Preparation Of Functional Agarose-based Hydrogels And Their Application In Combination Tumor Therapy

Currently,cancer has become a primary healthcare concern globally,which seriously threatshuman health.Surgury is exploited as the routine stragety for traditional cancer treatment,but usually accompanied by bleeding,risk of infection and a high recurrence rate.Alternatively,commonly used modalities including chemotherapy and radiotherapy suffer from inadequate therapeutic efficacy,particularly for middle-and late-stage cancer,owing to the incomplete tumor eradication.Moreover,undesirable complications and side effects may arise during these therapies because of poor targeting of chemotherapeutic drugs or deficient selectivity of radioactive exposures.Therefore,therapeutic strategies with high tumor specificity and efficacy as well as minimal adverse effect are in urgent demand for clinical practice.Compared with systemic methods（e.g.intravenous injection）,localized therapeutic approaches are attractive for tackling the abovementioned challenges,which may not only realize sustained drug release but also avoid the sysmetic circulation so as to reduce toxicity towards normal tissues.Considerable efforts have been devoted to designing polymer-based platforms to directly deliver chemotherapeutic drugs into tumors,which can be regulated by the degradation or dissolution of polymers.Injectable hydrogels with highly organized three-dimensional networks that mimic physiological tissue environments have been prevalently applied in the area of regenerative medicine,such as delivery of therapeuttaic agents in situ.Polymeric hydrogels with high water content,flexibility,biodegradability and biocompatibility may facilitate retaining the pharmaceutical activity of encapsulated drugs and customizing drug release in vivo.This thesis designed and prepared a series of functional hydrogel platforms,and is devided into two sections:First,we developed a composite hydrogel system named as SH/DOX@hydrogel,which was fabricated by loading sodium humic（SH）and doxorubicin（DOX）into the low-melting-point-agarose hydrogel.SH,as an efficient near-infrared（NIR）light absorber,can efficiently convert light energy into thermal energy,which further generate local hyperthermia to trigger sustained drug release from the hydrogel matrix through a typical gel-sol transition.And,an enhanced cellular uptake of DOX was concurrently realized upon endocytosis.Moreover,intratumoral injection of SH/DOX@hydrogel resulted in a combinedchemo-photothermal therapeutic effect against solid tumors under NIR laser irradiation,which effectively suppressed tumor growth and recurrence.In addition,the SH/DOX@hydrogel exhibited ultralow systemic toxicity as demonstrated by using an animal model.Second,to overcome local hypoxia in tumor microenvironment,a biocompatible agarose-based hydrogel composed of SH,manganese oxide（MnO₂）and chloride e6（Ce6）was synthesized as agarose@SH/MnO₂/Ce6 through a“co-trapped”strategy based on sol-gel transition,and employed for combined photothermal therapy（PTT）and enhanced photodynamic therapy（PDT）.NIR-induced local hyperthermia is responsible for not only activating Ce6 release,but also triggering the catalytic decomposition of H₂O₂ mediated by MnO₂ to relieve hypoxia.Such hybrid hydrogel realized a deep tissue penetration through intratumoral injection,and exhibited a remarkable tumor-site retention.Moreover,a programmed laser irradiation led to an extremely high tumor growth inhibition rate of 93.8%in virtue of enhanced PTT/PDT,occurrence was not observed during two weeks post-treatment.In addition,ultralow systemic toxicity arised from the hybrid hydrogel was further demonstrated in vivo.