Recombinant expressing angiopep-2 fused anti-VEGF single chain Fab (scFab) could cross blood–brain barrier and target glioma

Ji, Xuemei; Wang, Hongyan; Chen, Yue; Zhou, Junfei; Lan, Yu

doi:10.1186/s13568-019-0869-3

Cited by 19 publications

(15 citation statements)

References 29 publications

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“…LRP1, a transport receptor involved in various cellular processes at the BBB, including lipid and lipoprotein metabolism and protease degradation (30), has been shown to be upregulated in GBMs and their surrounding vasculature (31). As a result, there is interest in the design of therapeutics employing LRP1-mediated transport to cross the BBB and specifically target GBM (32)(33)(34). We investigated LRP1 expression in the BBB-GBM model and found that the presence of GBM spheroids increases LRP1 expression in vessels both near and far from the spheroid, compared to control devices without tumor (Fig.…”

Section: A Vascularized Glioblastoma Model For the Quantification Of Vascular Permeabilitymentioning

confidence: 99%

A predictive microfluidic model of human glioblastoma to assess trafficking of blood-brain barrier penetrant nanoparticles

Straehla

Hajal

Safford

et al. 2021

Preprint

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The blood-brain barrier represents a significant challenge for the treatment of high-grade gliomas, and our understanding of drug transport across this critical biointerface remains limited. To advance preclinical therapeutic development for gliomas, there is an urgent need for predictive in vitro models with realistic blood-brain barrier vasculature. Here, we report a vascularized human glioblastoma (GBM) model in a microfluidic device that accurately recapitulates brain tumor vasculature with self-assembled endothelial cells, astrocytes, and pericytes to investigate the transport of targeted nanotherapeutics across the blood-brain barrier and into GBM cells. Using modular layer-by-layer assembly, we functionalized the surface of nanoparticles with GBM-targeting motifs to improve trafficking to tumors. We directly compared nanoparticle transport in our in vitro platform with transport across mouse brain capillaries using intravital imaging, validating the ability of the platform to model in vivo blood-brain barrier transport. We investigated the therapeutic potential of functionalized nanoparticles by encapsulating cisplatin and showed improved efficacy of these GBM-targeted nanoparticles both in vitro and in an in vivo orthotopic xenograft model. Our vascularized GBM model represents a significant biomaterials advance, enabling in-depth investigation of brain tumor vasculature and accelerating the development of targeted nanotherapeutics.

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Section: A Vascularized Glioblastoma Model For the Quantification Of Vascular Permeabilitymentioning

confidence: 99%

A predictive microfluidic model of human glioblastoma to assess trafficking of blood-brain barrier penetrant nanoparticles

Straehla

Hajal

Safford

et al. 2021

Preprint

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“…We also demonstrated that ANG2 was active within fusion proteins regardless of whether it was fused to the N-or C-terminus of the protein. Whilst other studies of ANG2 use C-terminal labelling, our data suggest this is not an absolute requirement for ANG2 function [36,37]. Our transport assays were performed using b.End3 cells grown on a transwell insert.…”

Section: Discussionmentioning

confidence: 87%

“…As an additional control, we generated scTRAIL-ANG2, a single ANG2 fused to the C-terminus of scTRAIL interspaced with a glycine-serine linker (G 2 SG 2 ) 2 (Figure 1(Biii,Ciii)). Notably, we created our TRAIL-ANG2 fusion proteins (Figure 1(Biii,Ciii)) with ANG2 on the C-terminus in accordance with previous studies [36,37]. To determine if C-terminal fusion was only a convention or serves functional purposes, we created two separate ANG2-positive control proteins by fusing ANG2 to the C-or N-terminal end of an Fcγ receptor binding (FcγR)-deficient mutant Fc (Fc ∆ab ) [38], interspaced with a glycine-serine linker (G 4 S) 2 (Figure 1(Biv,v,Civ,v)).…”

