Functionalized Macrophage Exosomes with Panobinostat and PPM1D‐siRNA for Diffuse Intrinsic Pontine Gliomas Therapy

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor cell proliferation, and inhibition of PPM1D expression in DIPG cells with PPM1D mutation effectively reduces the proliferation activity of tumor cells. Panobinostat effectively kills DIPG tumor cells, but its systemic toxicity and low blood-brain barrier (BBB) permeability limits its application.In this paper, a nano drug delivery system based on functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for targeted therapy of DIPG with PPM1D mutation is prepared. The nano drug delivery system has higher drug delivery efficiency and better therapeutic effect than free drugs. In vivo and in vitro experimental results show that the nano drug delivery system can deliver panobinostat and siRNA across the BBB and achieve a targeted killing effect of DIPG tumor cells, resulting in the prolonged survival of orthotopic DIPG mice. This study provides new ideas for the delivery of small molecule drugs and gene drugs for DIPG therapy.

Immune Exosomes Loading Self-Assembled Nanomicelles Traverse the Blood–Brain Barrier for Chemo-immunotherapy against Glioblastoma

“…Coating pure drug self-assembled NPs with endogenous membranes helps delay their circulation time in vivo and improves their targeting to the lesion site. GBM cell membranes, macrophage membranes, and EXO membranes have been used to construct excellent GBM-targeted drug delivery systems. − …”

“… Since EXO are nanovesicles mainly composed of lipids, the liver and kidney are primarily involved in the metabolism and elimination of EXO. Additionally, it can also be found in many studies of excellent brain-targeted drug delivery systems that EXO-based NPs inevitably have partial accumulation in the lung. , But these results cannot deny the contribution of EXO to help loaded drugs accumulate at the glioma site. In the follow-up studies, we will focus on developing EXO-based brain-targeted nanodrug delivery systems that can further avoid nonspecific accumulation.…”

Nucleic acid drug vectors for diagnosis and treatment of brain diseases

“…Liang et al combined exosomes with PNPs. 565 They encapsulated siRNA in DSPE-PEG-PEI to form PNPs. DSPE-PEG-cRGD was inserted into the exosome membrane by hydrophobic interaction.…”

Radiovesicolomics-new approach in medical imaging

“…To deliver drugs to brain tumors, peptide-modified EVs need to be generated to pass the BBB and targeted glioma. The best results are observed for a peptide targeting low-density lipoprotein receptor-related protein-1 (LRP1), which mediates the transcytosis across the BBB, such as Angiopep-2 peptide or the integrin family protein - leukocyte function associated antigen 1 (LFA-1) ( Shan et al, 2022 ; Zhu et al, 2022 ). The other strategy may apply tumor derived EVs as a potential glioma vaccination due to their ability to display tumor antigens that can activate DCs, which can then activate CD8 + T cells having antitumor potential ( Fernández-Delgado et al, 2020 ).…”