Peptide Science
·
2023
·
IF 2.4
Qianyu Zhang,Hongjing Chen,Huali Chen
PASylation has been recently reported as a feasible alternative to PEGylation, which in essence is using polypeptides constituted of a combination of proline, alanine and serine for the hydrophilic modification of pharmaceuticals. In this work, we focused on the biocompatibility evaluation of two PAS peptides, (PAS) 8 and (PA 3 ) 7 as well as the more frequently used polymers polyethylene glycol (PEG) and polyglycerol (PG). It has been verified in this study that (PAS) 8 and (PA 3 ) 7 both exhibited low cell toxicity against HUVEC and RAW 264.7 cell lines. They also showed negligible RBC hemolysis and agglutination, which demonstrated adequate hemocompatibility. Their potential interactions with bovine serum albumin have also been investigated, and the results indicated little hydrophobic interactions between the polymers and protein. In conclusion, (PAS) 8 and (PA 3 ) 7 as well as PEG and PG all showed considerable compatibility and safety in these studies, suggesting that (PAS) 8 and (PA 3 ) 7 could be considered as potential candidates for PEG replacement in future studies. Graphical
研究领域:
药学
·
生物医学工程
·
材料科学
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产品关联
DOI
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 9
·3898-3905
·
IF 5.251
Yu Zhang,Pan He,Xinming Liu,Huailin Yang,Hongyu Zhang,Chunsheng Xiao,Xuesi Chen
To target a response to a high oxidative stress environment of inflammatory or tumor sites, various reactive oxygen species (ROS) sensitive polymers have been developed as drug delivery systems. In this study, a novel oxidation sensitive copolymer, phenylboronic acid pinacol ester-functionalized methoxyl poly(ethylene glycol)-block-poly(phthalic anhydride-alter-glycidyl propargyl ether) (mPEG-b-P(PA-alt-GPBAe)), was designed and synthesized by ring-opening alternating copolymerization (ROAP) and click reaction. The copolymers could self-assemble into micelles in aqueous solution with an average size of 20.3 ± 9.3 nm, and are able to load hydrophobic anticancer drug (doxorubicin, DOX) with a high encapsulation efficiency of 75.2%. Interestingly, the encapsulated drug showed accelerated release in the trigger of H2O2, or at low pH values. The copolymers have low cytotoxicity indicated by the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay towards 4T1 cells, which showed cell viabilities of more than 80% with treatment of our copolymers at concentrations up to 0.5 mg mL−1. The effective uptake of the drug-loaded micelles by 4T1 cells was investigated by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) analysis. Finally, compared with free DOX, the DOX-loaded nanoparticles exhibited a better antitumor effect and had lower systemic toxicity in 4T1 tumor-bearing mice. Therefore, this new kind of copolymer acting as a stimuli-responsive nanocarrier should represent a promising therapeutic platform for cancer therapy.
研究领域:
生物材料
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药剂学
·
肿瘤学
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2014
·Vol. 3
·期 8
·1507-1517
·
IF 0
Xiaojun Cai,Yongyong Li,Dong Yue,Qiangying Yi,Shuo Li,Donglu Shi,Zhongwu Gu
Gene carriers made from polylysine are of interest in relation to gene therapy but suffer from the lack of transfection efficiency due to limited stability and endosomal escape ability. To address this problem, we designed and developed Schiff-base linked imidazole modified polylysine with a reversible-PEGylation catiomer (SL-ImPEG-SS-PLL) for high efficiency gene delivery. The reversible PEGylation was introduced for in vivo circulation, as well as selective PEG detachment to augment the cellular internalization, while introducing Schiff-base linked imidazole residues into polylysine was expected to accelerate the endosomal escape of the DNA payload, as well as facilitate intracellular DNA unpacking and release, thus significantly enhancing gene delivery efficiency. The size alteration of the SL-I15mPEG-SS-PLL/pDNA polyplexes in the presence of 10 mM GSH suggests stimulus-induced PEG detachment under tumor relevant reduction conditions. Acid–base titration assays indicate that imidazole residues confer on polylysine remarkable buffering ability. The agarose gel retardation assay suggests that the Schiff-base linkages provide an increased DNA binding ability to protect DNA against nucleases and timely intracellular DNA unpacking to permit DNA dissociation from polylysine and access to transcriptional machinery. Biological efficacy assessment of this multifunctional carrier, using pEGFP and pGL-3 as reporter genes, indicates comparable to or even higher transfection efficiencies than gold standard PEI and their transfection efficiencies are slightly affected by serum. More importantly, in vivo transfection of pEGFP reveals that GFP expression was found not only in some of the important organs, such as the liver, spleen, kidneys and lungs, but also in the transplanted carcinoma. These experimental results suggest that the reversible PEGylation and Schiff-base linked imidazole modification make SL-ImPEG-SS-PLL a great potential candidate for an effective and biocompatible gene delivery system.
