Boron-rich Covalent Organic Framework Materials For Boron Neutron Capture And Immune Combinational Therapy Of Glioma

Gliomas are associated with a high degree of metastasis,infiltration and drug resistance,resulting in high recurrence and death rates and posing a serious threat to national health.Gliomas are difficult to be removed surgically due to the diffused infiltration and poorly defined borders.Radiation therapy is limited by the radiation dosage to the brain and is easily tolerated,resulting in poor treatment outcomes.In addition,the blood-brain barrier（BBB）,which is unique to the brain,greatly limits the efficiency of drug delivery to the brain and reduces the efficacy of chemotherapy.Based on the limitations of existing therapeutic approaches,we aim to find a novel therapeutic strategy that can target tumor cells while leaving normal cells and tissues undamaged,and inhibit tumor spread and recurrence.Boron Neutron Capture Therapy（BNCT）is a binary chemo-radiotherapy with strong targeting and high energy transfer density at the cellular scale,which has the advantages of strong tissue penetration,high controllability and short treatment time.The principle of action is that the stable isotope ¹⁰B is subjected to low energy（0.025 e V）thermal neutron or super thermal neutron（10,000 e V）radiation and undergoes neutron capture-fission reaction,which subsequently produces high energy and short range alpha particles(⁴He²⁺)and ⁷Li³⁺particles,and then exerts tumor cell killing effect.Since the ranges ofαparticles and ⁷Li³⁺particles are 10μm and 5μm,respectively,which are limited to the scale of target cells（～20μm）,the impact on non-target cells is small and the damage is low.Therefore,BNCT has a unique advantage over conventional radiation therapy in the treatment of glioma.Tumor cells commonly use multiple mechanisms to escape immune surveillance,and it is often difficult to effectively overcome tumor metastasis with a single therapeutic strategy.Although physical therapy such as BNCT can trigger immunogenic cell death（ICD）to some extent,the anti-tumor immune response induced by radiation therapy alone is not sufficient to effectively prevent tumor metastasis to distal tissues.In parallel the glioma microenvironment is highly immunosuppressive,further limiting the body to initiate immune protection.The immune agonist Vadimezan（DMXAA）binds to interferon gene stimulator（STING）on the endoplasmic reticulum of dendritic cells（DCs）,releasing interferon-β（INF-β）,promoting cell maturation and tumor-associated antigen presentation in DCs,increasing cytotoxic T lymphocyte（CTL）infiltration into the tumor area,and promoting the body’s specific anti-tumor immune response.To address the above problems,a multifunctional boron-rich nanosheet was constructed in this thesis,which contains a carrier module,a drug-carrying module,and a targeting module.The carrier module is a boron-rich covalent organic framework COF-1 with 12.35%of boron atoms,which serves as a drug carrier while providing sufficient number of ¹⁰B atoms.The drug delivery module is the STING pathway immune agonist DMXAA and the fluorescent probe Chlorin e6（Ce6）with 78.6%and 65.8%encapsulation rates,respectively,for amplifying the antitumor immune response and enabling real-time monitoring of the carrier.The targeting module is a short peptide of Angiopep-2,a ligand of low-density lipoprotein receptor-related protein 1（LRP1）bonded on the surface of the nanodrug,which can bind to LRP1 highly expressed on the surface of brain capillary endothelial cells（BCECs）and thus mediate trans-BBB transport for efficient delivery of ¹⁰B atoms,the immune adjuvant DMXAA and the fluorescent probe Ce6 to brain glioma lesions.