Construction Of Multifunctional Intelligent Hydrogel-based Drug Delivery Systems For Combinational Tumor Therapy

Cancer has always been one of the main theats to human health and life due to its great risk of morbidity and mortality.In order to improve the antitumor effect with reduced toxic effects to normal tissues,utilizing nanocarriers for targeted drug delivery has attracted increasing attention.However,conventional nanocarriers usually lack of specificity,have limited tumor accumulation and penetration due to the complex tumor microenvironment barriers and tumor heterogeneity at tumor regions,which leads to undesirable therapeutic effect.Recently,on the one hand,researchers employed live cells to engulf or cell membranes to camouflage the drug-loaded nanopartlces(NPs)to effevtively accumulated at tumor sites.On the other hand,the controllable localize administration can trap more of drugs within the tumor site,which is also expected to avoid the systemic toxicity caused by systemic administration.The key issue of these strategies is to construct the intelligent nanocarriers which are easy to be endocytosed by live cells,facilely coated by cell membranes or non-/minimally invasive local drug delivery platform with controllable drug release behavior.Among various nanocarriers,nanogels(NGs)with innate fluidity and soft-matter properties are easier to be engulfed by liver cells or coated by membranes.Injectable hydrogel can be served as an ideal carrier for minimally invasive local drug delivery.In addition,NGs and hydrogels is become popular as drug carriers due to their high drug loading capacity,easy multifunctionalization and intelligent stimuli-responsive property to pH,GSH or ROS in tumor microenvironment.Based on this,in order to address the issues involved of tumor accumulation and penetration,and to further improve the precision tumor therapy,we designed and constructed three novel platforms including live cell-mediated drug delivery system,cell membrane-camouflaged biomimetic nanogel system,and localized drug delivery based on injectable hydrogels.The main research contents of this thesis are as follows:(1)Macrophage-mediated tumor homing of hyaluronic acid nanogels loaded with polypyrrole and anticancer drug for targeted combinational photothermo-chemotherapyDevelopment of nanosystems that can be integrated with macrophages(MAs),an emerging carrier system,for effective tumor therapy remains to be challenging.We report here the development of MAs specifically loaded with hyaluronic acid(HA)nanogels(NGs)encapsulated with a photothermal agent of polypyrrole(PPy)and anticancer drug doxorubicin(DOX)(HA/DOX@PPy NGs)for tumor homing and combinational photothermo-chemotherapy.Cystamine dihydrochloride-crosslinked HA NGs were first prepared through a double emulsification method,then loaded with PPy via an in-situ oxidization polymerization and physically encapsulated with DOX.The created HA/DOX@PPy NGs were well characterized and subjected to be endocytosed by MAs(MAs-NGs).The MAs-mediated tumor-homing property,phenotype changes and photothermal performance of MAs-NGs were investigated in vitro,and a subcutaneous tumor model was also established to confirm their targeting capability and enhanced antitumor therapy in vivo.The generated hybrid NGs possess a size around 77 nm and good colloidal stability,and can be specifically endocytosed by MAs without appreciably affecting their normal biofunctionalities.In particular,NGloaded MAs display excellent in-vitro cancer cell and in-vivo tumor homing property.Systemic administration of the MAs-NGs leads to the significant inhibition of a subcutaneous tumor model through combinational photothermo-chemotherapy under laser irradiation.The developed hybrid HA-based NG nanosystem incorporated with PPy and DOX fully integrates the coordination and heating property of PPy to regulate the optimized DOX release in the tumor region with the assistance of MA-mediated tumor homing,providing a promising cell therapy strategy for enhanced antitumor therapy.(2)Macrophage membrane-camouflaged responsive polymer nanogels enable MR imagingguided chemo/chemodynamic therapy of orthotopic gliomaGlioma is one of most metastatic and fatal malignant tumors.Development of innovative nanomedicine formulations to traverse blood-brain barrier(BBB)for effective theranostics of glioma remains to be a great challenge.Herein,we report the creation of macrophage membrane-camouflaged multifunctional polymer nanogels co-loaded with manganese dioxide(MnO2)and cisplatin for magnetic resonance(MR)imaging-guided chemo/chemodynamic therapy of orthotopic glioma.Redox-responsive poly(N-vinylcaprolactam)(PVCL)nanogels(NGs)formed via precipitation polymerization were in-situ loaded with MnO2 and cisplatin to have a mean size of 106.3 nm,and coated with macrophage membranes to have a good colloidal stability.The generated hybrid NGs display dual pH-and redox-responsive cisplatin and Mn(?)release profiles,and can deplete glutathione(GSH)rich in tumor microenvironment through reaction with disulfide-containing crosslinkers within the NGs and MnO2.The thus created Mn(?)enable enhanced chemodynamic therapy(CDT)through a Fenton-like reaction and Ti-weighted MR imaging,while the loaded cisplatin not only exerts its chemotherapy effect,but also promotes the reactive oxygen species generation to enhance the CDT efficacy.Most strikingly,the macrophage membrane coating rendered the hybrid NGs with prolonged blood circulation time,ability to traverse BBB for specific targeted chemotherapy/CDT of orthotopic glioma,which may be extended to tackle other difficult cancer types.(3)Injectable multifunctional hydrogels for synergistic cancer combination therapyLocally administered drug delivery systems are promising as they allow to circumvent the side effects associated with the systematic administration.In this study,we constructed multifunctional hydrogels by simply mixing commercial alginate(ALG)sols with glucose oxidase(GOx)conjugated Fe3O4 nanoparticles(NPs)and Toll-like receptor 7/8 agonist resiquimod(R848).The injectable sols were able to transform into hydrogels(GPI/R848@ALG)by the ionic cross-linking between ALG and physiological Ca2+ to trap the therapeutic components within the hydrogel framework.Upon intratumoral injection,the hydrogels were employed for starvation therapy,promoted chemodynamic therapy and tumor-associated macrophages(TAMs)repolarization.The energy supply can be blocked by consuming the intratumoral glucose via the GOx-catalyzed conversion of glucose into gluconic acid and hydrogen peroxide(H2O2).In vitro results showed that the generated H2O2 could be further converted into highly cytotoxic hydroxyl radicals(·HO)by the Fenton reaction to induce enhanced chemodynamic therapy.The TAMs repolarization studies in vitro exhibited that the GPI/R848@ALG hydrogels up-regulated the expression of CD86 by 63.0%and down-regulated the proportion of CD206 by 14.4%with the synergy of Fe3O4 and R848,suggesting that the multifunctional hydrogels exert functions to direct the remodeling of TAMs from the tumor supportive M2-like phenotype to the tumor destructive M1-like phenotype for further contributing to the antitumor effect.Moreover,both in vitro and in vivo experiments demonstrate that the multifunctional hydrogels exhibit admirable antitumor performance toward 4T1 tumors.In summary,the novel targeted drug delivery system(DDS)of cell therapy,cell membranecamouflage technology and local administration has shown great advantages in biocompatibility and targeting potential.It is of great significance for developing safer and more efficient DDS and is also expected to be applied in personalized cancer treatment.