Optimization of a siRNA Carrier Modified with a pH-Sensitive Cationic Lipid and a Cyclic RGD Peptide for Efficiently Targeting Tumor Endothelial Cells

Hada, Tomoya; Sakurai, Yasuhisa; Harashima, Hideyoshi

doi:10.3390/pharmaceutics7030320

Cited by 23 publications

(20 citation statements)

References 21 publications

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“…54 Therefore, cRGD cyclic peptides, that have the sequence: cyclo (Arg-Gly-Asp-D-Phe-Cys), were used to modify hybrid phospholipids membrane aer coating ADG cores to achieve long-circulation prole and tumor targeting. 55 First, the RGD specically acts on the surface of the tumor cells or the surface of the a v b 3 integrin receptor on the tumor vascular endothelial cells. 56 Then the cell surface specic proteolytic enzyme cleaves the cRGD peptide to form an activated CendR peptide which can specically recognizes and activates the neuropilin-1 receptor on the cell surface and can therefore achieve targeted delivery through the cell membrane.…”

Section: Introductionmentioning

confidence: 99%

Construction of novel multifunctional luminescent nanoparticles based on DNA bridging and their inhibitory effect on tumor growth

Pan

Zhang

et al. 2019

RSC Adv.

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Section: Introductionmentioning

confidence: 99%

Construction of novel multifunctional luminescent nanoparticles based on DNA bridging and their inhibitory effect on tumor growth

Pan

Zhang

et al. 2019

RSC Adv.

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“…We previously examined the effect of a longer PEG-linker length (over 2,000) on in vivo knockdown efficiency. However, no drastic change was observed among PEG 2,000 , PEG 3,400 and PEG 5,000 linkers (Hada et al, 2015). It is generally known that long PEG chain hinders the cellular uptake and the endosomal escape of nanocarrier due to the ability to stabilize the membrane of liposomes, so called "PEG-dilemma" (Hatakeyama et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Failure of active targeting by a cholesterol-anchored ligand and improvement by altering the lipid composition to prevent ligand desorption

Yamamoto

Sakurai

Harashima

2018

International Journal of Pharmaceutics

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Although anti-angiogenic therapy is predicted to be an effective therapy for treating cancer, selectively targeting tumor endothelial cells (TECs), and not normal endothelial cells, remains a major obstacle. Modifying a drug carrier with a targeting ligand is a popular strategy for developing an active-targeting type drug delivery system (DDS). We previously reported that a cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD)-equipped liposome that contains encapsulated siRNA (RGD-MEND) achieved an efficient therapeutic outcome in a murine cancer model. To develop a more efficient TEC-targeting DDS, we examined the effect of the length of the polyethylene glycol (PEG) that is used as a peptide-linker on the cholesterol-scaffold, and liposomal composition on the efficiency of delivery of siRNA to cRGD receptor αβ integrin positive cells. An RGD-MEND modified with shorter linker/no-linker, PEG350 or no-PEG, showed a higher cellular uptake in vitro. However, a shorter or no-linker RGD-cholesterol-modified MEND showed no silencing effect despite its high, in vitro silencing efficiency. To examine the possibility that the cholesterol-scaffold ligand was removed from the surface of the RGD-MEND by interactions with serum proteins, the RGD-MEND was incubated in the presence of a 50% serum solution. The cellular uptake of the cholesterol-scaffold ligand was drastically reduced by the incubation in serum. Increasing the cholesterol ratio in the lipid envelope and adding a helper lipid improved the in vivo knockdown efficiency, probably due to an enhanced ligand retention, even in in vivo conditions. The findings reported herein suggest that the lipid composition and the ligand scaffold of the MEND are major factors in successfully developing an efficient active-targeting DDS.

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“…We previously reported that the RGD-MEND had the ability to suppress mRNA and protein expression specifically in TECs (ED50: 0.75 mg siRNA/kg) [37,38].…”

Section: Introductionmentioning

confidence: 99%

Modality of tumor endothelial VEGFR2 silencing-mediated improvement in intratumoral distribution of lipid nanoparticles

Yamamoto

Kato

Sakurai

et al. 2017

Journal of Controlled Release

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The vascular endothelial growth factor (VEGF)-mediated enhancement in vascular permeability is considered to be a major factor in tumor-targeting delivery via the enhanced permeability and retention (EPR) effect. We previously reported that the silencing of the endothelial VEGF receptor (VEGFR2) by a liposomal siRNA system (RGD-MEND) resulted in an enhanced intratumoral distribution of polyethylene glycol (PEG)-modified liposomes (LPs) in a renal cell carcinoma, a type of hypervascularized cancer, although the inhibition of VEGF signaling would be expected to decrease the permeability of the tumor vasculature. We herein report that the enhancement in the intratumoral distribution of LPs by VEGFR2 inhibition was dependent on the vascular type of the tumor (stroma vessel type; SV and tumor vessel type; TV). In the case of TV-type tumors (renal cell carcinoma and hepatocellular carcinoma), inhibiting VEGFR2 improved intratumoral distribution, while no effect was found in the case of SV-type tumors (colorectal cancer). Moreover, through a comparison of the intratumoral distribution of LPs with a variety of physical properties (100nm vs 400nm, neutral vs negative vs positive), VEGFR2 inhibition was found to alter the tumor microenvironment, including heparan sulfate proteoglycans (HSPGs). In addition, the results regarding the effect of the size of nanoparticles indicated that VEGFR2 inhibition improved the penetration of nanoparticles through the vessel wall, but not via permeability, suggesting the involvement of an unknown mechanism. Our findings suggest that a combination of anti-angiogenic therapy and delivery via the EPR effect would be useful in certain cases, and that altering the tumor microenvironment by VEGFR2 blockade has a drastic effect on the intratumoral distribution of nanoparticles.

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Optimization of a siRNA Carrier Modified with a pH-Sensitive Cationic Lipid and a Cyclic RGD Peptide for Efficiently Targeting Tumor Endothelial Cells

Cited by 23 publications

References 21 publications

Construction of novel multifunctional luminescent nanoparticles based on DNA bridging and their inhibitory effect on tumor growth

Construction of novel multifunctional luminescent nanoparticles based on DNA bridging and their inhibitory effect on tumor growth

Failure of active targeting by a cholesterol-anchored ligand and improvement by altering the lipid composition to prevent ligand desorption

Modality of tumor endothelial VEGFR2 silencing-mediated improvement in intratumoral distribution of lipid nanoparticles

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