| Cancer is the primary enemy of human life and health due to its high incidence and high mortality.In recent years,the construction of nano-delivery systems has greatly optimized the physical and chemical properties of drug molecules,improved their bioavailability,and endowed drug molecules with targeting properties to precisely attack tumor tissues,showing unique advantages over traditional medical methods in cancer treatment.However,the successive and contradictory physiological barriers during the drug delivery journey require nanocarriers have transformable propertise to combat specific needs in different delivery stages.Although most nano-delivery systems can efficiently enrich in tumor sites,the dense extracellular matrix(ECM),abnormal interstitial fluid pressure(IFP),and high degree of hypovascularity(HDH)in tumor tissues hinder their deep penetration.Studies have shown that small-sized nanoparticles can reduce diffusional resistance in the tumor interstitial space and facilitate intratumor penetration,however,they do not possess the ability of long circulation and are easily cleared by the body during bloodstream.Utilizing the difference between the tumor microenvironment(TME)and the normal physiological environment to design nanocarriers with size-transformable property.These drug delivery systems can change from large size to small size by responding to the stimulation of TME,which can not only effectively retain the characteristics of long circulation,ensure high-efficiency tumor enrichment,but also enhance intratumor infiltration.The contradiction between long retention and deep penetration of nanocarriers in tumor sites can be effectively reconciled,which provided a new insight for enhancing antitumor activity.Based on the strategy of particle size transformation,this paper takes the construction of supramolecular polymer nano-delivery system as the starting point,and aims to improve drug delivery efficiency and enhance anti-tumor activity.Two pH-responsive supramolecular polymer nano-delivery systems with size-transformable property were constructed and systematically evaluated its anti-tumor activity in vitro and in vivo.The details are shown as follows:(1)To enhance the long-circulation ability and intratumor permeability of the drug delivery system,a size-transformable acid-sensitive supramolecular polymer(DCD SNs)was constructed.The supramolecular polymer is formed by combining two natural polysaccharide chains through multivalent host-guest interactions.Multiple cyclodextrin(β-CD)repeating units and chemotherapeutic drug doxorubicin(DOX)are attached on the two dextran(DEX)polysaccharide backbones by acid-sensitive Schiff base bonds.The DCD SNs is formed through the multivalent binding of cyclodextrin units and guest drug molecules.In normal physiological environment,due to the multivalent host-guest interactions of two polysaccharide polymer chains,its binding affinity is enhanced,strong self-assembly is induced,and the instability of self-assembly is improved,which is beneficial to prolong blood circulation and prevent drugs of premature leakage.The resulting DCD SNs exhibited high stability and high drug loading.Under the stimulation of the acidic extracellular environment,the Schiff base bonds in DCD SNs would be broken,and the supramolecular polymers can be dissociated and transformed into small particles,thereby achieving deep infiltration of the tumor.In vivo and in vitro experimental results show that the supramolecular polymer exhibits superior intratumoral penetration and significant anti-tumor efficiency in mouse breast cancer cells(4T1)and tumor-bearing mouse models.The supramolecular polymer has strong stability,can better accumulate in the tumor focus and simultaneously penetrate into the tumor,thereby enhancing the anti-tumor activity.This work provides a new strategy for construction a long-circulation and deep-penetration intelligent drug delivery system in order to achieve efficient and accurate anti-tumor treatment.(2)In order to further improve the drug delivery efficiency,a pH cascade-responsive supramolecular polymer prodrug(PDNPs)with stepwise size shrinkage was constructed.PDNPs were composed of multiple polyethylene glycol(PEG)and DOX polymer-drug hybrid repeating blocks,coupled via ultra-pH-sensitive benzoic imide and hydrazone linkages to response the increasing acidity of the tumor microenvironment.The PEG unit of PDNPs endows it "stealth" in the blood circulation system,which can enhance the retention effect in vivo and ensure sufficient accumulation at the tumor site.Upon reaching the tumor microenvironment,the slightly acidic extracellular characteristic of the tumor(pH ～ 6.5)can lead to the protonation of ultra-pH-sensitive benzoic imide bonds,triggering a dramatic reduction in particle size and PEG detachment for deep tumor penetration.Following phagocytose,due to the more acidic endolysosomes(pH ～ 5.0),the hydrazone bonds of PDNPs are broken,resulting in complete decomposition of PDNPs into ultra-small particles to ensure precise intracellular delivery of DOX.Studies have shown that DOX can induce GSDME protein-mediated pyroptosis and release pro-inflammatory factors to activate the immune system and enhance immune responses.The pH cascade activation of PDNPs enables efficient and accurate delivery of DOX in tumor cells,which can effectively induce tumor cell pyroptosis,promote dendritic cell(DCs)maturation and toxic T cell infiltration to enhance anti-tumor immune responses,thereby enabling effectively settle the problem of low response rate of immune checkpoint inhibitor-mediated immunotherapy.By combination with the immune checkpoint inhibitor anti-PD-1,PDNPs can significantly amplify tumor suppression and extend survival of mice.The supramolecular polymer prodrugs constructed in this work can precisely deliver drugs and effectively induce pyroptosis,paving the way for high-efficiency immune checkpoint blockade therapy. |
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