研究领域:
生物技术
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基因治疗
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药学科学
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分子生物学
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产品关联
DOI
PubMed
SEPARATION AND PURIFICATION TECHNOLOGY
·
2024
·
IF 8.1
Xiujuan Zhang,Zelin Liao,Xinlu Zhang,Xuehua Ruan,Hao Gong,Xiaokun Wang,Wenji Zheng,Yan Dai,Gaohong He
Excellent hemocompatibility and long-term stability against blood wetting are important properties required for artificial lung membrane, the core component in extracorporeal membrane oxygenator which is life-saving for patients with severe lung dysfunctions. Herein, novel hydrophilic modified polyethersulfone (PES) asymmetric membranes were synthesized via thermal cross-linking, and characterization via SEM, FTIR, 1 HNMR and surface water contact angle measurements demonstrated that the modified asymmetric membranes composing a dense layer with hydrophilic surface on top of a microporous support layer were successfully fabricated without any observed defects. Among all the modified membranes, PEGylated PES membrane exhibited the smoothest membrane surface, improved mechanical property, good gas permeability and the best performance in hemocompatibility in terms of blood coagulation, protein adsorption and platelet adhesion. Moreover, the PEGylated PES membrane showed excellent long-term stability in membrane surface wettability as well as long-term stable performance against blood fouling and wetting. This research work provides valuable insights and new idea into synthesizing membranes, with simple synthesis process, long lasting high hemocompatibility and stability against wetting, for application as artificial lung membranes.
研究领域:
材料科学
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生物医学工程
·
膜技术
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产品关联
DOI
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2021
·
IF 5.268
Xiaodong Lv,Shi Wang,Yuhang Dong,Yafang Zhang,Xin Wang,Guoqing Yan,Jun Wang,Rupei Tang
To promote the highly selective synergistic chemotherapy, the pH-ultra-sensitive dynamic methotrexate nano-prodrugs with detachable PEGylation were successfully prepared via facile method, and the synergistic nanodrugs could be further constructed through encapsulating Doxorubicin (DOX) following the self-assembly process. The nano-prodrugs exhibited the low critical micelle concentration (CMC), negative zeta potential and stability for 5 days in PBS and FBS at physiological pH (7.4) for stable blood circulation, DePEGylation and dynamic size change at tumoral extracellular pH (6.8) for improved tumor accumulation and cellular internalization, and efficiently synergistic drug release at tumoral intracellular pH (5.0) for enhanced tumor apoptosis and cytotoxicity. Moreover, in vivo experiment suggested that the synergistic nanodrugs could significantly improve tumor accumulation and restrain tumor growth while decreasing adverse effects. Therefore, the dynamic methotrexate nano-prodrugs with detachable PEGylation are easy to clinically transform for highly selective synergistic chemotherapy.
研究领域:
药学
·
纳米技术
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肿瘤学
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药物递送系统
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2013
·Vol. 1
·期 46
·6418-6426
·
IF 0
Wenyu Li,Peng Zhang,Kun Zheng,Qiaoling Hu,Youxiang Wang
Extracellular stability to protect DNA against nucleases and stimulus-triggered intracellular DNA release are key factors in designing non-viral gene vectors. In this study, the diselenide-linked polycation mPEG–SeSe–PEI was developed as a new type of PEG-detachable gene vector for redox-responsive gene delivery. The corresponding stable analog mPEG–PEI and the disulfide-linked polycation mPEG–SS–PEI were synthesized as controls. The results showed that all the PEGylated polycations could condense DNA into tightly packed spherical nanoparticles about 80 nm in size, which showed excellent stability under physiological conditions. The results of zeta-potential measurements, stability tests and DNA release ability assay indicated that at a GSH concentration of 0.3 mM, the diselenide bonds were more easily cleaved than disulfide bonds, which facilitated dePEGylation and DNA release. Meanwhile, it was interestingly found that mPEG–SeSe–PEI/DNA polyplexes showed higher gene expression than mPEG–SS–PEI/DNA polyplexes in both HEK293T and HepG2 cells. Confocal laser scanning microscope (CLSM) images revealed that mPEG–SeSe–PEI/DNA polyplexes showed more efficient endosomal escape ability than mPEG–SS–PEI/DNA polyplexes. Based on these results, the diselenide bonds as a novel strategy are more suitable to address the challenging problem of extracellular stability and intracellular DNA release.
