Preparation And Antitumor Studies Of Tumor Trigger Targeting Ammonium Bicarbonate Liposomes And Human Serum Albumin-hyaluronic Acid Nanoparticles

Thermosensitive liposomes are currently considered as one of the tumor microenvironment sensitive drug delivery systems with the most potential for clinical application Ammonium bicarbonate（ABC）thermoresponsive liposomes,which are characterized by the decomposition of ammonium bicarbonate upon superheating（～42°C）,produce CO₂ bubbles,resulting in the formation of penetrating defects in the lipid bilayer,achieving drug-loaded liposomes in rapid release on overheating（50%doxorubicin released in 30 seconds）and improved plasma stability at physiological temperatures（only 15%doxorubicin was released in 1 hour）.Although ABC liposomes have the above advantages,its surface polyethylene glycol chain（PEG）hinders its uptake in tumor cells.Therefore,our research group targeted the surface-modified folic acid（FA）on ABC temperature-sensitive liposomes,and modified the long-chain PEG containing pH-sensitive Schiff base（C=N）on the surface of liposomes,to obtain tumors trigger-targeting ammonium bicarbonate temperature-sensitive liposomes（TT-ABC）.Although TT-ABC liposomes have long-circulating properties in the blood,The TT-ABC liposomes achieve uptake in tumor cells through breaking the long-chain PEGs on the surfaces and actively targeting of FA on the surface of PEGs in the acidic microenvironment of tumor tissues.However,the way that TT-ABC liposomes trigger drug release by heating has limitations.Therefore,in the second chapter,we prepared TT-ABC liposomes containing both the photothermal agent indocyanine green（ICG）and chemotherapic doxorubicin（DOX）.TT-ABC liposomes was expected to realize the three-mode cooperative therapy of chemotherapy/photodynamic therapy（PDT）/photothermal therapy（PTT）.Human serum albumin（HSA）-ICG-paclitaxel（PTX）nanomedicine achieve photothermal therapy and chemotherapy highly efficientunder the guidance of near-infrared imaging.The nanomedicine can not only completely eliminate subcutaneous tumors,but also provide a significant therapeutic effect for the treatment of metastatic tumor mice.However,the stability of HSA-ICG-PTX in blood and the controlled release of its loaded drugs need to be further improved.Therefore,in Chapter three,we prepared the HSA-ICG-DOX nanomedicine and then could be coated with hyaluronic acid（HA）by amidation reaction.In this system,HSA is a biocompatible carrier platform,PTX is an effective antitumor drug,ICG can serve as a fluorescent imaging probe and a photothermal agent,while HA is a ligand that actively targets into cancer cells overexpressing CD44 and can be decomposited by hyaluronidase to trigger particle size reduce.Therefore,our work develops a biocompatible theranostic agent that is purely composed by FDA-approved agents,promising for future imaging-guided combination therapy of cancer.