Tumor Microenvironment-responsive Mesoporous Silica Nanodrugs For Synergistic Antitumor Therapy

The tumor microenvironment(TME)is a special pathological microenvironment composed of tumor cells and an extracellular matrix.The occurrence and development of tumors promote the formation of TME,and TME also directly affects the growth of tumors.TME alters the formation of new blood vessels at the tumor site by regulating the tumor immune microenvironment and releasing related cytokines,thereby resulting in a highly hypoxic state of the tumor site.On the other hand,TME is also a state of high concentration of glutathione(GSH),weak acidity,and immunosuppression,which together create a complex pathological environment.Although complex TME has brought great challenges to traditional cancer treatment methods(surgery,chemotherapy,and radiotherapy,etc.),it also provides new opportunities and directions for the development of novel cancer treatment strategies.In recent years,considerable progress has been made in targeting the specificity of TME to construct functional nanomaterials with TME response.These materials can effectively address the pathological conditions inherent in the lesion area to improve the efficacy of imaging,drug delivery,and antitumor therapy.So far,a variety of nanomaterials(polymers,micelles,metallic materials,hydrogels,etc.)have been designed to address the therapeutic limitations posed by TME.Among the many nanomaterials,mesoporous silica nanoparticles(MSN)have better biocompatibility,controllable mesopore volume,and functionally modified surface and skeleton structure.It is widely used in the research of new anti-tumor therapeutic systems.Based on the complexity of TME and the excellent properties of MSN,two mesoporous silicon nano-drug delivery systems that can respond to TME were designed and fabricated on the basis of MSN.The applications of the two nanosystems in tumor imaging,drug delivery and anti-tumor therapy were explored through in vitro and in vivo experiments.First,we prepared core-shell MSNs with Fe₃O₄-Au core structure by sol-gel method for co-delivery of photosensitizer methylene blue(MB)and P^DPPA-1 pepetide(an anti-apoptotic cell death protein-1 ligand,PD-L1),and simultaneously achieved magnetic resonance imaging(MRI)and microelectronic computed tomography(?CT)imaging dual-modality imaging.The experimental results in vitro and in vivo showed that the prepared co-delivered nanomedicine(MB@MSP)could sequentially release PDPPA-1 and MB in response to matrix metalloproteinase-2(MMP-2)and GSH in the TME.Fe₃O₄-Au at the core of MB@MSP was used as a contrast agent for MRI and?CT imaging,enabling non-invasive diagnosis of solid tumors and simultaneous monitoring of drug delivery.MB@MSP undergoes size reduction and charge inversion in the TME,and these transitions promote the deep penetration of MB@MSP at tumor sites.The released P^DPPA-1 can block immune checkpoints,create an environment conducive to the activation of cytotoxic T lymphocytes,and enhance the antitumor immune response elicited by photodynamic therapy(PDT),thereby significantly improving the therapeutic effect.Studies on potential anti-tumor mechanisms showed that the designed MB@MSP could not only induce tumor cell apoptosis but also modulate the immunosuppressive TME,ultimately enhancing the effect of CD8⁺cytotoxic T cells on tumor metastasis.Based on the study of the first therapeutic system,in order to improve the effect of PDT and further alleviate tumor immunosuppressive TME,we designed and prepared mesoporous organic silica nanoparticles(MON)with a disulfide bridged skeleton.Furthermore,MB and L-Arginine(L-Arg)were simultaneously loaded into polyethylene glycol-modified MON to form L-Arg/MB@MSP nanomedicines that could disintegrate in response to GSH.According to the results of the pharmacokinetic study,L-Arg/MB@MP injected into rats via tail vein showed prolonged blood circulation time,and the bioavailability of both drugs was improved,72 h after administration nanoparticles are almost completely excreted.Under laser irradiation,L-Arg/MB@MP can generate a large amount of reactive oxygen species(ROS)for PDT,and some ROS can oxidize L-Arg to generate nitric oxide(NO).NO can be used not only for gas therapy(GT),but also as a biological messenger to regulate vasodilation to relieve tumor hypoxia.During GT,the rapidly released NO is further oxidized to reactive nitrogen species,which together with ROS induces G2/M phase arrest and apoptosis of cancer cells to promote immunogenic cell death,ultimately leading to enhanced antitumor immune responses.On the other hand,L-Arg/MB@MP further down-regulated the expression of PD-L1 on the basis of down-regulating the expression of hypoxia-inducible factor-1(HIF-1?),and finally relieved the immunosuppressive TME.Furthermore,the depletion of GSH in tumor tissue induced by L-Arg/MB@MP biodegradation could be combined with GT to synergistically amplify the therapeutic effect of PDT.In summary,two TME-responsive nanotherapeutic platforms(MB@MSP and L-Arg/MB@MP)were constructed based on MSN,which exhibited significant anti-tumor therapeutic effects in vitro and in vivo in this dissertation.The construction of these two nanotherapeutic systems lays the foundation for the further application of MSN overcoming TME in the biomedical field.