Novel brain-targeted nanomicelles for anti-glioma therapy mediated by the ApoE-enriched protein corona in vivo

Abstract

Background The interactions between nanoparticles (NPs) and plasma proteins form a protein corona around NPs after entering the biological environment, which provides new biological properties to NPs and mediates their interactions with cells and biological barriers. Given the inevitable interactions, we regard nanoparticle‒protein interactions as a tool for designing protein corona-mediated drug delivery systems. Herein, we demonstrate the successful application of protein corona-mediated brain-targeted nanomicelles in the treatment of glioma, loading them with paclitaxel (PTX), and decorating them with amyloid β-protein (Aβ)-CN peptide (PTX/Aβ-CN-PMs). Aβ-CN peptide, like the Aβ1–42 peptide, specifically binds to the lipid-binding domain of apolipoprotein E (ApoE) in vivo to form the ApoE-enriched protein corona surrounding Aβ-CN-PMs (ApoE/PTX/Aβ-CN-PMs). The receptor-binding domain of the ApoE then combines with low-density lipoprotein receptor (LDLr) and LDLr-related protein 1 receptor (LRP1r) expressed in the blood–brain barrier and glioma, effectively mediating brain-targeted delivery. Methods PTX/Aβ-CN-PMs were prepared using a film hydration method with sonication, which was simple and feasible. The specific formation of the ApoE-enriched protein corona around nanoparticles was characterized by Western blotting analysis and LC–MS/MS. The in vitro physicochemical properties and in vivo anti-glioma effects of PTX/Aβ-CN-PMs were also well studied. Results The average size and zeta potential of PTX/Aβ-CN-PMs and ApoE/PTX/Aβ-CN-PMs were 103.1 nm, 172.3 nm, 7.23 mV, and 0.715 mV, respectively. PTX was efficiently loaded into PTX/Aβ-CN-PMs, and the PTX release from rhApoE/PTX/Aβ-CN-PMs exhibited a sustained-release pattern in vitro. The formation of the ApoE-enriched protein corona significantly improved the cellular uptake of Aβ-CN-PMs on C6 cells and human umbilical vein endothelial cells (HUVECs) and enhanced permeability to the blood–brain tumor barrier in vitro. Meanwhile, PTX/Aβ-CN-PMs with ApoE-enriched protein corona had a greater ability to inhibit cell proliferation and induce cell apoptosis than taxol. Importantly, PTX/Aβ-CN-PMs exhibited better anti-glioma effects and tissue distribution profile with rapid accumulation in glioma tissues in vivo and prolonged median survival of glioma-bearing mice compared to those associated with PMs without the ApoE protein corona. Conclusions The designed PTX/Aβ-CN-PMs exhibited significantly enhanced anti-glioma efficacy. Importantly, this study provided a strategy for the rational design of a protein corona-based brain-targeted drug delivery system. More crucially, we utilized the unfavorable side of the protein corona and converted it into an advantage to achieve brain-targeted drug delivery. Graphical Abstract

Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into bone marrow-derived mouse mast cells

“…Apos can act as intrinsic docking and plasma membrane entry facilitators and are exploited by hepatitis C to enable virus entry 13 – 16 . Apos have recently been used to create thermostable lipid-like nanoparticles for delivery of RNAi 17 , miRNA 18 , siRNA 19 , and small molecule therapies 20 . These studies demonstrate that targeting of specific tissues appears to be dependent upon the type of Apo or combination of Apos that were used to coat the nanoparticles.…”

Harnessing Protein Corona for Biomimetic Nanomedicine Design

“…Zhe-Ao Zhang et al also designed a biomimetic peptide-modified NP system for brain target delivery by controlling the composition of protein corona [ 92 ]. The biomimetic peptide used in this study was the 11-amino acid fragment amyloid β-protein (Aβ) 25–35 (called Aβ-CN peptide), a widely used substitute for the full-length peptide Aβ 1–42 .…”

“… Biomimetic peptides modification to harness protein corona. ( A ) The Aβ-CN peptide modification will capture the ApoE in the biological fluids and form the ApoE-enriched protein corona for brain-targeting [ 92 ]. Copyright 2021, Springer Nature.…”

“…Copyright 2021, Springer Nature. ( B ) The in vivo fluorescence imaging of orthotopic glioma-bearing mice treated with saline, DiR/PMs, and DiR/Aβ-CN-PMs at different time points [ 92 ]. Copyright 2021, Springer Nature.…”

Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into terminally differentiated bone marrow-derived mouse mast cells

“…Apos can act as intrinsic docking and plasma membrane entry facilitators and are exploited by hepatitis C to enable virus entry [13][14][15][16]. Apos have recently been used to create thermostable lipid-like nanoparticles for delivery of RNAi [17], miRNA [18], siRNA [19], and small molecule therapies [20]. These studies demonstrate that targeting of speci c tissues appears to be dependent upon the type of Apo or combination of Apos that were used to coat the nanoparticles.…”