Pharmaceutics
·
2024
·Vol. 16
·期 1
·154
·
IF 4.9
Xueqin Gao,Dirong Dong,Chong Zhang,Yuxing Deng,Jiahui Ding,Shiqi Niu,Songwei Tan,Lili Sun
Gene therapy displays great promise in the treatment of cervical cancer. The occurrence of cervical cancer is highly related to persistent human papilloma virus (HPV) infection. The HPV oncogene can be cleaved via gene editing technology to eliminate carcinogenic elements. However, the successful application of the gene therapy method depends on effective gene delivery into the vagina. To improve mucosal penetration and adhesion ability, quaternized chitosan was introduced into the poly(β-amino ester) (PBAE) gene-delivery system in the form of quaternized chitosan-g-PBAE (QCP). At a mass ratio of PBAE:QCP of 2:1, the polymers exhibited the highest green fluorescent protein (GFP) transfection efficiency in HEK293T and ME180 cells, which was 1.1 and 5.4 times higher than that of PEI 25 kD. At this mass ratio, PBAE–QCP effectively compressed the GFP into spherical polyplex nanoparticles (PQ–GFP NPs) with a diameter of 255.5 nm. In vivo results indicated that owing to the mucopenetration and adhesion capability of quaternized CS, the GFP transfection efficiency of the PBAE–QCP hybrid system was considerably higher than those of PBAE and PEI 25 kD in the vaginal epithelial cells of Sprague–Dawley rats. Furthermore, the new system demonstrated low toxicity and good safety, laying an effective foundation for its further application in gene therapy.Keywords:gene delivery;poly(β-amino ester);chitosan;mucoadhesion
研究领域:
生物医学工程
·
基因治疗
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DOI
PubMed
高影响因子
Small Methods
·
2025
·
IF 9.1
Xinlong Liu,Yimeng Li,Xinhua Liu,Yangyang Huang,Fujun Wang,Jiafeng Li,Yuqi Guo,Xinyuan Zhu,Lijuan Zhu,Chuan Zhang
Plasmids are widely used gene vectors in gene therapy, yet their efficient delivery remains a major challenge for achieving optimal therapeutic outcomes. Recently, poly(β-amino esters) (PBAEs) have emerged as promising carriers for non-viral gene delivery due to their tunable structures and high delivery efficiency. Nonetheless, the cationic nature of PBAEs raises toxicity concerns, and their lack of tissue-specific targeting capability limits their clinical application. Herein, a novel PBAE for efficient plasmid delivery is constructed, which contains disulfide bonds in the backbone and N-acetylgalactosamine (GalNAc) moieties at the terminals (GalNAc-PBAEs). To address the potential reduction in nucleic acid condensing capacity caused by end-capping PBAE with GalNAc, the commonly used end-capping amines in conventional PBAE are employed as monomers to create GalNAc-PBAEs with tertiary amine side chains. Through side-chain screening, the optimized GalNAc-PBAE exhibits enhanced transfection efficiency, surpassing that of the conventional top-performing PBAE, C28-E7, and rivaling the commercial transfection reagent Lipo2000. Importantly, the GalNAc moieties enable the plasmid-PBAE polyplex to efficiently target the liver. In a mouse model with acute liver fibrosis, the efficient delivery and expression of a representative plasmid encoding HGF significantly mitigate liver fibrosis and improve liver function, demonstrating the potential of the designed PBAE in gene therapy.
