Synthesis And Their Applications Of Responsive Theranostic Polymers Based On Tumor Micro-Environment

The unique Tumor micro-environment(TME)of tumor tissue not only provides the best growth environment for the rapid proliferation and metastasis of tumor,but also weakens the defense of innate immune system against tumor cells.In addition,the characteristics of tumor microenvironment,such as hypoxia,weak acid and high interstitial pressure,also bring great challenges to the full application of theranostics materials in tumor areas.However,the difference between tumor microenvironment and normal tissue also provides a new opportunity for precision diagnosis and treatment of cancer.At present,theranostics materials based on tumor microenvironment have become a research hotspot,which has spawned a lot of creative designs and applications.However,there are still problems such as low sensitivity and poor penetration of nanomaterials.Therefore,it is necessary to design new nanomaterials to achieve accurate diagnosis and treatment of tumors.This thesis designed and prepared three novel theranostic materials for efficient tumor precise diagnostics and treatment based on the hypoxia and immunosuppression micro-environment by the combination of active target and specific activation,including a dual-channel fluorescent probe with hypoxia targeting and hypoxia activation capacity,a targeting and activatable polymer for hypoxia tumor penetration by transcytosis and a highly sensitive theranostics polymer probe with M2-like macrophages targeting and activation capacity.Firstly,a hypoxia targeting and activation dual-function probe was designed and synthesized.Hypoxia is one of the most important features of solid tumors,and effective hypoxia imaging can help clinicians to take the most appropriate treatment.However,the targeting and sensitivity of current hypoxia imaging probes still need to be improved.Hence,a two-channel near-infrared fluorescent ratio probe(OPDEA/BOD-NO2)with both hypoxia targeting and hypoxia activation functions has been designed firstly for tumor hypoxia imaging.OPDEA/BOD-NO2 was prepared by hypoxia targeting tertiary amine N-oxide(OPDEA)and nitrobenzene modified Aza-Bodipy(BOD-NO2)via selfassembly.The maximum absorption and emission of OPDEA/BOD-NO2 are 660 nm and 700 nm,respectively,which can be reduced to BOD by nitroreductase(NTR)in a hypoxia micro-environment.The maximum absorption and emission of OPDEA/BODNO2 can be redshifted to 700 nm and 740 nm,respectively,and the wavelength-shift is close to 60 nm.Therefore,a two-channel proportional probe can be constructed to detect tumors and their hypoxia degree.It was found that compared with PEG-based carriers,OPDEA-b-PS could increase probe accumulation in tumor region by about 3 times and improve signal-to-background ratio(SBR).OPDEA/BOD-NO2 can simultaneously observe the distribution and activation of probes in vivo,and its 48-h imaging window in tumor region is significantly better than existing molecular probes.Secondly,a targeting and activatable polymer for hypoxia tumor penetration by transcytosis was designed and synthesized.Tumor targeting and intratumoral penetration of nanomaterials are the key factors restricting their theranistic performance.Meanwhile,receptor recognition mediated transcytosis and charge shift can promote the active penetration of nanomaterials into tumors.Based on the azobenzene-charge shift of endocytosis and tumor targeting of ASGPR receptor on HepG2 cell membrane surface,a targeting and activatable polymer for hypoxia tumor penetration by transcytosis was designed and synthesized.Firstly,fluorescent ATRP initiator(Atom Transfer Radical Polymerization)BOD-Br was synthesized.Four nanoparticles(BOD-Paz-Gal,BODPgal,BOD-PEG and BOD-Paz-PEG)with similar molecular weight and size(about 25 nm)were synthesized precisely.It was found that the introduction of galactose significantly increased the uptake of nanoparticles in HepG2 cells,and the charge shift induced by hypoxia provided better tumor penetration and retention.BOD-Paz-gal conjugated with the chemotherapeutic drug camptothecin(CPT)can efficiently deliver the drug to the tumor area to improve the tumor inhibition rate.Finally,a highly sensitive theranostics polymer probe with M2-like macrophages targeting and activation capacity was designed and synthesized.In addition to hypoxia,the immunosuppressive micro-environment of tumor also has a great influence on the therapeutic effect of tumors.Macrophages,as the largest proportion of innate immune cells in tumor micro-environment,especially M2-like macrophages,play an important role in tumor growth and metastasis.Therefore,tracking M2-like macrophages may be an ideal method to detect ultra-early tumors.However,the monitoring of tumor metastasis through real-timly tracking of the migration of M2-like macrophages in animal models has not been reported so far.Hence,this paper designed and synthesized a M2-like macrophage-targeting NO-responsive nanoprobe NRP@M-PHCQ.The probe is self-assembled from a amphiphilic polymer(M-PHCQ)containing mannosehydroxychloroquine and a NIR-Ⅱ fluorescent probe(NRP)that can be activated by NO.It can efficiently target M2-like macrophages and track their polarization process.MPHCQ can target M2-like macrophages by mannose unit and polarize them by hydroxychloroquine unit to produce NO.Animal experiments showed that the NIR-Ⅱfluorescence imaging based on NRP@M-PHCQ could detect metastatic tumors in lymph nodes and lung metastasis with high sensitivity,which even earlier than Lucilablled bioluminescence,indicating that M2-like macrophages are extensively infiltrated in tumors and play a key role in tumor metastasis.Moreover,polarized Ml-like macrophages can effectively kill tumor cells,significantly inhibit early metastasis of tumor in lung metastasis model,and completely ablate tumor in subcutaneous tumor model combined with NO-activated photothermal therapy.