Lipid vesicles containing transferrin receptor binding peptide TfR-T12 and octa-arginine conjugate stearyl-R8 efficiently treat brain glioma along with glioma stem cells

Mu, Li-Min; Bu, Ying-Zi; Liu, Lei; Xie, Hongjun; Ju, Rui-Jun; Wu, Jia-Shuan; Zeng, Fan; Zhao, Yao; Zhang, Jingying; Lü, Wan-Liang

doi:10.1038/s41598-017-03805-7

Cited by 29 publications

(13 citation statements)

References 32 publications

(31 reference statements)

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“…A similar study was performed by Mu and collaborators. The authors developed vinblastine liposomes functionalized with a transferrin targeting molecule, the TfR-T12, to potentiate the translocation of vinblastine across the BBB and eliminate brain glioma [63]. As in the present study, the authors validated the BBB targeted lipid base nanoparticle in an in vitro model and observed a significant killing effect against the glioma cell line, further supporting the drug delivery strategy.…”

Section: Validation Of the Rg3 As A Bbb Drug Delivery Vectorsupporting

confidence: 75%

Highly Specific Blood-Brain Barrier Transmigrating Single-Domain Antibodies Selected by an In Vivo Phage Display Screening

et al. 2021

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A major bottleneck in the successful development of central nervous system (CNS) drugs is the discovery and design of molecules that can cross the blood-brain barrier (BBB). Nano-delivery strategies are a promising approach that take advantage of natural portals of entry into the brain such as monoclonal antibodies (mAbs) targeting endogenous BBB receptors. However, the main selected mAbs rely on targeting broadly expressed receptors, such as the transferrin and insulin receptors, and in selection processes that do not fully mimic the native receptor conformation, leading to mistargeting and a low fraction of the administered dose effectively reaching the brain. Thus, there is an urgent need to identify new BBB receptors and explore novel antibody selection approaches that can allow a more selective delivery into the brain. Considering that in vitro models fail to completely mimic brain structure complexity, we explored an in vivo cell immunization approach to construct a rabbit derived single-domain antibody (sdAb) library towards BBB endothelial cell receptors. The sdAb antibody library was used in an in vivo phage display screening as a functional selection of novel BBB targeting antibodies. Following three rounds of selections, next generation sequencing analysis, in vitro brain endothelial barrier (BEB) model screenings and in vivo biodistribution studies, five potential sdAbs were identified, three of which reaching >0.6% ID/g in the brain. To validate the brain drug delivery proof-of-concept, the most promising sdAb, namely RG3, was conjugated at the surface of liposomes encapsulated with a model drug, the pan-histone deacetylase inhibitor panobinostat (PAN). The translocation efficiency and activity of the conjugate liposome was determined in a dual functional in vitro BEB-glioblastoma model. The RG3 conjugated PAN liposomes enabled an efficient BEB translocation and presented a potent antitumoral activity against LN229 glioblastoma cells without influencing BEB integrity. In conclusion, our in vivo screening approach allowed the selection of highly specific nano-antibody scaffolds with promising properties for brain targeting and drug delivery.

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Section: Validation Of the Rg3 As A Bbb Drug Delivery Vectorsupporting

confidence: 75%

Highly Specific Blood-Brain Barrier Transmigrating Single-Domain Antibodies Selected by an In Vivo Phage Display Screening

et al. 2021

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“…Thus, e.g., PEGylated liposomes functionalised with two peptides with high affinities for transferrin receptors (TfRs) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR 2), respectively, showed gratifying tumor-targeting properties in a mouse orthotopic glioma model [44]. In an analogous study [45] decoration with a TfRs-targeting peptide and (optionally) octaarginine (R 8 ; a well known membrane-penetration device) also provided significant drug delivery to the brain of glioma-bearing mice, although organ selectivity was not very marked. Interestingly, the presence of the multiple positive charges of the oligo-arginine chain determined a pronounced association with mitochondria in in vitro experiments.…”

Section: Discussionmentioning

confidence: 99%

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

et al. 2017

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Background/Aims: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells. Methods: We investigated the expression of Kv1.3 in different glioma cell lines by immunocytochemistry, western blotting and electron microscopy and analyzed the effect of newly synthesized, mitochondria-targeted, Kv1.3 inhibitors on the induction of cell death in these cells. Finally, we performed in vivo studies on glioma bearing mice. Results: Here, we report that Kv1.3 is expressed in mitochondria of human and murine GL261, A172 and LN308 glioma cells. Treatment with the novel Kv1.3 inhibitors PAPTP or PCARBTP as well as with clofazimine induced massive cell death in glioma cells, while Psora-4 and PAP-1 were almost without effect. However, in vivo experiments revealed that the drugs had no effect on orthotopic brain tumors in vivo. Conclusion: These data serve as proof of principle that Kv1.3 inhibitors kills GBM cells, but drugs that act in vivo against glioblastoma must be developed to translate these findings in vivo.

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“…Another interesting paper reports on the efficacy of multifunctional vinblastine liposomes equipped with transferrin receptor binding peptide TfR-T 12 and octa-arginine conjugate stearyl-R8 that triggered necrosis, apoptosis and programmed cell death via autophagy in brain-glioma-bearing mice (Mu et al, 2017).…”

Section: Liposomes As An Alternative Strategy Against Autophagy-relatmentioning

confidence: 99%

“…Vinblastine: remote 110 −0.97 96 (Mu et al, 2017) SPC/chol/DSPE-PEG2000-TR (62:30:8 molar ratio) HCQ: remote PTX: passive 130 −25 81 84 (Chen et al, 2019) SPC/chol/DSPE-PEG2000-Fol (89.5:10:0.5 molar ratio)…”

Section: Referencementioning

confidence: 99%

The Exploitation of Liposomes in the Inhibition of Autophagy to Defeat Drug Resistance

Condello¹,

Mancini

Meschini³

2020

Front. Pharmacol.

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Autophagy is a mechanism involved in many human diseases and in cancers can have a cytotoxic/cytostatic or protective action, being in the latter case involved in multidrug resistance. Understanding which of these roles autophagy has in cancer is thus fundamental for therapeutical decisions because it permits to optimize the therapeutical approach by activating or inhibiting autophagy according to the progression of the disease. However, a serious drawback of cancer treatment is often the scarce availability of drugs and autophagy modulators at the sites of interest. In the recent years, several nanocarriers have been developed and investigated to improve the solubility, bioavailability, controlled release of therapeutics and increase their cytotoxic effect on cancer cell. Here we have reviewed only liposomes as carriers of chemotherapeutics and autophagy inhibitors because they have low toxicity and immunogenicity and they are biodegradable and versatile. In this review after the analysis of the dual role of autophagy, of the main autophagic pathways, and of the role of autophagy in multidrug resistance, we will focus on the most effective liposomal formulations, thus highlighting the great potential of these targeting systems to defeat cancer diseases.

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Lipid vesicles containing transferrin receptor binding peptide TfR-T12 and octa-arginine conjugate stearyl-R8 efficiently treat brain glioma along with glioma stem cells

Cited by 29 publications

References 32 publications

Highly Specific Blood-Brain Barrier Transmigrating Single-Domain Antibodies Selected by an In Vivo Phage Display Screening

Highly Specific Blood-Brain Barrier Transmigrating Single-Domain Antibodies Selected by an In Vivo Phage Display Screening

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells

The Exploitation of Liposomes in the Inhibition of Autophagy to Defeat Drug Resistance

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