High-affinity mutant Interleukin-13 targeted CAR T cells enhance delivery of clickable biodegradable fluorescent nanoparticles to glioblastoma  

作　　者：Gloria B.Kim Virginia Aragon-Sanabria Lauren Randolph Hali Jiang Joshua A.Reynolds Becky S.Webb Achuthamangalam Madhankumar Xiaojun Lian James R.Connor Jian Yang Cheng Dong 

机构地区：[1]Department of Biomedical Engineering,The Pennsylvania State University,University Park,PA,16802,United States [2]Department of Neurosurgery,M.S.Hershey Medical Center,The Pennsylvania State University,Hershey,PA,17033,United States

出　　处：《Bioactive Materials》2020年第3期624-635,共12页生物活性材料（英文）

基　　金：supported in part by PA Tobacco Settlement Fund(Grant 4100062216,to C.D.,J.Y.J.C);support from the National Institutes of Health Award(AR072731,to J.Y.and EB026035,to X.L.);the National Science Foundation(NSF)Award(CBET-BME1330663,to C.D.)。

摘　　要：Glioblastoma(GBM),the deadliest form of brain cancer,presents long-standing problems due to its localization.Chimeric antigen receptor(CAR)T cell immunotherapy has emerged as a powerful strategy to treat cancer.IL-13-receptor-α2(IL13Rα2),present in over 75%of GBMs,has been recognized as an attractive candidate for antiglioblastoma therapy.Here,we propose a novel multidisciplinary approach to target brain tumors using a combination of fluorescent,therapeutic nanoparticles and CAR T cells modified with a targeted-quadruplemutant of IL13(TQM-13)shown to have high binding affinity to IL13Rα2-expressing glioblastoma cells with low off-target toxicity.Azide-alkyne cycloaddition conjugation of nanoparticles to the surface of T cells allowed a facile,selective,and high-yielding clicking of the nanoparticles.Nanoparticles clicked onto T cells were retained for at least 8 days showing that the linkage is stable and promising a suitable time window for in vivo delivery.T cells clicked with doxorubicin-loaded nanoparticles showed a higher cytotoxic effect in vitro compared to bare T cells.In vitro and in vivo T cells expressing TQM-13 served as delivery shuttles for nanoparticles and significantly increased the number of nanoparticles reaching brain tumors compared to nanoparticles alone.This work represents a new platform to allow the delivery of therapeutic nanoparticles and T cells to solid tumors.

关 键 词：GLIOBLASTOMA T cells Nanoparticles Targeted drug delivery Citrate polymers Fluorescence 

分 类 号：R318[医药卫生—生物医学工程]