Application Of Nanomaterials In Cancer Radionuclide Therapy

Cancer is one of the main threats to public health,killing millions of people every year.Radiotherapy is one of the main clinical cancer treatment methods.Radionuclide therapy is a clinically used radiotherapy method that utilizes high-energy rays emitted during the decay of radionuclides to effectively kill cancer cells.Radionuclide therapy has an unparalleled advantage to effectively overcome tumor physical barriers.Accurate delivery of radionuclides to tumor to reduce the potential side effects of radiation has become a hot topic in the study of radionuclide therapy.On the other hand,as cancer may be tolerant to radiotherapy due to the unfavorable tumor microenvironment,the modulation of tumor microenvironment for enhanced radiotherapy has also attracted substantial interests in recent years.In this doctoral thesis,several types of multifunctional nanomaterials as radionuclide carriers have been synthesized to modulate the tumor microenvironment for enhancing the efficacy of radionuclide therapy through various mechanisms.The main findings are summarized as follows:Chapter 1:The applications of nanomaterials in biomedicine,especially for radionuclide therapy of cancer theranostic,as well as various methods for tumor microenvironment regulation and its effect on cancer therapy have been summarized in this chapter.The prospect of nanotechnology in cancer radionuclide therapy is then discussed.Chapter 2:Albumin-templated manganese dioxide nanomaterials for enhanced radionuclide therapy.131I-HSA-MnO2 nanoparticles are simply synthesized through biomineralization of langanese ions(Mn2+)and albumin,before radiolabeling for radionuclide therapy.Those nanoparticles not only exhibit specific tumor-homing ability,but also slowly degrade in the weak acidic tumor microenvironment to achieve effective intratumoral diffusion.Moreover,MnO2 can trigger decomposition of tumor endogenous hydrogen peroxide to produce oxygen and significantly relieve the hypoxic tumor microenvironment.MnO2 itself has no therapeutic effect,but can significantly enhance the therapeutic efficacy of radionuclide therapy.Therefore,the biodegradable nanomaterial 131I-HSA-MnO2 combining radionuclide therapy with MnO2 achieves excellent anti-tumor efficacy.Chapter 3:Radiolabeled albumin-paclitaxel nanoparticles for the combined chemo-radionuclide therapy.The chemotherapy drug paclitaxel(PTX)can induce self-assembly of radiolabeled albumins to form 131I-HSA-PTX nanoparticles.Paclitaxel as a classic chemotherapy drug not only effectively kills cancer cells,but also enhances tumor oxygen supply via reducing tumor interstitial fluid pressure(IFP)and relieving hypoxic tumor microenvironment.Therefore,131I-HS A-PTX nanoparticles combining chemotherapy with radionuclide therapy achieves good synergistic therapeutic effects.131I-HSA-PTX synthesized by a simple method has a similar structure to the FDA-approved chemotherapeutic drug Abraxane(?),and has significant translation potential in clinical combination therapy.Chapter 4:Multi-functional calcium bisphosphonates nanomaterials selectively depleting tumor-associated macrophage for enhanced radionuclide therapy.Calcium bisphosphonates nanomaterials are constructed with calcium ions and a clinical drug bisphosphonate via a reverse microemulsion method,and further modified with polyethylene glycol.Due to the fantastic chemical structure of bisphosphonate,calcium bisphosphonate nanomaterials can be chelator-freely radiolabeled with cationic radionuclide 99mTc4+ as a single photon emission computed tomography(SPECT)imaging contrast agent,as well as an anion radionuclide 32P via anion exchange for radionuclide therapy.Tumor-associated macrophages play a key role in regulating tumor microenvironment.Calcium bisphosphonate nanoparticle after tumor accumulation could selectively deplete tumor-associated macrophages,subsequently leading to macrophage depletion,angiogenesis inhibition,vascular normalization,enhanced perfusion and relieved hypoxia,which all would be favorable for radionuclide therapy.Therefore,32P-labeled calcium bisphosphonates nanoparticles combining tumor-related macrophage depletion and radionuclide therapy achieve good synergistic therapeutic effects.Those multifunctional nanomaterials composed of calcium ions and a clinical drug exhibit good biocompatibility and have attractive prospects for clinical translation.Chapter 5:The combination of radiotherapy(RT)with immune checkpoint blockade(ICB)has emerged as a promising combinational therapeutic methodology in recent clinic trials.The efficacies of both RT and ICB therapies,however,are hampered by the abnormal tumor microenvironment(TME)with hypoxic and immunosuppressive features.Herein,a new type of two-dimensional(2D)nanostructure is serendipitously discovered by mixing zinc ions and sodium nitroprusside(Na2Fe(CN)5NO),a clinical anti-hypertensive drug.The formed ZnFe(CN)5NO single-layer nanosheets could be labeled with radioisotope 32P(32PO43-)via a chelator-free manner.Interestingly,32P in this system not only serves as a therapeutic radioisotope,but also induces strong Cerenkov luminescence to persistently stimulate NO release from ZnFe(CN)5NO nanosheets.Upon local administration into tumors,such 32P-labeled ZnFe(CN)5NO nanosheets with long-term tumor retention are able to completely eliminate local tumors,offering greatly improved therapeutic outcome compared to its NO-free counterpart,owning to the released NO to overcome radio-resistance of tumors by modulating the hypoxic immunosuppressive TME.Furthermore,the combination of 32P-labeled ZnFe(CN)5NO nanosheets for RT together with ICB therapy offers a strong abscopal effect to inhibit distant tumors.Such 2D nanostructure composed by Zn2+and a clinical drug is thus a unique nano-platform that enables chelator-free radiolabeling,Cerenkov-luminescence-triggered NO release,effective TME modulation,and enhanced RT-ICB therapy,particularly promising for tumor metastasis treatment.In summary,a variety of nanomaterials are synthesized and applied as radionuclides carriers,which in the meanwhile could effectively regulate the tumor microenvironment through different mechanisms,thereby enhancing the efficacy of radionuclide therapy and combination therapy.These efforts would be helpful to advance the field of radionuclide therapy.