研究领域:
基因递送
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聚合物化学
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分子生物学
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生物医学工程
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DOI
PubMed
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2024
·
IF 4.4
Jianbo Li,Ertai Ye,Jingwen Huang,Meng Xu,Jieke Zhang,Junrong Zhang,Huijie Cai,Jinjie Zhang
The timely suppression of inflammatory mediator production and mitigation of their effects on pancreatic acinar cells are crucial for the successful management of acute pancreatitis . To achieve effective treatment, we present a novel approach utilizing cysteine modified PEG nanoparticles for both precise accumulation at the site of pancreatitis and specific targeting of acinar cells. Methylprednisolone , a nonsteroidal anti-inflammatory drug, was tailored to enhance its circulation time in the bloodstream, preferentially accumulate in the pancreas and enhance cell uptake efficiency by acinar cells through specifically targeting L-Type amino acid transporter 1. The nanosystem significantly downregulated pro-inflammatory cytokines in plasma, resulting in the effective suppression of inflammation in acinar cells within an acute pancreatitis rat model. The utilization of the dual targeted therapy strategy holds considerable potential for the clinical management of pancreatitis.
研究领域:
药学
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纳米技术
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炎症研究
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Yufei Pan,Yuejie Zhu,Yuan Ma,Jiamei Hong,Wenting Zhao,Yujing Gao,Jing Guan,Runan Ren,Qi Zhang,Jing Yu,Zhu Guan,Zhenjun Yang
Nucleic acid drugs are attracting significant attention as prospective therapeutics. However, their efficacy is hindered by challenges in penetrating cell membranes and reaching target tissues, limiting their applications. Nucleotidyl lipids, with their specific intermolecular interactions such as H-bonding and π-π stacking, offer a promising solution as gene delivery vehicles. In this study, a novel series of nucleotide-based amphiphiles were synthesized. These lipid molecules possess the ability to self-assemble into spherical vesicles of appropriate size and zeta potential in aqueous solution. Furthermore, their complexes with oligonucleotides demonstrated favorable biocompatibility and exhibited antiproliferative effects against a broad range of cancer cells. Additionally, when combined with the cationic lipid CLD, these complexes displayed promising in vitro performance and in vivo efficacy. By incorporating DSPE-PEGylated cRGD into the formulation, targeted accumulation of siG12D in pancreatic cancer cells increased from approximately 6% to 18%, leading to effective treatment outcomes (intravenous administration, 1 mg/kg). This finding holds significant importance for the liposomal delivery of nucleic acid drugs to extrahepatic tissues.
研究领域:
药学
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癌症治疗
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纳米技术
·
分子生物学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Zhi Qu,Yan Sun
The enormous accumulation of poly(ethylene terephthalate) (PET) waste has posed a serious threat to the environment and human health, and biodegradation with PET hydrolase (PETase) can be a possible solution. Herein, we propose site-specifically modifying PETase with amphiphilic polymers to improve the enzyme performance at ambient temperature. For this purpose, we devise a computer-aided strategy to prioritize the conjugation site, and polyethylene glycol (PEG) preparations of 0.55 to 10 kDa are site-specifically conjugated to PETase. The most active conjugate PETase–PEG 5k (PETase-5K) shows an increase of melting temperature (3.88 °C) and significantly improves PET degradation performance (3.5- and 3.1-fold increases at 30 and 40 °C, respectively). Experimental investigation and molecular dynamics simulations reveal that the site-specific PEGylation increases the hydrophobic solvent-accessible surface area and the binding capability to the PET surface, thickens the hydration layer, increases the intramolecular hydrogen bonding, reduces the interactions between water and the conjugated enzyme surface, and rigidifies the enzyme structure via hydrogen bonding and hydrophobic interactions between the polymer and the enzyme, thus leading to improved enzymatic performance of PETase-5K. We further validate the versatility of the site-specific PEGylation in one of the most evolved variants of PETase, FAST-PETase, by 1.8-fold improvement in PET degradation at 30 °C. The presented computer-aided site-specific conjugation strategy has opened a new avenue to enhancing PETase performance at ambient temperature, and the contribution of PEGylation to PETase unraveled in this work laid a foundation for the rational engineering of PET hydrolases.
研究领域:
环境科学
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生物化学
·
生物技术
·
分子生物学
·
材料科学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2015
·
IF 6.723
Kai Han,Wei-Na Yin,Jin-Xuan Fan,Feng-Yi Cao,Xian-Zheng Zhang
In this report, a UV sensitive, PEGylated PFSSTKTC (Pro-Phe-Ser-Ser-Thr-Lys-Thr-Cys) peptide was modified on quartz substrate to investigate the spatial controlled differentiation of stem cells. This substrate could restrict the cell adhesion due to the steric hindrance of PEG shell. With UV irradiation, PFSSTKTC became exposed owing to the breakage of o-nitrobenzyl group with the detachment of PEG shell. The irradiation boundary on substrate was stable in the long term. The in vitro osteogenic differentiation results revealed that under the site-specific irradiation, the mesenchymal stem cells (MSCs) could specifically differentiate into osteoblast under the induction of PFSSTKTC peptide. This photoactivatable biomaterial shows great potential for region controllable and precise MSCs differentiation.