研究领域:
生物医学工程
·
基因治疗
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
AUSTRALIAN JOURNAL OF CHEMISTRY
·
2015
·Vol. 69
·期 3
·349-356
·
IF 1.558
Yucheng Liu,Shufeng Li,Liandong Feng,Hao Yu,Xiaoliang Qi,Wei Wei,Junjian Li,Wei Dong,Yucheng Liu,Shufeng Li,Liandong Feng,Hao Yu,Xiaoliang Qi,Wei Wei,Junjian Li,Wei Dong
Poly(β-amino ester)s (PBAEs) have been proved to effectively transfer DNA to various cell types. However, PBAEs with high molecular weights also show considerable toxicities, partly resulting from inadequate degradation of their polyester backbone. In this study, we created novel poly(β-amino ester)s (SF-1, 2, 3, and 4; notation SFs refers to all the four polymers) which were characterised by the cleavable disulfide bonds. Moreover, a new technique, termed magnetofection that uses magnetic nanoparticles to enhance gene expression, has recently been well developed. The negatively charged magnetic nanoparticles (MNPs) with good biocompatibility in vitro were prepared here to subsequently combine with SFs and DNA via electrostatic interaction, leading to the formation of the magnetic gene complexes MNP/SFs/DNA. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and transfection experiments were performed in A549 cells to investigate all the resulting complexes. Studies indicated that the synthesised PBAEs exhibited good biodegradation and regulated release of DNA as a result of the reductive cleavage of the disulfide bonds, giving higher transfection efficiency along with much lower cytotoxicity compared with commercially available transfection agent polyethylenimine (Mw 25 kDa). Furthermore, when MNP was involved at a MNP/DNA weight ratio of 0.5, the magnetic gene complexes MNP/SFs/DNA showed enhanced levels of gene expression while maintaining low cytotoxicity.
研究领域:
生物材料学
·
基因治疗
·
分子生物学
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DOI
高影响因子
Polymer Chemistry
·
2013
·Vol. 4
·期 10
·3012-3019
·
IF 5.231
Haibo Wang,Fangming Xu,Yin Wang,Xiangsheng Liu,Qiao Jin,Jian Ji
The pH-triggered biodegradable micelles based on poly(β-amino ester)-graft-12-acryloyloxy dodecyl phosphorylcholine (PAE-graft-ADPC) were explored as an efficient acid-triggered anticancer drug delivery system. A pH-responsive biodegradable polymer was synthesized by using hydrophilic 12-acryloyloxy dodecyl phosphorylcholine (ADPC) and poly(β-amino ester) (PAE) via Michael addition reaction. Micelles with phosphorylcholine shells were prepared in aqueous solution and doxorubicin (DOX) was loaded into the core of the micelles with high efficiency (73%). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) demonstrated that the size of the drug-loaded micelles was about 230 nm. DOX-loaded micelles were stable in the physiological environment, whereas they disassembled at pH 6.5 which is similar to the extracellular pH of most tumors. In vitro drug release showed that DOX release from micelles was faster at pH 6.5 than at 7.4. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles at pH 6.5. Moreover, an in vitro cytotoxicity study indicated that the growth of HepG2 cells was inhibited remarkably when the cells were preincubated with DOX-loaded micelles at pH 6.5. The results indicated that the pH-triggered biodegradable micelles could serve as promising drug carriers for cancer therapy.
研究领域:
药剂学
·
肿瘤学
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产品关联
DOI
高影响因子
Arabian Journal of Chemistry
·
2023
·
IF 6
Hua Yuan,Changwei Zhang,Peng Zhou,Xiaoran Yang,Ran Tao,Jianzhong Ye,Chengzhang Wang
Lacking of substantial physiological activity and low utilization remains a problem for most conventional drug carriers. Polyprenol with beneficial medical effects and high availability could be an ideal candidate for solving this issue. Here, Ginkgo biloba leaves polyprenol (GBP)-based derivative was prepared by Michael addition reaction of poly (β-amino esters) (PBAE) with GBP and galactose (Gal). The intervention of poly (β-amino ester) and galactose promoted GBP-PBAE-Gal to depict as micellar carrier, enhancing the loading of hydrophobic DOX and the sensitivity to the specific tumor microenvironment, with the largest DOX loading of 28.62 ± 1.49 % and the efficient DOX release rate of 90.30 %. In the meantime, GBP-PBAE-Gal exhibited enhanced colloidal stability at 640-folds of dilution and in the presence of serum and realized the possibility of long-term storage at room temperature. Additionally, GBP-PBAE-Gal was safe for human red blood cells and human normal liver cells HL-7702. When applied for DOX delivery to HepG2 cells, GBP-PBAE-Gal increased the targeting of DOX to intensify its inhibition on HepG2 cells. Compared to free DOX, the DOX loaded into GBP-PBAE-Gal presented stronger anticancer activity, with IC 50 of 0.56 μg/mL at 72 h. Besides, the anticancer mechanism study revealed that GBP-PBAE-Gal arrested the cell cycle in HepG2 cells, suggesting the potential of GBP-based carrier for intensive treatment. This research evidenced the feasibility and high availability of the GBP to use as a drug carrier, providing a novel candidate for drug delivery systems.
