Introduction: Gboxin suppresses the growth of glioblastoma (GBM) cells by inhibiting a stage of respiration (oxidative phosphorylation) that occurs in mitochondria . And its anti-GBM effect is seriously limited by poor blood circulation, the blood brain barrier (BBB) and non-specific GBM tissue uptake, leading to insufficient Gboxin accumulation at GBM sites. we have found there is a delivery system that helps transport Gboxin to the target mitochondria using a membrane containing both cancer cell and mitochondrial membrane features. Using this delivery method. We present a biomimetic nanomedicine ( HM-NPs@G ) by coating cancer cell-mitochondria hybrid membrane ( HM ) on the surface of Gboxin-loaded nanoparticles. The HM camouflaging endows HM-NPs@G with unique features including good biocompatibility, improved pharmacokinetic profile, efficient BBB permeability and homotypic dual tumour cell and mitochondria targeting. Finally we achieved potent GBM tumour inhibition in vitro and in vivo leading to prolonged median survival time in mouse models.
Methods: Here we present a cancer cell-mitochondria hybrid membrane camouflaged reactive oxygen species (ROS)-responsive nanoparticle loaded with Gboxin (HM-NPs@G) to achieve targeting delivery of Gboxin in GBM mitochondria in non-invasive manner. The HM-NPs@G retain characteristic capabilities derived from each individual membrane type. The outer shell of the HM-NPs@G include multiple “self-marker” proteins embedded in both membranes which should improve the short blood circulation of Gboxin, leading to evasion of immune system clearance. And thre is a fact that mitochondria generate approximately 90% of intracellular ROS and that cancer cells have higher ROS levels than metabolically ‘quieter’ normal cells to leverage fast, at-site and Gboxin release using a ROS-responsive polymer. The accelerated release of Gboxin interrupts the functioning of ATP synthase at the mitochondria inner membrane, which results in disrupted electron transport and energy metabolism ultimately leading to mitochondria-mediated apoptosis in tumour cells.
Results: The fabrication of HM-NPs@G consists of two steps. First, the outer shell of cancer cell-mitochondria hybrid membrane (HM) was prepared using a one:one protein weight ratio of MM (mitochondria membrane) to CM (cancer membrane) as optimized and further characterized by förster resonance energy transfer (FRET). he core-shell structure of the developed HM-NPs@G was confirmed with the transmission electron microscopy (TEM) and also indicating the hybrid membrane is a single-membrane lipid bilayer which is agree with the reported results.The proteins (EpCAM and Integrin αv) which play vital roles in cancer homologous targeting were observed on U87MG cancer cell membrane (CM). Furthermore, glioblastoma stem cell (GSCs, X01) membrane CM (X01) had CD44, one of stem markers, as well as EpCAM, both of which were helpful to target homotypic cells.
Conclusion: We have found that the use of the novel therapeutic VT1021 in patients with recurrent glioblastoma (rGBM) showed durable responses by inhibiting the tumour growth via stimulation of thrombospondin-1, which altered the tumour microenvironment. And also long-term findings showed that patients with a better immune response throughout treatment had better results compared with those who did not exhibit much of an immune response. Finally after the NPs were coated with membranes we indicate successful shielding of nanoparticles by the negative outer membranes.