Angiopep-2-Modified Carboxymethyl Chitosan-Based pH/Reduction Dual-Stimuli-Responsive Nanogels for Enhanced Targeting Glioblastoma

Song, Panpan; Song, Nannan; Li, Li; Wu, Minghao; Lu, Zhongxia; Zhao, Xia

doi:10.1021/acs.biomac.1c00314

Cited by 38 publications

(23 citation statements)

References 54 publications

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“…The overexpression of receptors such as low-density lipoprotein receptors (LDLRs, including LRP-1, LRP-2, and LDLR), the transferrin receptor, and integrins on BBB and GBM cells provides a unique foundation for enhanced drug delivery to GBM. − We found that apolipoprotein E peptide (ApoE, sequence: LRKLRKRLLLRKLRKRLLC), which is the tandem-repeat dimer peptide of the apolipoprotein E protein receptor-binding region, could bind to LDLRs with a high affinity and mediate marked BBB penetration and protein delivery for orthotopic GBM . Herein, we designed and explored small, smart, and LDLR-specific micelles based on the poly(ethylene glycol)- b -poly(ε-caprolactone- co -dithiolane trimethylene carbonate)-mefenamate (PEG-P(CL-DTC)-MA) copolymer to efficiently load SF (LDLR-mSF) and to improve SF therapy of GBM by enhancing BBB penetration, GBM accumulation, and cell uptake (Scheme ).…”

Section: Introductionmentioning

confidence: 99%

Small, Smart, and LDLR-Specific Micelles Augment Sorafenib Therapy of Glioblastoma

et al. 2021

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Targeted molecular therapy, for example, with sorafenib (SF) is considered as a new and potent strategy for glioblastoma (GBM) that remains hard to treat today. Several clinical trials with SF, as monotherapy or combination therapy with current treatments, have not met the clinical endpoints, likely as a result of the blood–brain barrier (BBB) and inferior GBM delivery. Here, we designed and explored small, smart, and LDLR-specific micelles to load SF (LDLR-mSF) and to improve SF therapy of GBM by enhancing BBB penetration, GBM accumulation, and cell uptake. LDLR-mSF with 2.5% ApoE peptide functionality based on poly(ethylene glycol)-poly(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate exhibited nearly quantitative SF loading, small size (24 nm), high colloidal stability, and glutathione-activated SF release. The in vitro and in vivo studies certified that LDLR-mSF greatly enhanced BBB permeability and U-87 MG cell uptake and caused 10.6- and 12.9-fold stronger anti-GBM activity and 6.0- and 2.5-fold higher GBM accumulation compared with free SF and non-LDLR mSF controls, respectively. The treatment of an orthotopic human GBM tumor model revealed that LDLR-mSF at a safe dosage of 15 mg of SF/kg significantly retarded tumor progression and improved the survival rate by inducing tumor cell apoptosis and inhibiting tumor angiogenesis. These small, smart, and LDLR-specific micelles provide a potential solution to enhance targeted molecular therapy of GBM.

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Section: Introductionmentioning

confidence: 99%

Small, Smart, and LDLR-Specific Micelles Augment Sorafenib Therapy of Glioblastoma

et al. 2021

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“…All the results indicate that drug accumulation in the Ang2-Cou-6 liposomes was the highest in the bEnd.3 cells, illustrating the enhanced targeting effect enabled by the Ang2 modification. This may be mainly related to the endocytosis mediated by the binding of Ang2 to LRP receptors on bEnd.3 cells (Song et al., 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Multifunctional icariin and tanshinone IIA co-delivery liposomes with potential application for Alzheimer’s disease

et al. 2022

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The blood–brain barrier (BBB) is a protective barrier for brain safety, but it is also a major obstacle to the delivery of drugs to the cerebral parenchyma such as the hippocampus, hindering the treatment of central nervous system diseases such as Alzheimer’s disease (AD). In this work, an anti-AD brain-targeted nanodrug delivery system by co-loading icariin (ICA) and tanshinone IIA (TSIIA) into Aniopep-2-modified long-circulating (Ang2-ICA/TSIIA) liposomes was developed. Low-density lipoprotein receptor-related protein-1 (LRP1) was a receptor overexpressed on the BBB. Angiopep-2, a specific ligand of LRP1, exhibited a high binding efficiency with LRP1. Additionally, ICA and TSIIA, drugs with neuroprotective effects are loaded into the liposomes, so that the liposomes not only have an effective BBB penetration effect, but also have a potential anti-AD effect. The prepared Ang2-ICA/TSIIA liposomes appeared narrow dispersity and good stability with a diameter of 110 nm, and a round morphology. Cell uptake observations, BBB models in vitro , and imaging analysis in vivo showed that Ang2-ICA/TSIIA liposomes not only penetrate the BBB through endocytosis, but also accumulate in N2a cells or brain tissue. The pharmacodynamic analysis in vivo demonstrated that Ang2-ICA/TSIIA liposomes could improve AD-like pathological features in APP/PS1 mice, including inhibiting neuroinflammation and oxidative stress, reducing apoptosis, protecting neurons, and improving cognitive function. Therefore, Ang2-ICA/TSIIA liposomes are considered a potentially effective therapeutic strategy for AD.

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“…207,208 Vascular endothelin-2 (Angiopep-2, ANG) peptide from the aprotinin Kunitz domain can specifically target brain cells and bind to low-density lipoprotein receptor-associated protein-1 (LRP1) to achieve targeted delivery, which is overexpressed in the BBB and glioma. [209][210][211] IRGD (CRGD-KGPDC) binds to αvβ3 integrin, which is encapsulated by neuropilin 1 (NRP 1) after its cleavage, and then enters tumour cells through endocytosis. Due to the specificity of these two receptors, iRGD can target multiple tumour cells.…”

Section: Tumour-homing Cppsmentioning

confidence: 99%

The role of cell‐penetrating peptides in potential anti‐cancer therapy

Zhou

Zou

Cheng

et al. 2022

Clinical & Translational Med

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Due to the complex physiological structure, microenvironment and multiple physiological barriers, traditional anti‐cancer drugs are severely restricted from reaching the tumour site. Cell‐penetrating peptides (CPPs) are typically made up of 5–30 amino acids, and can be utilised as molecular transporters to facilitate the passage of therapeutic drugs across physiological barriers. Up to now, CPPs have widely been used in many anti‐cancer treatment strategies, serving as an excellent potential choice for oncology treatment. However, their drawbacks, such as the lack of cell specificity, short duration of action, poor stability in vivo, compatibility problems (i.e. immunogenicity), poor therapeutic efficacy and formation of unwanted metabolites, have limited their further application in cancer treatment. The cellular uptake mechanisms of CPPs involve mainly endocytosis and direct penetration, but still remain highly controversial in academia. The CPPs‐based drug delivery strategy could be improved by clever design or chemical modifications to develop the next‐generation CPPs with enhanced cell penetration capability, stability and selectivity. In addition, some recent advances in targeted cell penetration that involve CPPs provide some new ideas to optimise CPPs.

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Angiopep-2-Modified Carboxymethyl Chitosan-Based pH/Reduction Dual-Stimuli-Responsive Nanogels for Enhanced Targeting Glioblastoma

Cited by 38 publications

References 54 publications

Small, Smart, and LDLR-Specific Micelles Augment Sorafenib Therapy of Glioblastoma

Small, Smart, and LDLR-Specific Micelles Augment Sorafenib Therapy of Glioblastoma

Multifunctional icariin and tanshinone IIA co-delivery liposomes with potential application for Alzheimer’s disease

The role of cell‐penetrating peptides in potential anti‐cancer therapy

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