Protein-based Nanoreactors For Tumor Micro Environment Modulation And Enhanced Radiotherapy

Radiotherapy is a commonly used treatment in clinical practice.However,the lack of selectivity in killing normal tissues and tumor tissues may cause side effects to patients.At the same time,the hypoxic area of solid tumors would limit the therapeutic effect of radiotherapy.Therefore,human beings need to develop new and effective cancer therapeutic methods to overcome cancer as soon as possible.In recent years,nanomaterials have been widely used in tumor radiotherapy solve the problems and achieve better cancer therapeutic efficacy.However,even if radiotherapy successfully cures the primary tumor,radiotherapy is often useless for tumors that have metastasized and tumor recurrence,so it is urgent to develop a new strategy to solve this problem.Among them,immunotherapy,a treatment method that inhibits tumor growth by activating the autoimmune system,provides an opportunity to solve this problem.Therefore,three safe nanoparticles were constructed based on proteins in this thesis.These three protein nanoparticles could not only accumulate in tumor site effectively,but also relieve tumor hypoxia to improve efficacy of radiotherapy.Moreover,one of them can effectively inhibit tumor metastasis by being combined with an immunological checkpoint inhibitor.The main contents are summarized as follows:Chapter 1:This chapter provides a brief overview of tumor microenvironment and radiation therapy for cancer.Then it introduces how nanomaterials enhance effects of cancer radiotherapy and the main biomedical applications of protein nanomaterials.Chapter 2:Composite nanoparticles with albumin as template for enhanced external radiation therapy of tumors:Bovine serum albumin(BSA)was served as a template for growth of gold(Au)nanoclusters and manganese dioxide(MnO2)nanoparticles via biomineralization.The obtained nanoparticles(BSA-Au-MnO2)showed great physiological stability,good biocompatibility and effective body excretion.After i.v.injection,the nanoparticles would achieve efficient accumulation in tumor site through enhanced permeability and retention(EPR)effect.Once arriving in the acidic tumor microenvironment,the nanoparticles would decompose into smaller nanoparticles,which favored deep penetration within tumor tissues.In the meanwhile,Mn02 would catalyze the decomposition of endogenous hydrogen peroxide(H2O2)in the tumor microenvironment,which generated oxygen(O2)to modify tumor hypoxia,leading to enhanced external radiotherapy.In addition,the gold nanoclusters in the nanoparticles could effectively absorb X-rays,thereby further improving the external radiotherapy effects.Chapter 3:Nanoparticle-enhanced radiotherapy to trigger robust cancer immunotherapy:The adjuvant R837 and catalase were loaded into poly(lactic-co-glycolic)acid(PLGA)nanoparticles with good biocompatibility by double microemulsion.The obtained nanoparticles could not only enhance the effect of radiotherapy by improving hypoxia,but also promote the transformation of tumor-associated macrophages to M1 type.The study also found that the nanoparticle-based radiotherapy could not only promote the maturation of dendritic cells(DC),but also induce immunogenic cell death,causing a strong immune response.However,it also upregulated regulatory T cells(Treg)in the tumor.Therefore,when combined with ?CTLA-4 to inhibit Treg,it would not only effectively inhibit metastasis,but also produce long-term immune memory effect to prevent tumor recurrence.Chapter 4:Hybrid protein nano-reactors enable simultaneous increments of tumor oxygenation and iodine-131 delivery for enhanced radionuclide therapy:We constructed a protein nanoparticles of about 100 nm by crosslinking between human serum albumin(HSA)and catalase(CAT)induced by glutaraldehyde.It has been found that the stability of CAT in the nanoparticles was improved,which was beneficial for CAT to retain activity in complex physiological environments.Then,the radionuclide iodine 131(131I)was labeled on the nanoparticles via standard iodogen oxidation method.The obtained nanoparticles(131I-HSA-CAT)could effectively accumulate into the tumor site by passive targeting,thereby reducing their accumulation in vital organs,which was favorable to reduce toxic side effects and improve therapeutic efficacy.Besides,catalase within the nanoparticles would react with H2O2 in the tumor site to produce O2 to overcome tumor hypoxia.All above effects ultimately improved the therapeutic effects of 131I and showed obvious inhibition of subcutaneous tumors growth.We have successfully fabricated three biocompatible protein nanoparticles to overcome tumor hypoxia and improve efficacy of radiotherapy.It is hoped that the research results would provide valuable guidance for the development of protein nanomaterials in cancer theranostics.