The Potential Efficacy of R8-Modified Paclitaxel-Loaded Liposomes on Pulmonary Arterial Hypertension

Yin, Yujia; Wu, Xuemei; Yang, Zhang-Ya; Zhao, Jian; Wang, Xiaoshuang; Zhang, Qianyu; Yuan, Mingqing; Xie, Liang; Liu, Hanmin; He, Qin

doi:10.1007/s11095-013-1058-8

Cited by 36 publications

(23 citation statements)

References 33 publications

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“…For example, polyethylene glycol (PEG)ylation has been extensively employed to increase the accumulation of liposomes in tumor tissues via enhanced permeability and retention (EPR) effects (i.e., passive targeting) (11). To increase the specificity of the interactions between liposomes and tumor cells, various studies have focused on the development of active tumor-targeted liposomes modified with specific ligands, including transferrin (12), folic acid (13), peptides (14)(15)(16)(17)(18) or antibodies (19)(20)(21). These modified liposomes are able to selectively recognize and bind to specific receptors overexpressed on tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Effect of integrin receptor-targeted liposomal paclitaxel for hepatocellular carcinoma targeting and therapy

et al. 2015

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Abstract. The major aim of the present study was to develop an integrin receptor-targeted liposomal paclitaxel (PTX) to enhance the targeting specificity and therapeutic effect of PTX on hepatocellular carcinoma (HCC) cells. The specific Arg-Gly-Asp (RGD) ligand was conjugated to 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 to prepare the RGD-modified liposomes (RGD-LP). Furthermore, physicochemical characteristics of RGD-LP, including particle size, ζ potential, encapsulation efficiency and in vitro PTX release, were evaluated. RGD-modified liposomes were selected as the carrier for the present study, as they exhibit good biocompatibility and are easy to modify using RGD. The cellular uptake efficacy of RGD-LP by HepG2 cells was 3.3-fold higher than that of liposomes without RGD, indicating that RGD-LP may specifically target HepG2 cells by overexpressing integrin αvβ3 receptors. The RGD modification appeared to enhance the anti-proliferative activity of LP-PTX against HepG2 cells, with the extent of anti-proliferative activity dependent on the concentration of PTX and the incubation time. Additionally, evaluation of the homing specificity and anticancer efficacy of RGD-LP on the tumor spheroids indicated that solid tumor penetration was enhanced by the modification of RGD. In agreement with these in vitro findings, in vivo investigations demonstrated that RGD-LP-PTX exhibited a greater inhibitory effect on tumor growth in HepG2-bearing mice than LP-PTX or free PTX. Thus, RGD-LPs may represent an efficient targeted PTX delivery system for the treatment of patients with HCC.

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Section: Introductionmentioning

confidence: 99%

Effect of integrin receptor-targeted liposomal paclitaxel for hepatocellular carcinoma targeting and therapy

et al. 2015

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“…The delivery system of R8-modified liposomes has shown potential as a pulmonary drug delivery system for PAH treatment (25). We modified the lung-specific delivery system using siRNA-loaded liposomes (R8-Lip-siMEG3) and found that the biodistribution of R8-Lip in the lung reached high levels in 1 h, which were maintained for 24 h. Thus, we repeated this application of R8-Lip-siMEG3 during hypoxia treatment.…”

Section: Discussionmentioning

confidence: 99%

“…To silence the expression of lncRNA-MEG3, PASMCs were transfected with the small interfering RNA To knock down the expression of lncRNA-MEG3 in pulmonary arteries (PAs), siRNA against lncRNA-MEG3 (siMEG3) was loaded with octaarginine (R8) conjugated PEG2000-Lipid (R8-Lip) to form a lung-specific delivery system (R8-Lip-siMEG3) as previously described with some modifications. (25) Briefly, octaarginine (R8) and DSPE-PEG2000-Mal (molar ratio: 1.5:1) were mixed in chloroform/methanol (v/v = 2:1) at room temperature with gentle stirring for 48 h. The mixture was evaporated under vacuum and then re-dissolved in chloroform, after discarding the insoluble material; the supernatant (DSPE-PEG2000-R8) was evaporated again under vacuum. Lipid compositions of the prepared liposomes were as follows: R8 modified liposomes (R8-LIP), SPC/Chol/DSPE-PEG2000/DSPE-PEG2000-R8 (molar ratio 59:33:3:5).…”

