Preparation Of Hyaluronidase-modified Layered Double Hydroxide Nanomedicine For Enhanced Tumor Chemotherapy

Cancer,characteristic of uncontrolled growth and spread of abnormal cells,has become the second leading cause of death worldwide.Curing cancer with high therapeutic efficacy is an effective way to improve the survival rate of tumor patients.Chemotherapy,as a holistic treatment,is still the main tumor treatment strategy.However,there are many disadvantages of using chemotherapy alone for treatment,such as poor water solubility,serious side effects and low bioavailability of chemotherapy drugs.To address these issues,it is necessary to utilize a suitable carrier to efficiently transport the drugs to the tumor sites.In addition,tumor,especially pancreatic tumor,is characterized by complex tumor microenvironment and unusually dense extracellular matrix(ECM),forming substantial barriers against drug penetration and diffusion into tumor cells.Taking advantages of ECM mainly composed of hyaluronic acid(HA),researchers used HAase to degrade HA rapidly to loosen ECM and improve the penetration of nano-drugs into tumors,thereby enhancing therapeutic efficacy.However,in existing treatment using HAase to reconstruct tumor microenvironment,step-by-step injection is usually adopted.That is,HAase is first intratumorally or intravenously injected to degrade the hyaluronic acid of tumor tissues,and chemotherapy or gene drugs are then injected for enhanced therapy.These processes are quite complicated.Therefore,it is of great significance to develop novel delivery systems for conveying HAase and chemotherapeutic drugs simultaneously to enhance the infiltration of chemotherapeutic drugs in tumor cells and resultant high anti-tumor efficacy.Layered double hydroxides(LDH)have been successfully used as carriers for cancer diagnosis and treatment thanks to their high drug loading rate,good biocompatibility and acid response.In this study,LDH was used as the carrier platform to simultaneously load HAase and broad-spectrum chemotherapy drug doxorubicin(DOX)for enhanced chemotherapy of pancreatic cancer tumor models.We first synthesized LDH by co-precipitation method,then modified the HAase on its surface by electrostatic interaction and hydrogen bond,and finally physically encapsulated the anti-tumor drug DOX to obtain the DOX/LDH-HAase complex.The physicochemical characterization results showed that the fabricated LDH nanoparticles possessed good crystal structure,and the structure did not change after modification of HAase and loading of DOX.The DOX/LDH-HAase also demonstrated good stability,high enzyme activity and acid-responsive drug release features,indicative of a good potential for tumor therapy.The developed DOX/LDH-HAase complexes enabled more significant uptake by cancer cells and more penetration into 3-dimensional tumor spheroids than enzyme-free DOX/LDH complexes,thus displaying much better antitumor ability.In vivo experiments indicated that compared with DOX/LDH,DOX/LDH-HAase could degrade the hyaluronic acid of the tumor more effectively,increase more blood perfusion,and inhibit the tumor growth more significantly.In conclusion,the layered double hydroxide hybrid nano-platform modified by hyaluronidase and loaded with drugs prepared in this study can effectively promote the penetration of nano-drugs in tumor sites and enhance the therapeutic efficacy.These findings will provide new ideas to develop novel nanoplatforms for tumor therapy with high efficacy.