Brain co‐delivery of first‐line chemotherapy drug and epigenetic bromodomain inhibitor for multidimensional enhanced synergistic glioblastoma therapy

Abstract

Glioblastoma (GBM) is a central nervous system tumor with poor prognosis due to the rapid development of resistance to mono chemotherapy and poor brain targeted delivery. Chemoimmunotherapy (CIT) combines chemotherapy drugs with activators of innate immunity that hold great promise for GBM synergistic therapy. Herein, we chose temozolomide, TMZ, and the epigenetic bromodomain inhibitor, OTX015, and further co‐encapsulated them within our well‐established erythrocyte membrane camouflaged nanoparticle to yield ApoE peptide decorated biomimetic nanomedicine (ABNM@TMZ/OTX). Our nanoplatform successfully addressed the limitations in brain‐targeted drug co‐delivery, and simultaneously achieved multidimensional enhanced GBM synergistic CIT. In mice bearing orthotopic GL261 GBM, treatment with ABNM@TMZ/OTX resulted in marked tumor inhibition and greatly extended survival time with little side effects. The pronounced GBM treatment efficacy can be ascribed to three key factors: (i) improved nanoparticle‐mediated GBM targeting delivery of therapeutic agents by greatly enhanced blood circulation time and blood–brain barrier penetration; (ii) inhibited cellular DNA repair and enhanced TMZ sensitivity to tumor cells; (iii) enhanced anti‐tumor immune responses by inducing immunogenic cell death and inhibiting PD‐1/PD‐L1 conjugation leading to enhanced expression of CD4+ and CD8+ T cells. The study validated a biomimetic nanomedicine to yield a potential new treatment for GBM.

Glioblastoma Multiforme Selective Nanomedicines for Improved Anti-Cancer Treatments

“…The third strategy, and the focus of this work, consists in using cell-specific ligands, which take advantage of upregulated receptors on the cell surface. Due to the variations in the biochemical identity of tumour cells, a myriad of reviews and research papers have been dedicated to the different ligands for GBM targeting, ranging from small molecules to peptides to antibodies [ 77 , 95 , 96 , 97 , 98 , 99 ]. While having so many options is beneficial, and this targeting strategy is generally more effective compared to the previous two, it is important to remember that many of these have characteristics that could still limit their use, such as poor specificity, low affinity, incapacity to internalise or activate the receptor with nano-sized cargo, saturability etc.…”

Delivering the Promise of Gene Therapy with Nanomedicines in Treating Central Nervous System Diseases

“…Most of the studies focus on developing the peptides targeting the specific receptors within the BBB and facilitating the active transportation, such as, T7 targeting TfR, [ 343 ] Angiopep‐2 targeting LDR‐1, [ 344 ] and ApoE‐derived peptides targeting LDL receptors. [ 345 , 346 ] RVG, a peptide derived from the rabit virus glycoprotein, targeting nicotinic acetylcholine receptor (nAchR), is one of the most extensively used peptides to modify various NPs for BBB penetration. [ 347 , 348 ] Besides, various strategies are being investigated to identify other potential peptides that could facilitate BBB transportation with high specificity, such as phage display, computer‐based techniques, and chemical libraries screening.…”

TfR Aptamer Enhanced Blood‐Brain Barrier Penetration of Biomimetic Nanocomplexes for Intracellular Transglutaminase 2 Imaging and Silencing in Glioma

“…[16] For example, a targeting ligand ApoE peptide which can target multiple low-density lipoprotein family receptors expressed on the BBB was introduced onto biomimetic nanoparticles for brain-targeted drug delivery. [17,18] Brain metastatic melanoma-derived B16F10 cell membrane was used to camouflage nanoparticles to cross the BBB based on its brain metastatic nature and the interaction between brain-metastatic tumor cell-surface receptor and endothelial cell adhesion molecules (including integrin, selectin, and chemokines). [19] Although these biomimetic nanocarriers enhanced BBB penetration ability to some extent, the tedious synthesis process and low brain accumulation rate still hindered their practical applications.…”