Multivalent nanoparticles bind the retinal and choroidal vasculature.
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.
Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Germany.
Robert
R
Hennig
Department for Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
Andreas
A
Ohlmann
Department of Physiology, University of Regensburg, Regensburg, Germany.
Janina
J
Staffel
Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Germany.
Klaus
K
Pollinger
Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Germany.
Alexandra
A
Haunberger
Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Germany.
Miriam
M
Breunig
Department of Physiology, University of Regensburg, Regensburg, Germany.
Frank
F
Schweda
Department for Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
Ernst R
ER
Tamm
Department of Pharmaceutical Technology, University of Regensburg, Regensburg, Germany. Electronic address: achim.goepferich@chemie.uni-regensburg.de.
Achim
A
Goepferich
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001667:Binding, Competitive; D020013:Calcium Signaling / Q000187:drug effects; D002196:Capillaries / Q000378:metabolism*; D002829:Choroid / Q000098:blood supply*; D004337:Drug Carriers; D006367:HeLa Cells; D006801:Humans; D007275:Injections, Intravenous; D019808:Losartan / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D011485:Protein Binding; D045663:Quantum Dots; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism*; D013499:Surface Properties; D014018:Tissue Distribution
C544065:AGTR1 protein, human; D047228:Angiotensin II Type 1 Receptor Blockers; D004337:Drug Carriers; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C066026:losartan carboxylic acid; D019808:Losartan
Age-related macular degeneration; Angiotensin II; Angiotensin II (PubChem CID: 172198); Diabetic retinopathy; EXP3174; EXP3174 (PubChem CID: 108185); Multivalency; Quantum dots