Enhanced Glioblastoma Targeting Ability of Carfilzomib Enabled by a ^DA7R-Modified Lipid Nanodisk

Abstract

The robust proliferation of tumors relies on a rich neovasculature for nutrient supplies. Therefore, a basic strategy of tumor targeting therapy should include not only killing regular cancer cells but also blocking tumor neovasculature. D-peptide A7R, which was previously reported to specifically bind vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1), could achieve the goal of multitarget recognition. Accordingly, the main purposes of this work were to establish a carfilzomib-loaded lipid nanodisk modified with multifunctional peptideA7R (A7R-ND/CFZ) and to evaluate its anti-glioblastoma efficacy in vitro and in vivo. It is testified that the A7R peptide-conjugated lipid nanodisk can be specifically taken up by U87MG cells and HUVECs. Furthermore,A7R-ND demonstrated a more enhanced penetration than that of the nonmodified formulation on the tumor spheroid model in vitro and more tumor region accumulation in vivo on the subcutaneous and intracranial tumor-bearing nude mice model. A7R-ND was shown to co-localize with tumor neovasculature in vivo. When loaded with proteasome inhibitor carfilzomib, theA7R-decorated nanodisk could remarkably suppress tumor proliferation, extend survival time of nude mice bearing an intracranial tumor, and inhibit neovasculature formation with an efficacy higher than that of the nonmodified nanodisk in vitro and in vivo. The present study verified that the heptapeptide A7R-conjugated nanodisk is a promising nanocarrier for glioblastoma targeting therapy.

Phototheranostics: Active Targeting of Orthotopic Glioma Using Biomimetic Proteolipid Nanoparticles

“…To address these limitations, different bioconjugates between poly­(ethylene glycol) (PEG) and target ligands including human H-ferritin, chlorotoxin, cyclic arginine-glycine-aspartic acid (c-RGD), and d -peptide have been developed to cross BBB and serve as active targeting theranostics. − For example, Lu et al . reported RGD-targeted hollow gold nanospheres for photoacoustic imaging and PTT of GMB .…”

STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity

“…PEGylated LND morphologies were first described in the late 1990s 41 , and a few groups have explored this type of LND for drug delivery 42 – 44 , but the tumour-penetrating capacity of these nanomaterials has not been analysed in detail in vivo. Our computational models of LND versus liposome pore penetration demonstrate that the lack of an enclosed aqueous volume makes nanodiscs amenable to dramatic deformations in response to weak forces, favouring effective convection or diffusion through ECM.…”

Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

“…Meng et al (1999) described that DHE antitumor activity, as also observed for structurally related compounds, is explained through inhibition of the proteasome function, but epoxyketonecontaining antitumor natural products may differ in their antiproliferative activity, proteasome subunit binding specificity, and rates of proteasome inhibition. Considering the intriguing structure-activity relationship for this class of compounds (Kim et al, 1999;Groll et al, 2000) and the emerging knowledge on the antiglioma effects of the proteasome inhibitors (Di et al, 2016;Zhang et al, 2018;Veggiani et al, 2019), we further assayed DHE and BRA-346 epoxyketone-containing fraction in glioma cells HOG and T98G, revealing their potent antiproliferative effects in the ng/mL-range and the modulation of ER-stress related and pro-apoptotic related genes, along with unfolded protein response and the ubiquitin-proteasome system itself.…”