Construction Of Multifunctional Antitumor Platforms Based On Covalent Nanocapsules In Collaboration With Live Bacteria

Malignant tumors have gradually become one of the major threats to human health,and their incidence and mortality rates are increasing year by year worldwide.To combat cancer,many kinds of anticancer drugs with anticancer activity have been discovered.However,the inability of drug molecules to actively enrich at the tumor site,resulting in severe side effects,has limited the use of anticancer drugs.Immediately afterwards,scientists developed a series of drug delivery systems in the hope of targeting drug delivery to the tumor site and reducing toxic side effects.The types of drug delivery systems include inorganic nanomaterials,phospholipid vesicles,polymers,supramolecular self-assembled capsules,covalent self-assembled capsules,etc.Among them,covalent self-assembled capsules have attracted attention due to their easy synthesis,easy modification,and high stability.Covalent self-assembly has the advantages of one-step synthesis and does not require a template.Covalent self-assembly uses molecules with multiple reactive groups in the horizontal direction as building blocks to form a variety of nanomaterials including nanotubes,nanocapsules,and nanocircles by covalent cross-linking.The closed nature of nanocapsules allows them to have an encapsulation function and have the potential to be used as drug delivery systems.The choice of building blocks is diverse,as long as the molecules meet the planar rigidity and have multiple reflective groups around them,they have the possibility to be used as building blocks.For example,the main macrocyclic molecules,porphyrins,cyclic peptides and so on.Macrocyclic main molecules possess excellent host-guest complex functions and can modify functional molecules.In addition,covalent nanocapsules can also introduce a variety of functional-like groups on their surfaces through chemical modification.Therefore,covalent nanocapsules have the potential to become multifunctional nanoplatforms.Bacteria,as a living organism,are also increasingly being used as a promising anti-cancer tool.Anaerobic and parthenogenic bacteria can actively target oxygen-deprived tumor sites;bacteria,as a living microorganism,can also actively evade the immune system;bacteria,as immunogenic microorganisms,can elicit an immune response;and metabolites produced by certain life activities of bacteria may also serve as an anti-cancer mechanism.Based on the above concepts,we designed three kinds of covalent nanocapsules with different functions by using covalent self-assembly.And these nanocapsules were used for the construction of anti-tumor drug delivery system;or the capsules were combined with different species of bacteria to form a living-nonliving hybrid system,and the active targeting function or metabolites of bacteria were used to assist the nanocapsules to construct a live bacteria-assisted anti-cancer platform.1.Constructing light/reduction dual-stimuli-responsive covalent nanocapsules for drug deliveryDrug delivery systems can deliver drugs to specific sites,reduce drug leakage and loss,and enhance therapeutic effects.Covalent nanocapsules are gradually becoming another new option for anticancer drug delivery systems due to their ease of synthesis,modification and stability.In this work cystamine and o-nitrobenzyl derivatives were chosen as two linkers to synthesize a dual stimuli-responsive pillar[5]arenes based thin-walled covalent nanocapsules for drug delivery and high performance anticancer effect.In the presence of reducing environments or light,the drug delivery system ruptures and effectively releases its contents due to the breakable nature of disulfide bonds or o-nitrobenzyl group.Moreover,when nanocapsules encapsulated with the anticancer drug camptothecin（CPT）and photothermal molecules（ICG）,the combined therapeutic effect of chemotherapy and photothermal therapy（PTT）was observed in in vitro experiments.In conclusion,the pillar[5]arene-based therapeutic platform exhibited remarkable stability,controlled drug release,and significant in vitro anticancer effects.2.Combining live bacteria and multifunctional covalent nanocapsules to construct an efficient anti-tumor platformLive bacteria-based drug delivery systems have raised as promising tools for enhancing drug delivery into tumors due to their active tumor targeting and easy surface modifiability.In this work,a“（highly integrated nanocapsules）@E.coli hybrid”（HINE-Hybrid）was successfully constructed through highly integrated covalent self-assembly prodrug nanocapsules（HINCs）with the facultative anaerobic bacterium Escherichia coli MG 1655（E.coli MG 1655）for combined chemotherapy,PTT,and chemodynamic therapy（CDT）.HINCs is constructed by covalent cross-linking of pillar[5]arene derivatives and cisplatin prodrug linker,which can be endocytosed and lysed to release therapeutic agents.Under the NIR light（at 808 nm）irradiation,the system temperature can be significantly increased by HINCs,which further leads to the highly efficient generation of ROS species.In addition,HINE-Hybrid shows significant antitumor effects in vitro and in vivo studies and also promotes immune cell infiltration and antitumor cytokine expression in the tumor microenvironment（TME）.HINE-Hybrid exerts its anticancer properties efficiently due to selective enrichment and multiplication of E.coli at tumor sites,which is important for the construction of bacterial-assisted antitumor platforms.3.Oxygen-producing cyanobacteria cascade with photosensitive covalent nanocapsules to construct an efficient antitumor platformPDT is gradually becoming a major tool in the fight against cancer due to its temporal and spatial controllability,low side effects and biocompatibility.However,the high dependence of PDT on oxygen makes its application in oxygen-deprived tumor sites very limited.Moreover,most photosensitizers have disadvantages such as poor water solubility and easy aggregation,which reduce the efficiency of PDT.In this chapter of work,we chose the positively charged porphyrin derivative Zn-tetrahexanoic acid pyridine porphyrin（Zn Thpp）as the building block and oxidized cisplatin（Oxocisplatin）as the linker to synthesize photosensitized covalent capsules containing photosensitizers.The formation of covalent capsules prevents aggregation between porphyrin molecules and produces singly linear oxygen（¹O₂）in the presence of light.To increase the oxygen supply,cyanobacteria capable of oxygen-producing photosynthesis were selected to be electrostatically combined with the photosensitive capsule.Under light,the cyanobacteria produce oxygen and the photosensitive capsule directly converts the produced oxygen into ¹O₂,further increasing the amount of ¹O₂production.