Abstract
Venous malformation (VM), which causes severe damage to patients’ appearance and organ function, is one of the most common vascular malformations. At present, many drugs in clinical treatment cause various adverse reactions. Herein, we synthesized cationic amphiphilic gelators (TA6, TA8, and TA9) by introducing saturated carbon chains of different lengths to tranexamic acid (TA), which could self-assemble into low-molecular-weight gels (LMWGs) as drug delivery carriers by hydrogen bonds, van der Waals forces, and hydrophobic interactions. The rheological properties, gelation driving force and drug release profiles of TA6, TA8, and TA9 hydrogels were characterized, and the results indicated that the hydrogels prepared in this study possessed the typical characteristics of a gel and could release drugs slowly. More importantly, the TA9 gelator showed significant pharmacological activity, in that it served as both an active drug compound and a drug carrier. The in vitro experiments demonstrated that TA9 induced HUVECs death and hemolysis by destroying cell membranes in a dose-dependent manner, and caused cell death and hemolysis at a concentration of 0.09 µM/mL. Meanwhile, we found TA9 could interact not only with fibrinogen, but also with other endogenous molecules in the blood. After the administration of TA9 hydrogel for 15 days, macroscopic imaging and histological evaluation in mice and rabbits displayed obvious thrombi, inflammatory reactions, and venous embolization, indicating that the mechanism of the TA9 hydrogel in treating VM was involved in two processes. Firstly, the TA9 hydrogel relied on its mechanical strength to physically block veins and continuously release TA9, in situ, for targeted therapy. Then, TA9 destroyed endothelial cells and damaged venous walls critically, causing thrombi. Most excitingly, TA9 was hydrolyzed to TA by enzymes that inhibited the degradation of thrombi by plasmin to prolong the embolization time and to promote venous fibrosis. Compared with other clinically available sclerosants, the degradation of TA9 also empowered a better biocompatibility and biodegradability for the TA9 hydrogel. In conclusion, we synthesized a potentially safe and effective derivative of TA and developed a low-molecular-weight gel as a self-delivery system for TA in treating VM.
Highlights
The International Society for the Study of Vascular Anomalies (ISSVA) classifies vascular abnormalities into hemangioma and vascular malformation based on the biological characteristics of vascular endothelial cells proposed by John B
We synthesized a novel type of cationic amphiphilic molecule with tranexamic acid (TA) as the basic structure, which could be driven by hydrogen bond, van der Waals forces and hydrophobic forces to form a transparent hydrogel as a self-delivery carrier
From the results of the hydrogel characterization, it was found that the increased length and concentration of carbon chains affected the thermal stability and mechanical properties of the hydrogels [26], which was attributed to the slight changes in the hydrogel fibers caused by the change of intermolecular van der Waals forces and hydrophobic forces, and this change enhanced the mechanical strength of the hydrogel
Summary
The International Society for the Study of Vascular Anomalies (ISSVA) classifies vascular abnormalities into hemangioma and vascular malformation based on the biological characteristics of vascular endothelial cells proposed by John B. VM is a type of vascular malformation, caused by abnormal development of the venous system. Its pathological manifestations are an abnormal expansion of the venous sinus, reduction of the smooth muscle of the venous wall, and degeneration of adventitia fibers. These abnormally dilated veins proliferate in child development and, generally, without selfhealing, eventually causing abnormal appearance, organ dysfunction, and other chronic diseases [3]. Sclerotherapy is the injection of sclerosants into malformed veins to damage endothelial cells, peel off the intima, and expose the collagen fibers under the membrane, thickening the venous wall and making the abnormal veins occlude or atrophy. Accurate embolization, increasing the retention of active drugs in the lesions, prolonging the half-life, and reducing systemic side effects are the key to relevant drug research and development for the treatment of VM [10]
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