Targeted Nanoparticles For The Treatment Of Brain Tumors

Brain tumors including glioma,and central nervous system lymphoma,etc.show high mortality rate,and poses a severe threat to human health.The presence of the blood-brain barrier(BBB)greatly affects the efficiency of drug delivery to the brain and reduces the efficacy of chemotherapy.Moreover,brain tumors develop a unique immune microenvironment that limits the effectiveness of tumor immunotherapy.To solve these problems,this thesis designed two angiopep-2(ANG)conjugated nanoparticles to cross the BBB and improve the treatment efficacy of chemotherapy and immunotherapy of brain tumors.The ANG-conjugated particles can target the low-density lipoprotein receptor-related protein 1(LRP1)overexpressed on the surface of brain capillary endothelial cells(BCECs),and could thus either deliver doxorubicin(DOX)more efficiently or induce immunogenic cell death(ICD)to enhance the treatment of primary central nervous system lymphoma and glioma,respectively.Specific research contents were as the followings:1.The APP@DOX nanoparticles,prepared by modifying poly(ethylene glycol)-b-poly(?-caprolactone)(PEG-b-PCL)with the ANG peptides and loading with DOX,were able to overcome BBB and improve the therapeutic effect of DOX in the in situ tumor model of primary central nervous system lymphoma.The nanoparticles were self-assembled from PEG-b-PCL and their hydrophobic core could be loaded with hydrophobic DOX.In this chapter,the particle size,morphology and drug release were well characterized.APP@DOX improved the targeting ability to BCECs and facilitated BBB transporting through receptor-mediated endocytosis,so as to achieve higher drug accumulation in the brain.In the primary central nervous system lymphoma mice model,we confirmed that the targeted nanoparticles APP@DOX were able to inhibit tumor growth more effectively,thus prolonging the survival period of the mice.2.ANG peptide modified nanoparticles(denoted as APD)were prepared to increase BBB penetration and improve therapeutic efficacy of glioma.APD nanoparticles could induce the ICD effect more effectively to glioma cell line,activate the immune microenvironment of glioma,and improve the therapeutic effect.APD nanoparticles were prepared by single emulsion method.In cellular level studies,APD nanoparticles were demonstrated to induce ICD to GL261 cell line,and the increased expression of calreticulin(CRT)was detected.In vivo experiments showed that the concentration of APD-Rh B nanoparticles in the brain was higher than that of nontargeting D47-Rh B nanoparticles.In the GL261-luc in situ glioblastoma mice model,the treatment effect of APD nanoparticles was better than that of other control groups,significantly prolonged the survival time of mice.