研究领域:
药剂学
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肿瘤学
·
生物材料
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产品关联
DOI
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2016
·Vol. 40
·期 11
·9806-9812
·
IF 3.277
Zhibing Sun,Dezhong Zhou
Three oligomeric linear poly(beta-amino esters) (PAEs) were synthesized and used to improve the gene transfection efficiency and reduce the cytotoxicity of poly(L-lysine) (PLL). The synthesized PAEs can co-assemble with PLL and plasmid DNA to form PLL/PAE/DNA ternary complexes of nanoscale sizes and moderate surface charges. The existence of multiple tertiary amines on PAE backbones imparts the ternary complexes with strong proton buffering capacity and therefore enhances the endosomal escape ability of the ternary complexes. In HeLa cells, the PLL/PAE/DNA ternary complexes show up to 476-fold enhancement in gene transfection efficiency when compared with the PLL/DNA binary complexes. Meanwhile, the incorporation of PAE oligomers significantly reduced the cytotoxicity of PLL. The strategy proposed here may provide insights into the development of PLL based gene delivery systems.
研究领域:
生物化学
·
分子生物学
·
基因治疗
✓ 已验证
产品关联
DOI
高影响因子
Pharmaceutics
·
2020
·Vol. 12
·期 2
·111
·
IF 4.421
Weinan Li,Jialin Sun,Xiaoyu Zhang,Li Jia,Mingxi Qiao,Xiuli Zhao,Haiyang Hu,Dawei Chen,Yanhong Wang
PEG-poly(β-amino ester) (PEG-PBAE), which is an effective pH-responsive copolymer, was mainly synthesized by Michael step polymerization. Thioridazine (Thz), which was reported to selectively eliminate cancer stem cells (CSCs), was loaded into PEG-PBAE micelles (PPM) prepared by self-assembly at low concentrations. The critical micelle concentrations (CMC) of PPM in water were 2.49 μg/mL. The pH-responsive PBAE segment was soluble due to protonated tertiary amine groups when the pH decreased below pH 6.8, but it was insoluble at pH 7.4. The Thz-loaded PEG-PBAE micelle (Thz/PPM) exhibited a spherical shape, and the drug loading was 15.5%. In vitro release of Thz/PPM showed that this pH-sensitivity triggered the rapid release of encapsulated Thz in a weakly acidic environment. The in vitro cytotoxicity and cellular uptake of various formulations at pH 7.4 and 5.5 were evaluated on the mammospheres (MS), which were sorted by MCF-7 human breast cancer cell lines and identified to be a CD44+/CD24−phenotype. The results of the cytotoxicity assay showed that blank micelles were nontoxic and Thz/PPM exhibited a similar anti-CSC effect on MS compared to Thz solution. Stronger fluorescence signal of Coumarin-6 (C6) was observed in MS treated by C6-loaded PPM (C6/PPM) at pH 5.5. The tumor inhibition rate and tumor weight of the free DOX and Thz/PPM groups were significantly different from those of the other groups, which free DOX and Thz/PPM effectively suppressed breast tumor growth in vivo. The above experimental results showed that Thz/PPM is an ideal and effective pH-responsive drug delivery carrier to a targeted therapy of CSCs.Keywords:poly(β-amino ester);polymeric micelles;pH-responsive;cancer stem cells;thioridazine
研究领域:
药学
·
肿瘤学
·
生物材料学
