Synthesis of Multiarm Peptide Dendrimers for Dual Targeted Thrombolysis

Current thrombolytic agents generally possess low specificity and pose a high risk of intracranial hemorrhage. Here, various generations of multiarm polylactic acid-polyglutamic acid peptide dendrimers were synthesized, and then nattokinase-combining magnetic Fe3O4 nanoparticles and RGD-modified dendrimers (Fe3O4-(4-PLA(G3)4)-RGD) were fabricated for targeted thrombi dissolution. Their in vitro and in vivo thrombolytic properties were determined. In vitro determination indicated that Fe3O4-(4-PLA(G3)4)-RGD/nattokinase provided 3-fold higher blood clot dissolution than that obtained with free nattokinase. An in vivo thrombolytic examination revealed that most of the thrombi were dissolved under an external magnetic field. In addition, there were many nanoparticles in vascular endothelial cells, demonstrating the RGD and magnetic dual targeting capacity of Fe3O4-(4-PLA(G3)4)-RGD/nattokinase. These results demonstrated that Fe3O4-(4-PLA(G3)4)-RGD nanoparticles not only will deliver targeted thrombolytic agents to enhance the efficacy of site-specific thrombolytic treatment but also have potential in the diagnosis of thrombotic disease in its early stages.