研究领域:
生物材料
·
干细胞生物学
·
组织工程
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2014
·
IF 5.9
Haiyan Zhu,Chunyan Dong,Haiqing Dong,Tianbin Ren,Xuejun Wen,Jiansheng Su,Yongyong Li
Polylysine with cleavable PEGylation and hydrophobic histidylation (mPEG-SS-Lysn-r-Hism) was designed and developed for efficient siRNA delivery and tumor therapy. mPEG-SS-Lysn-r-Hism was used to carry and deliver small interfering RNA (siRNA) for silencing endogenous vascular endothelial growth factor (VEGF) expression and inhibiting tumor growth in HepG2 tumor-bearing mice. In this gene vector, histidine(Bzl) was selected for hydrophobic histidylation for the proton sponge ability of the imidazole ring and hydrophobic benzyl group. Cleavable PEGylation was introduced for in vivo circulation as well as selective PEG detachment in response to intracellular reduction condition in order to release the genetic payload. PEG detachment induced gene release was supported by agarose gel electrophoresis retardation assay, undertaken in the intracellular relevant reduction condition. In vitro transfection evaluation of histidylated copolymers, using pEGFP as genetic model, indicated significantly higher GFP expression than unmodified counterparts, comparable to the gold standard PEI. The efficacy of hydrophobic histidylation was found to be pronounced in mesenchymal stem cells (MSCs). In vivo application of the VEGF-siRNA package by tailored mPEG-SS-Lysn-r-Hism showed distinct tumor suppression in terms of macroscopic tumor volume and molecular analysis.
研究领域:
药学
·
分子生物学
·
基因治疗
·
癌症研究
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2019
·
IF 6.638
Qi Yang,Shuo Liu,Xin Liu,Zonghua Liu,Wei Xue,Yi Zhang
As an effective and well-recognized strategy used in many delivery systems, such as polycation gene vectors , charge reversal refers to the alternation of vector surface charge from negative (in blood circulation) to positive (in the targeted tissue) in response to specific stimuli to simultaneously satisfy the requirements of biocompatibility and targeting. Although charge reversal vectors are intended to avoid interactions with blood in their application, no overall or systematic investigation has been carried out to verify the role of charge reversal in the blood compatibility. Herein, we comprehensively mapped the effects of a typical charge-reversible polycation gene vector based on pH-responsive 2,3-dimethylmaleic anhydride (DMMA)-modified polyethylenimine (PEI)/pDNA complex in terms of blood components, coagulation function, and immune response as compared to conventional PEGylated modification. The in vitro and in vivo results displayed that charge-reversal modification significantly improves the PEI/pDNA-induced abnormal effect on vascular endothelial cells, platelet activation , clotting factor activity, fibrinogen polymerization, blood coagulation process, and pro-inflammatory cytokine expression. Unexpectedly, (PEI/pDNA)-DMMA induced the cytoskeleton impairment-mediated erythrocyte morphological alternation and complement activation even more than PEI/pDNA. Further, transcriptome sequencing demonstrated that the overexpression of pro-inflammatory cytokines was correlated with vector-induced differentially expressed gene number and mediated by inflammation-related signaling pathways (MAPK, NF-κB, Toll-like receptor, and JAK-STAT) activation. By comparison, charge-reversal modification improved the hemocompatibility to a greater extent than dose PEGylation except for erythrocyte rupture. Nevertheless, it is inferior to mPEG modification in terms of immunocompatibility. These findings provide comprehensive insights to understand the molecular mechanisms of the effects of charge reversal on blood components and their function and to provide valuable information for its potential applications from laboratory to clinic. Statement of Significance The seemingly revolutionary charge reversal strategy has been believed to possess stealth character with negative charge eluding interaction with blood components during circulation. However to date, no overall or systematic investigation has been carried out to verify the role of charge-reversal on the blood/immune compatibility, which impede their development from laboratory to bedside. Therefore, we comprehensively mapped the effects of a typical charge-reversible polycationic gene vector on blood components (vascular endothelial cell, platelet, clotting factors, fibrinogen, RBCs and coagulation function) and immune response (complement and pro-inflammatory cytokines) at cellular and molecular level in comparison to PEGylation modification. These findings help to elucidate the molecular mechanisms for the effects of charge-reversal on blood components and functions, and provide valuable information for the possible application in clinical settings.
研究领域:
药学
·
生物医学工程
·
分子生物学
·
免疫学
·
血液学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）