Section: Design Production and Purification Of A Cns-targeted Hexavalent Trail-receptor Agonistmentioning

confidence: 90%

Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma

et al. 2021

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Glioblastoma (GBM) is the most malignant and aggressive form of glioma and is associated with a poor survival rate. Latest generation Tumour Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL)-based therapeutics potently induce apoptosis in cancer cells, including GBM cells, by binding to death receptors. However, the blood–brain barrier (BBB) is a major obstacle for these biologics to enter the central nervous system (CNS). We therefore investigated if antibody-based fusion proteins that combine hexavalent TRAIL and angiopep-2 (ANG2) moieties can be developed, with ANG2 promoting receptor-mediated transcytosis (RMT) across the BBB. We demonstrate that these fusion proteins retain the potent apoptosis induction of hexavalent TRAIL-receptor agonists. Importantly, blood–brain barrier cells instead remained highly resistant to this fusion protein. Binding studies indicated that ANG2 is active in these constructs but that TRAIL-ANG2 fusion proteins bind preferentially to BBB endothelial cells via the TRAIL moiety. Consequently, transport studies indicated that TRAIL-ANG2 fusion proteins can, in principle, be shuttled across BBB endothelial cells, but that low TRAIL receptor expression on BBB endothelial cells interferes with efficient transport. Our work therefore demonstrates that TRAIL-ANG2 fusion proteins remain highly potent in inducing apoptosis, but that therapeutic avenues will require combinatorial strategies, such as TRAIL-R masking, to achieve effective CNS transport.

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“…For a brain-targeted drug delivery system, one of the promising options is homing peptides combined with receptor-mediated transcytosis [ 73 ]. Derived from the Kunitz domains of aprotinin, Angiopep-2 (ANG) is a 19-aa oligopeptide that can bind to low-density lipoprotein receptor-related protein-1 (LRP1) and penetrate through the BBB [ 74 ]. Recently, Srimanee et al modified PF14 and PF28 by applying both covalent conjugation and non-covalent complex formation to achieve more selective targeting of glioma along with an enhanced gene-silencing efficacy.…”

Section: Delivery Of Nucleic Acidsmentioning

confidence: 99%

Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade

et al. 2021

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Cell-penetrating peptides (CPPs), also known as protein transduction domains, are a class of diverse amino acid sequences with the ability to cross cellular membranes. CPPs can deliver several bioactive cargos, including proteins, peptides, nucleic acids and chemotherapeutics, into cells. Ever since their discovery, synthetic and natural CPPs have been utilized in therapeutics delivery, gene editing and cell imaging in fundamental research and clinical experiments. Over the years, CPPs have gained significant attention due to their low cytotoxicity and high transduction efficacy. In the last decade, multiple investigations demonstrated the potential of CPPs as carriers for the delivery of therapeutics to treat various types of cancer. Besides their remarkable efficacy owing to fast and efficient delivery, a crucial benefit of CPP-based cancer treatments is delivering anticancer agents selectively, rather than mediating toxicities toward normal tissues. To obtain a higher therapeutic index and to improve cell and tissue selectivity, CPP-cargo constructions can also be complexed with other agents such as nanocarriers and liposomes to obtain encouraging outcomes. This review summarizes various types of CPPs conjugated to anticancer cargos. Furthermore, we present a brief history of CPP utilization as delivery systems for anticancer agents in the last decade and evaluate several reports on the applications of CPPs in basic research and preclinical studies.

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Recombinant expressing angiopep-2 fused anti-VEGF single chain Fab (scFab) could cross blood–brain barrier and target glioma

Cited by 19 publications

References 29 publications

A predictive microfluidic model of human glioblastoma to assess trafficking of blood-brain barrier penetrant nanoparticles

A predictive microfluidic model of human glioblastoma to assess trafficking of blood-brain barrier penetrant nanoparticles

Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma

Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade

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