Construction And Application Of Stimulus-Responsive Nanoplatforms In Tumor Therapy

Malignant tumors have been disturbing human health and threatening human life for a long time,and relevant statistics show that the number of deaths caused by cancer in various countries is rising every year around the world,indicating that cancer treatment has become a huge challenge that human beings need to face.However,the three traditional methods used in the clinical treatment of tumors,surgery,chemotherapy,and radiotherapy,all have their limitations.With the development of nanotechnology,new treatments based on nanomaterials have become a research hotspot in the field of tumor treatment.Tumor proliferation and metabolism are relatively fast,resulting in the internal and external environment of the tumor different from normal tissue,realizing the characteristics of low pH,over-expression H₂O₂ and GSH,high sugar,etc.Inducing apoptosis by modulating tumor microenvironment（TME）has been widely recognized as a clever way to fight cancer.Based on this,this article will take TME stimulus-response as the basis to develop TME intelligent regulation nanoplatform combined with direct cancer treatment（such as photothermal therapy（PTT）,chemodynamic therapy（CDT）,sonodynamic therapy（SDT）,and other methods）,and is committed to discussing the construction of a TME-responsive nanoplatform and the influence of regulating TME on tumor treatment.First,considering that the enhancement of antitumor effects depends on the development of biocompatible nanomaterials and the combination of multiple therapies,in the second chapter of this paper,we develop GBD-Fe targeting a multilevel cascade response to TME,a nanoplatform that effectively integrates chemotherapy（CT）,CDT,and PTT to generate synergistic effects and avoid drug resistance.GBD-Fe uses gold nanorods（GNRs）as photothermal agents and encapsulates the chemotherapy drug doxorubicin to amplify the Fe³⁺-guided CDT effect by producing H₂O₂ and reducing intracellular glutathione levels.In this work,we discussed（1）that the efficacy of CDT depends on the H₂O₂ concentration in TME,and the effect of GSH leads to poor efficacy;（2）It is difficult for chemotherapy drugs to accumulate specifically at the tumor site,and there is a problem of tumor drug resistance.In vitro and in vivo experiments have shown that GBD-Fe releases DOX and Fe³⁺through protonation in response to an acidic environment,and uses Fe³⁺to consume GSH in situ to reduce to Fe²⁺to start CDT.As PTT progresses,tumor temperature increases,cells become more sensitive to DOX,and drug resistance decreases.The protein regulation of DOX on tumor cells can further reduce GSH levels,promote the production of H₂O₂,and enhance the efficacy of CDT.Magnetic resonance imaging（MRI）demonstrated the effective accumulation of GBD-Fe in tumor foci in organisms and guided the antitumor effect.This synergistic treatment method with CT/CDT/PTT interaction effectively induces tumor cytotoxicity and inhibits tumor growth in tumor-bearing mice,and is a promising and effective strategy for the treatment of tumors.Secondly,the low pH based on tumors is the formation of an active ecological niche for tumor pathogenesis and evolution,which will promote the particularity of cancer development and spread,in the second chapter of this paper,we use the gas phase diffusion method to co-condense calcium ions with the sonosensitizers protoporphyrin（PpIX）,encapsulate PpIX in amorphous calcium carbonate（ACC）nucleus,and then cover the tumor cell membrane with PpIX-ACC to increase water solubility while improving the homologous targeting of nanoparticles.Preparation of pH-responsive nanoparticles（PpIX-ACC@CMs）at tumor sites.In this work,we discussed（1）the difficulties of tumor delivery,easy photobleaching and poor biocompatibility of acoustic sensitizer PpIX;（2）Acid microenvironment on tumor immunosuppression.Relevant research data show that PpIX-ACC@CMs have a spherical structure and uniform size,which can snipe the pH of TME,neutralize the pH of TME,reshape TME,and induce an immune response.In addition,PpIX achieves SDT under ultrasound action,and reactive oxygen species（ROS）is generated to apoptosis tumor cells.In vivo experiments,after sonication of PpIX-ACC@CMs,the ROS produced further inhibits the tumor malignant phenotype,induces an immune response by submitting antigens to the immune system,and produces more CD 4⁺and CD 8⁺T cells in the tumor.In the fourth chapter of this paper,taking the third chapter as the research basis,the focus is on the upstream of the acidic substances production,which is the nutrients consumed by tumor cells,mainly Au NPs as glucose-like oxidases,uniformly deposited on Mn Ox by in situ growth,using the layered morphology of Mn Ox and high specific surface area to increase the catalytic activity of nanoenzymes,while providing the ability to load model antigen OVA protein,and developing nanoplatforms（Mn Ox-Au@OVA）with catalytic active sites.Mn Ox-Au@OVA has a nanoflower structure,has good water solubility,and can be efficiently taken up by cells.This work mainly discusses（1）the catalytic activity of Mn Ox-Au@OVA nano platform based on Au NPs nanoenzymes;（2）The activation of tumor immune cells by tumor nutrient consumption.Relevant data prove that Mn Ox can induce an oxidative stress response,consume H₂O₂,and adjust pH at the tumor site,the generated O₂ can feed back the glucose-catalyzed reaction of Au NPs nanoenzymes,and the Fenton-like reaction of Mn²⁺can induce ROS to further kill tumor cells.As a model antigen,OVA protein activates immune cells at the tumor site after alleviating glucose metabolism and realizes immune response.In vivo and in vivo related data can verify that Mn Ox-Au@OVA has good glucose consumption capacity,and its TME response research is of great significance in the field of tumor treatment.