A brain glioma gene delivery strategy by angiopep-2 and TAT-modified magnetic lipid-polymer hybrid nanoparticles

Qiao, Liang; Qin, Yu; Wang, Yaxin; Liang, Yi; Zhu, Dunwan; Xiong, Wei; Li, Lü; Bao, Di; Zhang, Linhua; Jin, Xiaona

doi:10.1039/d0ra07161g

Cited by 10 publications

(6 citation statements)

References 57 publications

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“…The cells were cultured on the apical side in the Transwell plate (Figure S5A), and TEER measurements were used to monitor the formation of a tight monolayer over 8–10 days, as shown in Figure A. A TEER reading of 50–60 Ω·cm 2 was considered an acceptable value to proceed with the permeability studies around day 8, which is also consistent with previous reports of TEER values in the range of 30–130 Ω·cm 2 . ,− Figure B shows the transport ratio of the different samples across the formed BBB-mimicking cell monolayers over 24 h. Cubosomes presented a gradual transport and accumulation pattern in the basolateral compartment over time, reaching ∼14 and ∼24% at 24 h for NP and Ang2-NP, respectively. The Ang2 conjugation can increase the penetration of the nanoparticles by up to 10% compared with that of unconjugated NPs.…”

Section: Resultssupporting

confidence: 83%

“…TEER values of 30–130 Ω·cm 2 for the hCMEC/D3 monolayer are considered an acceptable range to pursue the permeability experiments. ,− The cells were treated with 25 μg/mL Cyanine 5.5-labeled cubosomes in 500 μL of cell media. At different time points (0, 0.5, 1, 2, 4, 6, and 24 h), 100 μL samples were collected from the basolateral acceptor compartment with the help of fresh cell culture media.…”

Section: Methodsmentioning

confidence: 99%

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Angiopep-2-Functionalized Lipid Cubosomes for Blood–Brain Barrier Crossing and Glioblastoma Treatment

Cai,

Refaat,

Gan

et al. 2024

ACS Appl. Mater. Interfaces

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Glioblastoma multiforme (GBM) is an aggressive brain cancer with high malignancy and resistance to conventional treatments, resulting in a bleak prognosis. Nanoparticles offer a way to cross the blood–brain barrier (BBB) and deliver precise therapies to tumor sites with reduced side effects. In this study, we developed angiopep-2 (Ang2)-functionalized lipid cubosomes loaded with cisplatin (CDDP) and temozolomide (TMZ) for crossing the BBB and providing targeted glioblastoma therapy. Developed lipid cubosomes showed a particle size of around 300 nm and possessed an internal ordered inverse primitive cubic phase, a high conjugation efficiency of Ang2 to the particle surface, and an encapsulation efficiency of more than 70% of CDDP and TMZ. In vitro models, including BBB hCMEC/D3 cell tight monolayer, 3D BBB cell spheroid, and microfluidic BBB/GBM-on-a-chip models with cocultured BBB and glioblastoma cells, were employed to study the efficiency of the developed cubosomes to cross the BBB and showed that Ang2-functionalized cubosomes can penetrate the BBB more effectively. Furthermore, Ang2-functionalized cubosomes showed significantly higher uptake by U87 glioblastoma cells, with a 3-fold increase observed in the BBB/GBM-on-a-chip model as compared to that of the bare cubosomes. Additionally, the in vivo biodistribution showed that Ang2 modification could significantly enhance the brain accumulation of cubosomes in comparison to that of non-functionalized particles. Moreover, CDDP-loaded Ang2-functionalized cubosomes presented an enhanced toxic effect on U87 spheroids. These findings suggest that the developed Ang2-cubosomes are prospective for improved BBB crossing and enhanced delivery of therapeutics to glioblastoma and are worth pursuing further as a potential application of nanomedicine for GBM treatment.

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Section: Resultssupporting

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Angiopep-2-Functionalized Lipid Cubosomes for Blood–Brain Barrier Crossing and Glioblastoma Treatment

Cai,

Refaat,

Gan

et al. 2024

ACS Appl. Mater. Interfaces

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show abstract

“…It should also be noted that the TEER value was unchanged after different treatments (Figure 2e), further verifying the biocompatibility of the nanosystems. [ 52 ] We also explored the potential influence of protein corona (Figure S5a, Supporting Information). RDMR adsorbed ≈70 µg proteins per mg NPs, which was significantly higher than that of RDM (Figure S5b, c, Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Brain‐Penetration and Neuron‐Targeting DNA Nanoflowers Co‐Delivering miR‐124 and Rutin for Synergistic Therapy of Alzheimer's Disease

