Abstract
Chimeric antigen receptor T cells (CAR-T cells) targeting of CD19 antigen has been proven to be effective and successful in B cell acute lymphoblastic leukemia. The traditional CAR delivery systems have several problems such as poor biosafety, low loading capacity, and low transfection efficiency. Utilization of nanocarriers for CAR delivery offers new possibilities for CAR-T treatment. In the present study, an anti-CD19 CAR expression lentivirus plasmid was constructed for CAR delivery and immunotherapy. In addition, a three-segment amphiphilic co-polymer, methoxy polyethylene glycol-branched polyethyleneimine-poly(2-ethylbutyl phospholane) (mPEG-bPEI-PEBP) was synthesized via click reaction as the carrier with cationic PEI, capable of delivering the CAR and packaging plasmids to co-transfect Jurkat cells and undergo expression. The PEBP and mPEG parts of the co-polymer provide hydrophobic and hydrophilic interfaces and lead to the co-polymer self-assembly into micelles in water and encapsulation of the DNA plasmids. The mPEG-bPEI-PEBP-DNA composites with different N/P ratios were incubated with the CD19 overexpression K562 cells to identify the CAR functions. The obtained CAR-Jurkat cells had the ability to secrete interferon-γ and interleukin-2. The cytotoxic effects to CD19-K562 cells suggest that the induced CAR-Jurkat cells have an excellent targeted antitumor activity.
Highlights
Traditional radiotherapy and chemotherapy, the main modalities of cancer treatment, have numerous limitations including toxicity and lack of speci c targeting
The mPEG-branched polyethyleneimine (bPEI)-PEBP-DNA composites with different N/P ratios were incubated with the CD19 overexpression K562 cells to identify the chimeric antigen receptor (CAR) functions
Alkyne-terminated PEBP was synthesized via ring-opening polymerization (ROP), a reaction extensively used to synthesize various biocompatible and degradable polymers including polyesters, polypeptides and polyphosphoesters.[30,31,32]
Summary
Traditional radiotherapy and chemotherapy, the main modalities of cancer treatment, have numerous limitations including toxicity and lack of speci c targeting. Various modi cations of tumor immunotherapy have been developed in recent years following discovery of the underlying immune mechanisms.[1] Among them, chimeric antigen receptor (CAR) T cell therapy has acquired considerable attention. CAR-T cells express surface chimeric receptors that can be used for tumor-speci c targeting, and act as immune activators and stimulators of T cells. A er reinfusion in vivo, CAR-T cells are capable of ampli cation, establishing immune memory and providing. The polyethyleneimine (PEI) polymer is rich in amine groups and displays a high cationic charge density, which allows ionic interactions with the phosphate backbone of DNA.[17] The PEIDNA complex can pass through the cell membrane anionic charge to deliver loaded DNA into the cell where it can perform its biological functions.[18,19,20,21,22,23] We have demonstrated previously that the cytotoxicity and side effects of branched polyethyleneimine (bPEI) can be decreased by wrapping the
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