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DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2020
·
IF 2.734
Hongyan Zhang,Shuang Dong,Sheng Zhang,Yufen Li,Ji Li,Yinghui Dai,Dongkai Wang
Effective delivery of anti-tumor drugs to the tumor site remain a challenging issue, such as insufficient uptake by tumor cells, degradation by lysosomes and insufficient drug release. Therefore, it is crucial to utilize smart nanoparticles (NPs) designed with the ability to target the tumor site and respond to the unique microenvironment of the tumor tissue. In this paper, we prepared a novel pH responsive core-shell lipid polymer NPs (FA/PBAE/DTX-NPs). The NPs are composed of a mixed lipid shell (DSPE-PEG 2000 , FA-DSPE-PEG 2000 and lecithin) and a polymer core (poly (β-amino ester), PBAE) for targeted delivery of docetaxel (DTX) to breast cancer. FA-PBAE/DTX-NPs had uniform particle size and excellent physical stability. The study of drug release in vitro showed that FA/PBAE/DTX-NPs could release DTX on demand under different pH.Blank NPs were considered nontoxic, while drug-loaded NPs have strong cytotoxicity to 4T1 cells in vitro . The tertiary amine group of PBAE enhanced endosomal/lysosomal escape of the NPs via the proton sponge effect, which triggers the rapid release of DTX. What's more, in vivo experiments have shown that FA/PBAE/DTX-NPs have favorable targeting, antitumor effect, and minimal systemic toxicity in tumor-bearing mice. To sum up, FA/PBAE/DTX-NPs could be selected as a candidate to delivery drug for breast cancer and improving the efficacy of chemotherapy.
研究领域:
药剂学
·
肿瘤学
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产品关联
DOI
高影响因子
CANADIAN JOURNAL OF CHEMICAL ENGINEERING
·
2022
·Vol. 101
·期 5
·2485-2492
·
IF 2.5
Xiujun Wang,Jian Zhang,Bo Huang,Ming Duan
Polymer-contained oily sludge is inevitably produced when the oily wastewater produced from polymer flooding (OWPF) is treated by a cationic polymer clarifier, and it severely affects oilfield production. This study designed a novel degradable cationic clarifier (DCC) based on the ester bond and prepared it in light of the poly(β-amino ester) used in the area of generic material delivery. First, the copolymer of N -[3-(dimethylamino) propyl] methacryamide (DMAPMA) and diallylamine (PDMAPMA-NH) were synthesized by radical copolymerization. Then, the DCC was prepared by Michael addition between PDMAPMA-NH and poly(ethylene glycol) diacrylate. The synthesis conditions of DCC were investigated, and a DCC with excellent flocculant performance and good degradability was successfully prepared. At 70°C, both the degradations of DCC and the water-insoluble polymer complex formed by DCC and the polymer used for polymer flooding can be completed in 10 h, which is beneficial for the self-disappearance of the polymer-contained oily sludge. The flocs formed by DCC were observed at different times, and the results confirmed that the flocs can change to an oil film and that the polymer-contained oily sludge cannot exist for a long time. This study provides inspiration for OWPF treatment and expands the new application for poly(β-amino ester).
