severe ocular diseases such as diabetic retinopathy and age-related macular degeneration. However, small molecule angiotensin receptor blockers (ARBs) have not proven to be a significant therapeutic success. We report here on a nanoparticle system consisting of ARB molecules presented in a multivalent fashion on the surface of quantum dots (Qdots). As a result of the multivalent receptor binding, nanoparticles targeted cells with high AT₁R expression and inhibited their angiotensin receptor signaling with an IC₅₀ of 3.8 nM while showing only minor association to cells with low AT₁R expression. After intravenous injection into the tail vein of mice, multivalent nanoparticles accumulated in retinal and choroidal blood vessels of the posterior eye. At the same time, multivalent ligand display doubled the Qdot concentration in the blood vessels compared to non-targeted Qdots. Remarkably, ARB-targeted Qdots showed no pronounced accumulation in AT₁R-expressing off-target tissues such as the kidney. Following systemic application, this multivalent targeting approach has the potential to amplify AT₁R blockade in the eye and concomitantly deliver a therapeutic payload into ocular lesions.