ApoE-Decorated Polymersomal Inhibitor Enables Highly Safe And Potent Treatment Of Orthotopic Glioblastoma

Glioblastoma(GBM)as one of primary tumors of central nervous system is regardd as grade Ⅳ astrocytoma by the world health organization(WHO).Patients following the treatment often display a survival rate of 47%in one year,and an overall median survival time of 12-14 months.Currently,chemotherapeutics is often used for GBM treatment in the clinic,but suffers from poor penetration of the blood-brain barrier and adverse side effects.Recently,nanomedicines with decreased adverse toxicity and enhanced therapeutic efficacy are increasingly employed to treat GBM.In the first chapter,we introduced the clinical statuses and treatment strategies of GBM,and highlighted the design and construction of various nanocarrier systems for GBM treatment.Small molecule inhibitors with defined target sites,superb safety and tumor selectivity have been widely used for the safe and efficient treatment of a variety of tumors Similar to most chemotherapeutics,small molecule inhibitors have poor penetration efficiency of blood-brain barrier and the drug availability is relatively low,thus can be hardly employed for the treatment of GBM.In chapter 2,we report that RGS loaded in apolipoprotein E derived peptide(ApoE)-targeted chimaeric polymersomes(ApoE-CP)is safe and highly potent against human GBM in mice.ApoE-CP exhibited stable loading of RGS in its lumen giving RGS nanoformulations(ApoE-CP-RGS)with a size of 60 nm and reduction-triggered drug release behavior.Notably,ApoE-CP-RGS induced markedly enhanced G2/M cell cycle arrest and inhibitory effect in U-87 MG glioblastoma cells compared with the non-targeted CP-RGS and free RGS.The therapeutic outcomes in orthotopic U-87 MG GBM models demonstrated that ApoE-CP-RGS brought about effective GBM inhibition,greatly prolonged survival time,and depleted adverse effects.Rigosertib formulated in ApoE-targeted chimaeric polymersomes has emerged as a novel,highly specific,efficacious and non-toxic treatment for glioblastoma.By efficiently suppressing the expression of indoleamine 2,3-dioxygenase(IDO),1-methyl-tryptophan(1-MT),a small molecule inhibitor,can relieve immunosuppression,activate T cells,and inhibit the tumor growth,thus hold a potential on the treatment of lung cancer,pancreatic cancer,GBM and so on.However,1-MT alone often induces suboptimum therapeutic effect.In chapter 3,we combined 1-MT and protein nanotherapeutics to achieve synergistic and efficient therapy of orthotopic GBM.Protein nanotherapeutics was developed by encapsulating saporin(SAP)into ApoE-CP that was developed in Chapter 2.SAP-loaded ApoE-CP(ApoE-CP-SAP)exhibited a small size of about 60 nm and high stability against extensive dilution and 10%FBS.Under reductive environments,the protein release from ApoE-CP-SAP was triggered,in which 80%of protein was released in 24 h.Moreover,the released SAP revealed similar seconday structure to free protein.In comparison with non-targeted CP-SAP,ApoE-CP-SAP displayed 3.8-fold more endocytosis in C6-luc mouse glioblastoma cells,and induced significant higher cytotoxicity with an IC50 of 37.7 nM that was far lower than that of non-targeted CP-SAP(>100 nM).Therefore,the protein nanotherapeutics following the combination with small molecule inhibitors holds great potential on the synergistic and efficient therapy of GBM.In chapter 4,we summarize this thesis,and present a short perspective on the future work.