| As a prominent global public health problem,cancer has brought a heavy burden on both economic and social development.The disruption of mechanisms that regulate cell death and cell division leads cancer cells to proliferate uncontrollably and invade surrounding normal tissue.Moreover,these malignant cells possess the ability to metastasize to distant sites within the body,inflicting significant harm.Therefore,it is crucial to explore effective therapeutic strategies for cancer eradication or profound inhibition of its progression.Photothermal therapy,as an emerging therapeutic modality,has exhibited promising prospect in cancer therapy due to the minimal invasion and high efficacy.In the process of photothermal therapy,high-performance photothermal agents are usually used to convert light energy into heat,achieving non-invasive thermal ablation of tumors.Additionally,tumors treated with thermal ablation can release tumor-associated antigens as immune activators to active the immune system,thereby realizing synergistic tumor suppression.However,there are also certain limitations to photothermal therapy in practical applications:(1)Under the stimulation of photothermal therapy,tumor cells will express a large amount of heat shock proteins to enhance the heat tolerance of cells,resulting in thermal resistance to photothermal therapy.(2)Another obstacle for the application of photothermal therapy is the inflammatory response.Inflammation can promote the growth and metastasis of tumors to a certain extent,compromising the effectiveness of tumor treatment.(3)The poor tumor targeting ability,low photothermal conversion efficiency,and restricted laser penetration depth of photothermal agents have also impeded the development and application of photothermal therapy.Therefore,it is crucial to construct novel photothermal platforms for resisting the limiting factors in the process of photothermal therapy and explore effective methods to synergistically enhance photothermal therapy.Aiming at the limiting factors of photothermal therapy,a series of functionalized nearinfrared photothermal platforms based on cyanine or thioxanthene-hemicyanine photothermal molecules with excellent photothermal conversion properties were designed and synthesized to achieve efficient photothermal ablation of tumors.The accumulation of photothermal agents in tumor tissue was realized by the formulation into nanoparticles,while the release of functional molecules was triggered by the overexpressed markers in tumor tissue.The specific designs are as follows:1.A nitroreductase-actived photothermal platform was constructed to enhance the therapeutic effect by mitigating the thermal-induced inflammatory response.Inflammation resulting from hyperthermia possess the risk of promoting tumor metastasis regeneration.To address this issue,the triphenylphosphine-modified thioxanthene-hemicyanine molecule and anti-inflammatory drug diclofenac were combined using a nitroreductase-actived ligand to create a multifunctional photothermal agent with anti-inflammatory property.Nitroreductase could mediate the release of both photothermal molecules and anti-inflammatory drugs.Upon nearinfrared laser irradiation,the respectable photothermal effects could result in effective damage to tumor cells,while the released diclofenac mitigated the inflammatory response and minimized the side effects during the process of photothermal therapy.Contributing to its lipophilic cationic structure of triphenylphosphine,this photothermal platform could effectively target and disrupt the function of mitochondria.Combined with the inhibitory effect of diclofenac on glucose transporter 1,the production of cellular energy was absolutely limited,thereby achieving the inhibition of heat shock protein expression.Experimental results showed that diclofenac effectively reduced the level of pro-inflammatory factors,which greatly enhanced the effect of photothermal therapy.2.High temperature can accelerate the efficiency of Fenton(Fenton-like)reaction and promote the generation of hydroxyl radical.At the same time,the oxidative damage caused by free radicals will destroy cell homeostasis and heighten the sensitivity of tumor cells to heat.In this part,a small molecule Fenton agent that could reduce intracellular p H to improve the efficiency of chemodynamic therapy was first designed and synthesized based on the strategy of chemodynamic therapy synergistically enhancing mild photothermal therapy.This Fenton agent provided an effective tool for subsequent combination with photothermal therapy.The catalyst ferrocene and carbonic anhydrase inhibitor were connected by a ligand containing disulfide bond and could be released under the presence of overexpressed glutathione.Carbonic anhydrase inhibitors inhibited the activity of carbonic anhydrase IX,preventing it from maintaining homeostasis of intracellular p H levels,resulting in the accumulation of hydrogen ions in the cell.The acidified microenvironment promoted ferrocene to catalyze hydrogen peroxide into hydroxyl radical,causing oxidative damage to cells.This small molecule Fenton agent would facilitate the subsequent combined application with photothermal therapy.3.A near-infrared photothermal platform with high Fenton catalytic activity was constructed to augment the effect of mild photothermal therapy through enhanced chemodynamic therapy.The aforementioned small molecule Fenton agent was utilized to assemble with photothermal agent and amphiphilic polymer DSPE-PEG to form nanoparticles.The utilization of small molecule Fenton agent resulted in enhanced chemodynamic therapy by reducing intracellular p H,which circumvented the limitation of laser penetration depth and made the damaged tumor cells more sensitive to the mild photothermal therapy.Meanwhile,the heat generated by photothermal therapy also promoted the efficiency of Fenton reaction,thus achieving the purpose of the synergistically enhanced tumor ablation.The results of in vivo tumor suppression showed that the enhanced Fenton reaction effectively promoted the anti-tumor effect of mild photothermal therapy,and tumor growth was significantly inhibited.4.A molecule photothermal agent,triggered by the tumor-overexpressed glutathione,was designed and synthesized to augment mild photothermal therapy through the inhibition of heat shock protein.By simultaneously blocking oxidative phosphorylation and glycolysis,this photothermal agent could significantly inhibit the ATP production and further mediated the decrease of heat shock protein expression.This photothermal agent was constructed by combining a thioxanthene-hemicyanine photothermal molecule with glycolysis inhibitor lonidamine via a glutathione-responsive linker.Photothermal reagent and lonidamine could be released by the overexpressed glutathione in tumor tissue.Under the irradiation of near-infrared light,the generated heat could directly destroy mitochondria for tumor cell ablation.Simultaneously,the inhibition of oxidative phosphorylation triggered by mitochondria damage coupled with lonidamine-mediated glycolysis blocking synergistically limited the production of ATP in tumor cells,and then inhibited the expression of heat shock proteins during mild photothermal therapy.Experimental results showed that the photothermal effect on tumor cells was significantly improved.This photothermal platform provided a new paradigm for designing and synthesizing photothermal agents with heat shock proteins-inhibiting ability. |
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