Manganese Dioxide-Entrapping Dendrimers Co-Deliver Protein and Nucleotide for Magnetic Resonance Imaging-Guided Chemodynamic/Starvation/Immune Therapy of Tumors.
Yue GaoZhijun OuyangSiyan ShenHongwei YuBingyang JiaHan WangMingwu ShenXiangyang ShiPublished in: ACS nano (2023)
Development of a nanoscale drug delivery system that can simultaneously exert efficient tumor therapeutic efficacy while creating the desired antitumor immune responses is still challenging. Herein, we report the use of a manganese dioxide (MnO 2 )-entrapping dendrimer nanocarrier to codeliver glucose oxidase (GOx) and cyclic GMP-AMP (cGAMP), an agonist of the stimulator of interferon genes (STING) for improved tumor chemodynamic/starvation/immune therapy. Methoxy poly(ethylene glycol) ( m PEG)- and phenylboronic acid (PBA)-modified generation 5 (G5) poly(amidoamine) dendrimers were first synthesized and then entrapped with MnO 2 nanoparticles (NPs) to generate the hybrid MnO 2 @G5- m PEG-PBA (MGPP) NPs. The created MGPP NPs with an MnO 2 core size of 2.8 nm display efficient glutathione depletion ability, and a favorable Mn 2+ release profile under a tumor microenvironment mimetic condition to enable Fenton-like reaction and T 1 -weighted magnetic resonance (MR) imaging. We show that the MGPP-mediated GOx delivery facilitates enhanced chemodynamic/starvation therapy of cancer cells in vitro, and further codelivery of cGAMP can effectively trigger immunogenic cell death (ICD) to strongly promote the maturation of dendritic cells. In a bilateral mouse colorectal tumor model, the dendrimer delivery nanosystem elicits a potent antitumor performance with a strong abscopal effect, greatly improving the overall mouse survival rate. Importantly, the dendrimer-mediated codelivery not only allows the coordination of Mn 2+ with GOx and cGAMP for respective chemodynamic/starvation-triggered ICD and augmented STING activation to boost systemic antitumor immune responses, but also enables T 1 -weighted tumor MR imaging, potentially serving as a promising nanoplatform for enhanced antitumor therapy with desired immune responses.
Keyphrases
- immune response
- dendritic cells
- magnetic resonance
- contrast enhanced
- magnetic resonance imaging
- cell death
- drug delivery
- oxide nanoparticles
- computed tomography
- type diabetes
- photodynamic therapy
- insulin resistance
- gene expression
- mass spectrometry
- escherichia coli
- transcription factor
- nitric oxide
- mesenchymal stem cells
- genome wide
- bone marrow
- staphylococcus aureus
- cell cycle arrest
- protein kinase
- case report
- candida albicans
- single molecule
- transition metal
- glycemic control