A Preliminary Study On Macromolecular MRI Contrast Agent With Hyaluronic Acid As The Carrier

The combination of targeted magnetic resonance diagnostic imaging and therapeutic drugs is one of the research trends to improve the performance and efficacy of nanomedicines.The development of imaging and treatment delivery systems for cancer and other diseases has important clinical implications.Due to its advantages of high biocompatibility,biodegradability,and easy chemical modification,glyco-based biopolymers have rapidly increased applications in the biomedical field and are widely used in the preparation of various types of targeted contrast agents or drug delivery systems.Hyaluronic acid has good tumor targeting and biosafety performance,in this paper,using hyaluronic acid as the carrier of macromolecular drugs,(1)a contrast agent based on hyaluronic acid targeting tumorspecific response to release therapeutic drugs was constructed through the design of functional groups;(2)two hyaluronic acid-based targeted gadolinium-based magnetic resonance imaging contrast agents were designed and synthesized.The research in this thesis is as follows:(a)The design and synthesis of HA-SS-a-Gd-DOTA,a contrast agent with hyaluronic acid as a macromolecular carrier with the function of targeting tumorspecific response to release therapeutic drugs,was completed.It was able to specifically release the small molecule drug cytarabine at higher concentrations of GSH at the tumor site with a release rate of 63.4%,and the cytotoxicity experiment showed that HA-SS-a-Gd-DOTA can inhibit tumor growth to a limited extent,and the relaxation performance test results showed that the relaxation efficiency was 21.9 mmol-1·L·s-1,which was about four times that of the clinical contrast agent Dotarem(4.9 mmol-1·L·s-1).In acidic conditions and in the presence of reducing agents,it has responsive release properties.The ultra-low hemolysis rate showed that HA-SSa-Gd-DOTA can be administered intravenously.After hyaluronic acid was targeted and aggregated at the tumor site,magnetic resonance imaging was performed,the imaging effect was enhanced by 58%after injection of HA-SS-a-Gd-DOTA.The results of organ coefficient and tissue section experiments in nude mice showed that some organs in mice were enlarged,and the cells grew normally,the morphology was intact,there were no abnormal lesions,which could be inferred that HA-SS-aGd-DOTA had good biological safety.The advantage of hyaluronic acid macromolecular chain being degradable in the body makes it not damage the important organs of the organism,and is an ideal tumor imaging diagnostic agent.(b)Two macromolecule gadolinium-based T1 contrast agents HA-ASP-CYSGD-DOTA and HA-ASP-CH2-Gd-DOTA were designed and synthesized with hyaluronic acid as the carrier.Both drugs linked hyaluronic acid and Gd-DOTA through amide reaction,which promoted the enrichment of MRI contrast agent in the tumor area to achieve the effect of targeting tumors,and the relaxation efficiency was 6.76 and 7.86 mmol-1·L·s-1,respectively.