Construction Of Several Targeted Nanomedicines For Theranostics In Glioblastoma

Glioblastoma is one of the most aggressive cancers and difficult to cure.Patients with GBM have a median survival of 14 months and a 5-year survival of less than 5%.The grim statistic has remained unchanged over the last 50 years.The treatment effect of clinical standard treatments of GBM(e.g.,maximal surgical resection with adjuvant radio-chemotherapy)is poor for a variety of reasons,such as the incapacity of surgery to remove all GBM cells,resulting in the high recurrence rates.In addition,the bloodbrain barrier(BBB)prevents chemotherapy drugs from entering the central nervous system(CNS),leading to the low enrichment in the glioma site.The specific location of GBM makes it difficult to eradicate GBM cells while avoiding damaging healthy brain cells.Therefore,there is an urgent need to develop efficient and safe drugs based on the disease characteristics of GBM for improving the current treatment status of glioma.Nanotherapeutics and nanomedicines exhibit good potential for cancer treatment because of their advantages in improving targeted therapies and reducing side effects.Although an increasing number of nanomedicine-based treatments have shown promising applications,few highly specific and efficient theranostic nanomedicines have been developed for overcoming the challenges of glioma treatment.Based on the above background,we mainly carried out following works:1.It is difficult to distinguish the margins of GBM during surgical resection,and the low permeability of BBB impedes drug utilization,resulting in poor therapeutic efficacy.Therefore,it is urgently needed to develop nanodrug delivery systems with high BBB penetration ability for fluorescence-guided surgery(FGS)of GBM.To this end,we constructed a biodegradable nanocapsule P@GMT-R by encapsulating Gd2O3:Nd3+nanodots,MnO2 and temozolomide(TMZ)into poly(lactic-co-glycolic acid)(PLGA)and modifying rabies virus glycoprotein(RVG29)on the surface.The RVG29 modification endows the nanocapsules with good BBB permeability and the ability of targeting and accumulating to deep gliomas.P@GMT-R nanocapsules could be used for NIR-Ⅱ fluorescence imaging and MRI through the intact skull,which allows them to be promising for fluorescence imaging surgical navigation of orthotopic GBM.In addition,the nanocapsules released TMZ and generated O2 under the stimulation of the tumor microenvironment(TME),significantly improving the utilization of chemotherapeutic agents,achieving enhanced tumor treatment selectivity and reducing toxic side effects with the assistance of Gd2O3:Nd3+sensitizing radiotherapy.Notably,P@GMT-R nanocapsules are biodegradable and can be cleared from the body through the hepatobiliary system and kidney,showing the high biosafety.2.GBM are intimately associated with the fine structures of the brain.Photothermal therapy(PTT)has recently shown the promise as an effective treatment for gliomas.However,nonspecific accumulation of photothermal agents may affect adjacent normal brain function,and the inflammatory response induced by PTT may result in an increased risk of brain tumor recurrence or metastasis.Based on this,we constructed the intelligent nanomachine G@IT-R by growing Ir nanodots in situ on Gd2O3 nanosheets,loading tetramethylbenzidine(TMB),and modifying RVG29.This nanomachine can achieve tumor-specific-PTT and eliminate inflammation to protect normal brain tissue.The modification of rabies virus glycopeptide-29 peptide(RVG29)assists the nanomachine to pass through the BBB and target gliomas.In the TME,Ir nanozymes can act as logic control systems to trigger chromogenic reaction of TMB for tumor-specific PTT,whereas in normal brain tissues,they scavenge reactive oxygen species(ROS)generated by adverse therapy as protective agents.Autophagy inhibition of Gd2O3 enables excellent photothermal therapeutic effects on orthotopic gliomas and protection against inflammation in normal cells.3.The outcome of immunotherapy for GBM is unsatisfactory due to the strong immunosuppressive microenvironment.Immune checkpoint blockade(ICB)therapy,one of the most promising approaches of immunotherapy,is poorly effective and plagued by immune-related adverse events,mainly because immune checkpoint inhibitors(ICIs)are impeded by the blood-brain barrier(BBB)and have inevitable cross-reactivity with healthy tissues.Based on this,we constructed HN@CaCL-R nanomedicines by loading 2’,6’-dimethylcarbonylphenyl-10-sulfopropylacridinium-9carboxylate 4’-N-hydroxysuccinimide(4’-NHS)ester(NSP-DMAE-NHS)in hydrogen-bonded organic frameworks(HOF)NPs and coating CaCO3 layers,followed by loading cholesterol oxidase and LXR-623,modifying RVG29.HN@CaCL-R with the ability to penetrate the BBB and target glioblastomas could bidirectionally downregulate the expression of immune checkpoints(such as programmed cell death-1,programmed death-ligand 1 and 2B4)to realize ICB therapy.Moreover,the HN@CaCL-R provided an activated immune microenvironment for ICB therapy by eliciting immunogenic cell death(ICD)through chemiexcited photodynamic therapy(PDT)under the tumor microenvironment(TME).HN@CaCLR effectively blocked the infinite supply of cholesterol to glioma cells,and reduced tumour viability and invasiveness,dramatically diminishing cell migration and invasiveness.More importantly,the nanomedicine was completely biodegradable and exhibited outstanding biocompatibility.