研究领域:
环境科学
·
材料科学
·
石油工程
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2016
·
IF 4.342
Haijun Zhao,Qian Li,Zehui Hong
Although PEGylation allows a drug delivery vehicle to have prolonged blood circulation time, it faces the problem of reduced cellular uptake. Removal of the polyethylene glycol (PEG)-shell at the appropriate time through tumor-microenvironment triggers could be a feasible solution to this problem. Here, paclitaxel (PTX)-loaded mixed micelles (PTX-mM) self-assembled from stearate-modified hyaluronic acid (SHA), mPEG-b-poly(β-amino ester) (mPEG-b-PAE), and ethylene acetyl-b-poly(β-amino ester) (EA-b-PAE) were developed. In the preparation of PTX-mM, SHA micelles were coated with EA-b-PAE followed by coloading of PTX and mPEG-b-PAE. PTX-mM were capable of extracellular pH-triggered PEG-detachment and poly(β-amino ester) (PAE)-mediated endosomal escape. When the pH was changed from pH 7.4 to pH 6.8, the particle size of PTX-mM significantly decreased from 97.5 ± 4.4 to 71.5 ± 2.3 nm. It also resulted in rapid and complete release of mPEG-b-PAE from PTX-mM as monitored using quartz crystal microbalance (QCM) technology. PTX-mM capable of PEG detachment provided significant enhancement of PTX accumulation in SKOV-3 cells compared to PEG nondetachable PTX-mM. Interestingly, intracellular transport studies using confocal laser scanning microscopy (CLSM) showed that EA-b-PAE could promote the escape of micelles from endolysosomes. The half-maximal inhibitory concentration (IC50) of PTX-mM against SKOV-3 cells was 5.7 μg/mL, and PTX-mM containing 20 μg/mL of PTX induced apoptosis in 53.0% of the cell population. PTX-mM exhibited a highly prolonged elimination half-life (t1/2, 2.83 ± 0.37 h) and improved area under the curve (AUC, 7724.82 ± 1190.75 ng/mL/h) than the PTX-loaded SHA micelles (PTX-M). Furthermore, PTX-mM showed the highest tumor inhibition rate (64.9%) and the longest survival time (53 days) against the SKOV-3 ovarian cancer xenograft models among all formulations. Taken together, the results suggested that PTX-mM have potential as an efficient anticancer formulation in treatment of ovarian cancer.
研究领域:
药学
·
癌症研究
·
药物递送系统
·
纳米技术
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2015
·
IF 3.368
Jing Zhao,Lei Yang,Ping Huang,ZhiYong Wang,Yan Tan,Hong Liu,JiaJia Pan,Cheng-Yi He,Zhi-Ying Chen
Gene therapy has held great promise for treating specific acquired and inherited diseases. However, the lack of safe and efficient gene delivery systems remains as the major challenge. Poly(β-amino ester)s (PBAEs) have attracted much attention due to their outstanding properties in biosafety, DNA delivery efficiency and convenience in synthesis. In this paper, we reported the further enhancement of the PBAE functions by increasing its positive charge through conjugating with low molecular weight polyethylenimine (LPEI). The resulted LPEI–PBAE polymer was able to condense minicircle DNA (mcDNA) forming nanoparticles with a diameter of 50–200 nm. Furthermore, as compared to parental PBAE and a commercial transfection reagent very common in laboratory application, the LPEI–PBAE demonstrated significantly higher transfection efficiency with little cytotoxicity. These results suggested LPEI–PBAEs are worthy of further optimization for gene therapy applications.
研究领域:
基因治疗
·
药学
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Xiong Jinfeng,Li Guannan,Mei Xinyu,Ding Jiahui,Shen Hui,Zhu Da,Wang Hui
The p53 gene has the highest mutation frequency in tumors, and its inactivation can lead to malignant transformation, such as cell cycle arrest and apoptotic inhibition. Persistent high-risk human papillomavirus (HR-HPV) infection is the leading cause of cervical cancer. P53 was inactivated by HPV oncoprotein E6, promoting abnormal cell proliferation and carcinogenesis. To study the treatment of cervical intraepithelial neoplasia (CIN) and cervical cancer by restoring p53 expression and inactivating HPV oncoprotein, and to verify the effectiveness of nano drugs based on nucleic acid delivery in cancer treatment, we developed poly (beta-amino ester)537, to form biocompatible and degradable nanoparticles with plasmids (expressing p53 and targeting E7). In vitro and in vivo experiments show that nanoparticles have low toxicity and high transfection efficiency. Nanoparticles inhibited the growth of xenograft tumors and successfully reversed HPV transgenic mice’s cervical intraepithelial neoplasia. Our work suggests that the restoration of p53 expression and the inactivation of HPV16 E7 are essential for blocking the development of cervical cancer. This study provides new insights into the precise treatment of HPV-related cervical lesions.
研究领域:
肿瘤学
·
分子生物学
·
纳米技术
·
基因治疗
·
癌症研究
✓ 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）