Polydopamine-based Smart Nanomedicines For Photothermal-enhanced Tumor Combination Therapy

In recent years,photothermal therapy（PTT）,which uses photothermal conversion materials to generate sufficient heat to kill cancer cells under near-infrared（NIR）laser irradiation,has become an emerging tumor treatment strategy in addition to traditional treatments because of its advantages of minimally invasive,high selectivity and low toxicity.However,due to the limited penetration depth of laser,insufficient enrichment at the tumor site and the complexity of the tumor microenvironment（TME）,single photothermal therapy is often insufficient to completely eradicate tumors.Therefore,combining PTT with other therapeutic modalities is expected to achieve synergistically enhanced antitumor efficacy through complementary advantages.Most of the currently reported nanoplatforms are simple combinations of therapeutic functions and lack tumor-specific response mechanisms,which greatly reduce the safety and efficacy of synergistic therapy,so there is an urgent need to construct stimuli-responsive multifunctional nanoplatforms for photothermal combination therapy.Polydopamine（PDA）,as a photothermal conversion material with extraordinary adhesion,good biocompatibility and high chemical responsiveness,shows great potential in the construction of multifunctional nanoplatforms.Based on the microenvironmental characteristics of tumor weak acidity,high glutathione（GSH）concentration and enzyme overexpression,three stimuli-responsive polydopamine-based nanocomposites were designed and prepared in this thesis to achieve safe and efficient tumor combination therapy by combining internal smart response with external physical sensitization.The main contents are as follows.（1）Taking advantage of the strong adhesion property of PDA,a p H-responsive cascade nanoreactor（h MAP）with H2O2 self-supplying and GSH depleting abilities was successfully constructed by wrapping a PDA coating on the surface of honeycomb manganese dioxide nanoparticles（h Mn O2）loaded with ultra-small gold nanoparticles（Au NPs）.In the normal physiological environment（p H 7.4）,the PDA coating ensures the stability of h MAP,while it will decompose in the tumor microenvironment（p H 6.0）,exposing h Mn O2 and Au NPs.On the one hand,h Mn O2can undergo redox reaction with GSH,generating Mn²⁺while consuming GSH;on the other hand,Au NPs with glucose oxidase-like activity can catalyze the oxidation of glucose to produce H2O2 and generate highly toxic hydroxyl radicals（·OH）through Fenton-like reactions in the presence of Mn²⁺.Notably,h MAP with high photothermal conversion efficiency is not only capable of PTT under 808 nm laser irradiation,but also generates large amounts of ROS through a photothermally enhanced cascade catalytic reaction,thus significantly enhancing intracellular oxidative stress.In vitro and in vivo experiments showed that h MAP exhibited excellent anti-tumor activity and good biosafety under 808 nm laser irradiation,providing a paradigm for rational design of TME-responsive and NIR-enhanced nanocatalytic tumor treatment strategies.（2）Inspired by the regular pore structure and high specific surface area of mesoporous polydopamine（MPDA）,a p H/GSH dual-responsive nanoplatform（MIM）with self-oxygen supply function was successfully constructed by loading the photosensitizer indocyanine green（ICG）into MPDA throughπ-πinteraction and wrapping Mn O2 in the outer layer.After MIM enters the tumor cells through endocytosis,the Mn O2 coating with peroxidase-like activity can catalyze the decomposition of H2O2 in TME to generate O2,thus effectively alleviating tumor hypoxia and enhancing the efficacy of oxygen-dependent photodynamic therapy（PDT）;in addition,the acidic and reducing TME will also will trigger the dissociation of the outer layer of Mn O2,releasing ICG and Mn²⁺while consuming GSH.Regardless of the normoxic or hypoxic environment,MIM irradiated by 808nm laser is able to achieve efficient tumor treatment through MPDA-mediated PTT,ICG-mediated PDT and Mn²⁺-mediated chemodynamic therapy（CDT）.Thus,this work provides a new idea to enhance tumor-specific combination therapy under single light source stimulation.（3）Based on the above research work,Cu²⁺with tannic acid（TA）was coated on the surface of MPDA loaded with 2,2’-azobis[2-（2-imidazolin-2-yl）propane]dihydrochloride（AIPH）and modified with hyaluronic acid（HA）to successfully construct a free radical nanogenerator（MACTH）that integrates tumor targeting and dual response.MACTH can specifically accumulate at tumor sites through enhanced permeability and retention（EPR）effects and CD44-mediated active targeting mechanism,followed by the release of Cu²⁺and AIPH upon stimulation by hyaluronidase（HAase）and acidic environment.Released Cu²⁺can generate Cu⁺by redox reaction by consuming GSH and then catalyzes H2O2 to produce·OH.Under808 nm laser irradiation,MACTH-induced local hyperthermia not only triggers the breakdown of AIPH to produce oxygen-independent alkyl radicals（·R）for thermodynamic therapy（TDT）,but also enhances Cu⁺-mediated CDT.Regardless of the normoxic or hypoxic environment,MACTH irradiated by 808 nm laser can disrupt the intracellular redox homeostasis by depleting GSH and generating large amounts of free radicals（·OH/·R）.In vitro and in vivo experiments showed that MACTH under 808 nm laser irradiation significantly enhanced the tumor treatment effect through the synergistic effect of PTT/TDT/CDT,and no significant toxic side effects were found,which laid a good foundation for the development of TME-responsive and NIR-triggered free radical generation strategies.