Section: Lncrna-meg3 Knockdown In Vivo and In Vitromentioning

confidence: 99%

Long Noncoding RNA- Maternally Expressed Gene 3 Contributes to Hypoxic Pulmonary Hypertension

Zhu

Xing

Zheng

et al. 2018

Preprint

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The expression and function of long noncoding RNAs (lncRNAs) in the development of hypoxic pulmonary hypertension, especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs) are largely unknown. Here, we characterized the expression of lncRNA-maternally expressed gene 3 (lncRNA-MEG3) was significantly increased and primarily located in the cytoplasm of PASMCs by hypoxia. LncRNA-MEG3 knockdown by lung-specific delivery of small interfering RNAs (siRNAs) significantly prevented the development of hypoxic pulmonary hypertension in vivo.Silencing of lncRNA-MEG3 by siRNAs and gapmers attenuated PASMC responses to hypoxia in vitro.Mechanically, we found that lncRNA-MEG3 acts as a molecular sponge of microRNA-328 (miR-328); upon hypoxia, lncRNA-MEG3 interacts and sequesters miR-328, leading to the upregulation of insulin-like growth factor 1 receptor (IGF1R). Additionally, higher expression of lncRNA-MEG3 and IGF1R, and lower expression of miR-328 were observed in PASMCs of iPAH patients. These data provide insight into the contribution of lncRNA-MEG3 in hypoxia pulmonary hypertension.Upregulation of lncRNA-MEG3 sequesters cytoplasmic miR-328, eventually leading to the expression of IGF1R, revealing a regulatory mechanism by lncRNAs in hypoxia-induced PASMC proliferation.

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“…A few parts of the lungs from Group M2, in which ATM expression was increased, were used for PA-SMCs isolation and culture. Rat PA-SMCs were isolated and cultured following the protocol previously described by Yin [ 17 ]. Assays were performed at passages 3-5.…”

Section: Methodsmentioning

confidence: 99%

Ataxia-Telangiectasia Mutated (ATM) Protein Signaling Participates in Development of Pulmonary Arterial Hypertension in Rats

Liu

et al. 2017

Med Sci Monit

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BackgroundPrevious studies revealed physiological and pathogenetic similarity between vascular smooth muscles cells with severe pulmonary arterial hypertension and tumors. The DNA damage response was found in both pulmonary arterial hypertension (PAH) cells and tumors. The ataxia-telangiectasia mutated proteins (ATM) pathway is considered an important factor in the DNA damage response of tumor formation, but its function in the development of PAH remains unknown.Material/MethodsThe Sprague-Dawley rat PAH model was established. Three weeks (Group M1), 5 weeks (Group M2), and 7 weeks (Group M3) after drug injection, pulmonary expression of ATM, Checkpoint kinase 2 (Chk2), P53, and P21 were measured. A section of the lungs from Group M2 was used for pulmonary artery vascular smooth muscles cells (PA-SMCs) isolation and culture. The effect of KU60019 in the proliferation and apoptosis of primary cultured rat PA-SMCs was measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and TdT-mediated dUTP nick-end labeling (TUNEL), respectively.ResultsImmunohistochemistry results show that the expression of ATM, Chk2, and P21 increased in Groups M1 and M2, and decreased in Group M3. Additionally, expression of P53 increased in Group M1, and decreased in Groups M2 and M3. RT-PCR and Western blotting demonstrated that in Groups M1 and M2, the expression of ATM, Chk2, P53, and P21 increased, whereas it decreased in Group M3. In cell culture, 0.3 μM and 0.5 μM KU60019 increased the growth of PA-SMCs, and 0.5 μM KU60019 reduced cell apoptosis.ConclusionsExpression of the ATM-Chk2 pathway increased in early stages of PAH formation, but decreased in late stages. In primary cultured PA-SMCs, KU60019 increased cell proliferation and inhibited cell apoptosis.

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The Potential Efficacy of R8-Modified Paclitaxel-Loaded Liposomes on Pulmonary Arterial Hypertension

Cited by 36 publications

References 33 publications

Effect of integrin receptor-targeted liposomal paclitaxel for hepatocellular carcinoma targeting and therapy

Effect of integrin receptor-targeted liposomal paclitaxel for hepatocellular carcinoma targeting and therapy

Long Noncoding RNA- Maternally Expressed Gene 3 Contributes to Hypoxic Pulmonary Hypertension

Ataxia-Telangiectasia Mutated (ATM) Protein Signaling Participates in Development of Pulmonary Arterial Hypertension in Rats

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