Ouyang

Zhu

et al. 2022

Small

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tau hyperphosphorylation, mitochondrial dysfunction and oxidative stress, and neuroinflammatory response. [3] Among them, the amyloid theory that focuses on excessive deposition of β-amyloid (Aβ) has been extensively studied with wide acceptance. [4] In this theory, imbalance of Aβ metabolism and catabolism in the central nervous system (CNS) has been regarded as the main reason for AD-like pathology. [5] Aβ is the product of a proteolytic process of a transmembrane protein, amyloid precursor protein (APP), by β-secretase 1 (BACE1, β-site APP cleavage enzyme 1) and the γ-secretase. [6] The overgeneration and abnormal aggregation of Aβ 1-42 can cause the collapse of dendritic spines and neuronal loss, induce oxidative stress, and promote inflammatory by activating microglia, which in turn exacerbates the pathogenesis of AD. [7] Several strategies focus on blocking Aβ aggregation and alleviating Aβ-mediated neurotoxicity have been developed, including aggregation inhibition, copper chelation, Aβ photo-oxidation, fibril thermal dissociation, and Aβ degradation. [8] However, many Aβ targeting pharmacological treatments failed to slow down genitive decline or improve global functioning in phase 3 clinical trials although with definite efficacy at animal model. [9] Besides the pathological discrepancy between real clinical patient and AD animal model, [10] another important reason is that AD is a multifactorial disease and therapy targeting Aβ alone is far more enough. [11] Despite significant Alzheimer disease (AD) is the leading cause of dementia that affects millions of old people. Despite significant advances in the understanding of AD pathobiology, no disease modifying treatment is available. MicroRNA-124 (miR-124) is the most abundant miRNA in the normal brain with great potency to ameliorate AD-like pathology, while it is deficient in AD brain. Herein, the authors develop a DNA nanoflowers (DFs)-based delivery system to realize exogenous supplementation of miR-124 for AD therapy. The DFs with well-controlled size and morphology are prepared, and a miR-124 chimera is attached via hybridization. The DFs are further modified with RVG29 peptide to simultaneously realize brain-blood barrier (BBB) penetration and neuron targeting. Meanwhile, Rutin, a small molecular ancillary drug, is co-loaded into the DFs structure via its intercalation into the double stranded DNA region. Interestingly, Rutin could synergize miR-124 to suppress the expression of both BACE1 and APP, thus achieving a robust inhibition of amyloid β generation. The nanosystem could pro-long miR-124 circulation in vivo, promote its BBB penetration and neuron targeting, resulting in a significant increase of miR-124 in the hippocampus of APP/PS1 mice and robust therapeutic efficacy in vivo. Such a bio-derived therapeutic system shows promise as a biocompatible nanomedicine for AD therapy.

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“…Pharmacodynamic data revealed that rats in the group with five injections of targeted DNA-bound NPs improved in locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups [117]. In a proof of principle study, Angiopep-2 and TAT dual modified magnetic lipid-polymer hybrid NPs delivered a reporter gene effectively in C6 cells in a magnetic field [76]. Angiopep-2 NPs have been applied to the delivery of siRNA against genes involved in brain cancer progression and survival.…”

Section: Nucleic Acid Deliverymentioning

confidence: 98%

“…Hence, brain-targeted magnetic NPs are comprised of hybrid materials. These include Angiopep-2 decorated iron gold alloy NPs [75] and magnetic lipid-polymer hybrid NPs [76]. Of great interest is the possibility of utilizing an external magnetic field to promote deposition of the NP at the desired locality and, in this way, modulating the release of the therapeutics [74].…”

Section: Angiopep-2-decorated Nanoparticlesmentioning

confidence: 99%

Angiopep-2-Modified Nanoparticles for Brain-Directed Delivery of Therapeutics: A Review

Habib

Singh

2022

Polymers

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Nanotechnology has opened up a world of possibilities for the treatment of brain disorders. Nanosystems can be designed to encapsulate, carry, and deliver a variety of therapeutic agents, including drugs and nucleic acids. Nanoparticles may also be formulated to contain photosensitizers or, on their own, serve as photothermal conversion agents for phototherapy. Furthermore, nano-delivery agents can enhance the efficacy of contrast agents for improved brain imaging and diagnostics. However, effective nano-delivery to the brain is seriously hampered by the formidable blood–brain barrier (BBB). Advances in understanding natural transport routes across the BBB have led to receptor-mediated transcytosis being exploited as a possible means of nanoparticle uptake. In this regard, the oligopeptide Angiopep-2, which has high BBB transcytosis capacity, has been utilized as a targeting ligand. Various organic and inorganic nanostructures have been functionalized with Angiopep-2 to direct therapeutic and diagnostic agents to the brain. Not only have these shown great promise in the treatment and diagnosis of brain cancer but they have also been investigated for the treatment of brain injury, stroke, epilepsy, Parkinson’s disease, and Alzheimer’s disease. This review focuses on studies conducted from 2010 to 2021 with Angiopep-2-modified nanoparticles aimed at the treatment and diagnosis of brain disorders.

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A brain glioma gene delivery strategy by angiopep-2 and TAT-modified magnetic lipid-polymer hybrid nanoparticles

Abstract: The gene delivery system can penetrate the BBB model efficiently and transfect C6 glioma cells effectively in magnetic field.

Cited by 10 publications

References 57 publications

Angiopep-2-Functionalized Lipid Cubosomes for Blood–Brain Barrier Crossing and Glioblastoma Treatment

Angiopep-2-Functionalized Lipid Cubosomes for Blood–Brain Barrier Crossing and Glioblastoma Treatment

Brain‐Penetration and Neuron‐Targeting DNA Nanoflowers Co‐Delivering miR‐124 and Rutin for Synergistic Therapy of Alzheimer's Disease

Angiopep-2-Modified Nanoparticles for Brain-Directed Delivery of Therapeutics: A Review

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