RGD Modified Protein–Polymer Conjugates for pH-Triggered Targeted Thrombolysis

Abstract

It holds great promise to develop thrombolytic agent delivery systems with prolonged circulation time, minimized adverse effect, and preferential thrombolytic activity at the thrombus site. In this work, a pH-triggered delivery system for the thrombolytic agent was synthesized. Fluorescein isothiocyanate-labeled urokinase-type plasminogen activator (uPA) was conjugated to oxidized dextran (Oxd) via the pH-sensitive imine linkage, and then the conjugation was modified with RGD peptide. The uPA-Oxd conjugates displayed enhanced stability to resist enzymatic hydrolysis in comparison with the native uPA. Meanwhile, the bioactivity of uPA in the uPA-Oxd conjugates was masked at physiological pH and regenerated under weak acidic condition due to the release of uPA via the hydrolysis of imine bond in the conjugates. RGD modification endowed the conjugates with targeting ability to the thrombus site due to the specific peptide-GP IIb/IIIa binding and enhanced the thrombolysis efficacy via an endogenous low-pH triggered uPA release at the thrombus site, reducing the risk of acute hemorrhage complication. Thus, the RGD modified pH-sensitive uPA-Oxd conjugates provide a promising potential of the system in local thrombolysis therapy.

Biomineralization of Aggregation-Induced Emission-Active Photosensitizers for pH-Mediated Tumor Imaging and Photodynamic Therapy

“…As a nanoprobe for cancer diagnosis and treatment, it is very important and meaningful to have excellent tumor-targeted responsiveness. Usually, the tumor site is weakly acidic (∼pH 6.8) because of the excess lactic acid produced by glycolysis under hypoxic conditions . Moreover, the accumulation of nanoparticles in cells is generally through the way of endocytosis to lysosomes, while both the endosomes and lysosomes have a higher concentration of H + than the tumor environment (endosome’s pH is about 6.0 and lysosome’s pH is about 5.0). − Therefore, the pH-responsive property of the BSA/AIEgen@CaCO 3 nanoprobe was first investigated before its application in bioimaging/PDT.…”

Theranostic nanoparticles for the management of thrombosis

“…Upon occlusion of a blood vessel by a thrombus, the blood surrounding the thrombus becomes oxygen-starved, resulting in a lowered pH 102 . Several drug delivery systems have exploited this reduction in pH as a stimulus for drug release, by covalently conjugating the drug to the nanoparticle through a pH-sensitive imine 103 , 104 . The immobilised drug has a reduced activity, which is restored upon cleavage of the imine.…”

“…The immobilised drug has a reduced activity, which is restored upon cleavage of the imine. However, the release of the drug is not highly specific, as this cleavage also occurs at physiological pH, albeit at a slower rate 103 . Additionally, such an acidic environment is not specific to thrombosis, where, most notably, tumour microenvironments also exhibit a lower pH 105 .…”

Thrombus-Targeting Polymeric Nanocarriers and Their Biomedical Applications in Thrombolytic Therapy

“…Several studies have demonstrated that cRGD-modified nanosystems can effectively induce the selective lysis of fibrin and blood clots, thus suggesting that they are promising candidates for targeted thrombolytic therapy ( Li et al, 2019 ; Zhang et al, 2019 ; Zhong et al, 2020 ). However, it is worth noting that studies have shown that platelet activation primarily occurs during the early stage of thrombosis, and the influence of integrin GPIIb/IIIa on platelet aggregation and thrombosis also decreases with the progression from the early to the late stage of the thrombosis process ( Yan et al, 2000 ; Zhou et al, 2011 ; Gambino et al, 2021 ).…”