Design And Synthesis Of Functionalized Polysaccharide-based Drug Delivery System And Its Application For Tumor Therapy

Cancer has posed a major threat to human health and life.However,current clinical tumor therapy modalities(such as chemotherapy)and newly developed therapy modalities(such as photodynamic therapy and starvation therapy)still have shortcomings that must be solved.To improve therapeutic outcome,exploring and developing efficient drug delivery system has attracted great attention.In this thesis,starting off with the construction of novel functionalized polysaccharides,three drug delivery strategies were proposed,i.e.,microneedle-assisted p H-responsive drug release,oxygen-responsive drug release,and ROS(reactive oxygen species)-reponsive drug release,to overcome the challenge of tumor therapy.The main research contents are listed as follows.(1)Microneedle-assisted p H-responsive co-delivery platform for photodynamic/immune combined tumor therapy.Despite advances in photodynamic therapy(PDT)for treating superficial tumor,the prospect of this monotherapy remains challenges in the context of systemic phototoxicity and poor efficacy.In this work,a physiologically self-degradable microneedle(MN)-assisted platform was developed for combining PDT and immunotherapy via controlled co-delivery of photosensitizer(PS)and checkpoint inhibitor anti-CTLA4 antibody(a CTLA4),which generated synergistic reinforcement outcome while reducing side effects.MN was composed of biocompatible hyaluronic acid integrated with the p H-sensitive dextran nanoparticles,which was fabricated to simultaneously encapsulate hydrophobic(Zinc Phthalocyanine)and hydrophilic agents(a CTLA4)via a double emulsion method.This co-loading carrier could aggregate effectively around topical tumor by microneedle-assisted transdermal delivery.In vivo studies using 4T1 mouse models,PDT firstly exerted its effect to killing tumor and triggers the immune responses,subsequently,facilitating the immunotherapy with immune checkpoint inhibitor(a CTLA4).The possible mechanism and systemic effects of the combined therapy were investigated,which demonstrate that this co-administration platform can be a promising tool for focal cancer treatment.(2)Oxygen-responsive chitosan conjugate for hypoxia-activated chemotherapy/photothermal combined tumor therapy.Hypoxia-activated prodrugs(HAPs)promise to mitigate side effects of conventional chemotherapy and to enable precise medication treatment.One challenge facing HAPs-based chemotherapy is prodrug failure in normoxic tumor region,impeding the optimal application of HAPs.Herein,a novel self-activating nanovesicle,TH-302@BR-Chitosan NPs,was constructed by assembling bilirubin-chitosan conjugate(named as BR-Chitosan)with a HAP,TH-302.It was interesting to find that the BR-Chitosan showed the inherent oxygen-depleting performance,especially in the presence of over expressed H₂O₂ in tumor area,during which the BR-Chitosan could facily transform into biliverdin-chitosan(BV-Chitosan)and subsequently result in the disassembly of nanovesicle to release and activate the prodrug.Thus,this in situ strengthening hypoxia level of tumor could greatly promote the chemotherapy efficacy of HAPs.Moreover,as the oxidiation derivatives of BR-Chitosan,BV-Chitosan could act as an effective photothermal agent for photothermal therapy(PTT).This biodegradable and self-activating nanovesicle with concise formulation demonstrated greatly enhanced synergistic therapeutic outcome in the activatable chemo-thermo combined therapy,showing much promising in future clinical transformation.(3)Oxygen/ROS-responsive polysaccharide hydrogel for hypoxia-based chemotherapy/starvation combined tumor therapy.Enhancing tumor hypoxia is considered as an effective strategy for HAP-based chemotherapy.However,enhanced hypoxia could improve the malignant degree of tumor,resulting in tumor matestasis and in turn reducing therapeutic effect.Herein,an oxygen/ROS-responsive chitosan hydrogel(CS-FA/TK)was synthesized by coupling ferulic acid(FA)and ROS-sensitive thioketal(TK)to amine groups of Chitosan backbone.In laccsed-mediated reactions,CS-FA/TK were crosslinked to form hydrogel due to the dimerization of FA by consuming oxygen,which could further enhance the tumor hypoxia and activate HAP,AQ4N.Moreover,antiangiogenic inhibitor(PAZ)could be grafted to CS-FA/TK to form CS-FA/TK-PAZ through TK moiety.When exposured to tumor microenvironment,CS-FA/TK-PAZ hydrogel could release PAZ in a ROS-responsive manner and achieve chemotherapy/starvation cooperative therapy combined with AQ4N.The research results indicated that the constructed hydrogel exhibited inhibiting effect to tumor proliferation and VEGFR signalling,which could be a promising drug delivery system for optimizing hypoxia-based tumor therapy.