COLLOIDS AND SURFACES B-BIOINTERFACES
·
2015
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IF 4.152
Tingxian Liu,Mingfang Wang,Tianqi Wang,Yao Yao,Na Zhang
The greatest challenge in combining chemotherapy and gene therapy is the construction of a suitable platform for the co-delivery of the drug and the therapeutic gene. In this study, a simplified and effective system for the co-loading and intracellular co-delivery of doxorubicin (Dox) and siRNA was developed. Oligodeoxynucleotides with CGA repeating units (CGA-ODNs) were introduced to load Dox. The loading mechanism was based on the ability of Dox to intercalate within double-stranded 5′-GC-3′ or 5′-CG-3′ sequences. Poly(ethyleneimine) (PEI) was used to condense siRNA and Dox loaded CGA-ODNs (CGA-ODNs-Dox) to obtain Dox and siRNA co-loaded nanocomplexes (PEI/CGA-ODNs-Dox&siRNA, PDR). The cellular uptake of PDR in A549 and HepG2 cells was 39.52% and 36.78%, respectively, indicating that the co-loading and co-delivery effect was achieved through the mono-loading method. An in vitro drug release study indicated that CMCS-poly(ethylene glycol) (PEG)-NGR (CPN) modified PDR (CPN-PDR) displayed a pH-triggered drug release property due to the reversed surface charge of CMCS in an acidic environment. Cellular uptake studies also confirmed that the disassembly of CPN-PDR was induced by an acidic pH in the extracellular matrix. Moreover, lysosomal escape of both Dox and siRNA was observed. Successful accumulation of Dox in the cell nucleus and siRNA in the cytoplasm was also demonstrated. Consequently, the novel construction of a simplified loading method and high co-delivery efficiency was proven to be a promising platform for the co-delivery of drug and siRNA.
研究领域:
药学
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分子生物学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2021
·Vol. 26
·期 11
·3238
·
IF 4.412
Shuang Liu,Shaohui Deng,Xiaoxia Li,Du Cheng
Though siRNA-based therapy has achieved great progress, efficient siRNA delivery remains a challenge. Here, we synthesized a copolymer PAsp(-N=C-PEG)-PCys-PAsp(DETA) consisting of a poly(aspartate) block grafted with comb-like PEG side chains via a pH-sensitive imine bond (PAsp(-N=C-PEG) block), a poly(l-cysteine) block with a thiol group (PCys block), and a cationic poly(aspartate) block grafted with diethylenetriamine (PAsp(DETA) block). The cationic polymers efficiently complexed siRNA into polyplexes, showing a sandwich-like structure with a PAsp(-N=C-PEG) out-layer, a crosslinked PCys interlayer, and a complexing core of siRNA and PAsp(DETA). Low pH-triggered breakage of pH-sensitive imine bonds caused PEG shedding. The disulfide bond-crosslinking and pH-triggered PEG shedding synergistically decreased the polyplexes’ size from 75 nm to 26 nm. To neutralize excessive positive charges and introduce the targeting ligand, the polyplexes without a PEG layer were coated with an anionic copolymer modified with the targeting ligand lauric acid. The resulting polyplexes exhibited high transfection efficiency and lysosomal escape capacity. This study provides a promising strategy to engineer the size and surface of polyplexes, allowing long blood circulation and targeted delivery of siRNA.Keywords:small polyplex;pH-sensitive PEG shedding;disulfide bond-crosslinking;siRNA delivery;targeting delivery
研究领域:
药学
·
分子生物学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2021
·Vol. 9
·期 19
·6501-6509
·
IF 6.843
Bo Zhang,Chen-wen Shao,Kang-Min Zhou,Qin Li,Yong-Tao Duan,Yu-Shun Yang,Hai-Liang Zhu
Recently, hypothermal photothermal therapy (HPTT) seemed essential for the future clinical transformation of cancer optical therapies. However, at a lower working temperature, heat shock proteins (HSPs) seriously affect the anti-tumor effect of HPTT. This work reports a reasonable design of a dual-responsive nanoplatform for the synergistic treatment of chemotherapy and HPTT. We adopted a one-step method to wrap indocyanine green (ICG) into imidazole skeleton-8 (ZIF-8) and further loaded it with the chemotherapy drug doxorubicin (DOX). Furthermore, we introduced Hsp-70 siRNA to block the affection of HSPs at an upstream node, thereby avoiding the side effects of traditional heat shock protein inhibitors. The prepared ZIF-8@ICG@DOX@siRNA nanoparticles (ZID-Si NPs) could significantly improve the stability of siRNA to effectively down-regulate the expression of HSP70 protein during the photothermal therapy, thus realizing the pH-controlled and NIR-triggered release of the chemotherapeutical drug DOX. Moreover, tumors were also imaged accurately by ICG wrapped in ZID-Si nanoparticles. After the evaluation of the in vitro and in vivo photothermal effect as well as the anti-tumor activity, we found that the added Hsp-70 siRNA enhanced the synergistic anti-cancer activity of HPTT and chemotherapy. In summary, this work holds great potential in cancer treatment, and suggests better efficacy of synergistic chemo/HPTT than the single-agent therapy.
研究领域:
癌症治疗
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纳米技术
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光热疗法
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化疗
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基因沉默
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
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IF 13.3
Jialu Gao,Hua Zhu,Huanhuan Cai,Qihang Ding,Xiaoxing Xiong,Tong Zhang,Bo Chen,Wumei Wang,Xinpeng Ju,Jianying Huang,Xiaodong Zeng,Jong Seung Kim,Xuechuan Hong
Reducing foam cell formation and accumulation within plaques is a critical strategy for treating atherosclerosis. Although current lipid-lowering therapies have significantly improved the management of atherosclerosis, the risk of cardiovascular events remains. Thus, it is necessary to explore next-generation therapies to reduce foam cell formation, inflammation, and oxidative stress. To address these challenges, we present an innovative near-infrared II (NIR-II) fluorescent dye coupled with a lesion-targeting peptide, forming a molecular self-assembly nanoplatform for effective in vitro small interfering RNA (siRNA) delivery. This platform downregulates Epsin1/2, a family of ubiquitin-binding endocytic adaptors, upregulates the expressions of ABCG1 and LRP-1 proteins, and markedly reduces foam cell formation. Additionally, this system enables real-time tracking of plaque accumulation, therapeutic response, and efficacy through in vivo noninvasive NIR-II imaging. Systemic siRNA delivery significantly suppresses lipid accumulation, plaque size, and necrotic core area in the carotid plaque model of ApoE −/− mice. These results suggest that this multi-functional nanoplatform could become an effective tool for NIR-II image-guided siRNA delivery for personalized treatment of atherosclerosis.
研究领域:
医学
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生物技术
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
BIOMATERIALS
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2015
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IF 8.557
Bing-Feng Zhang,Lei Xing,Peng-Fei Cui,Feng-Zhen Wang,Rong-Lin Xie,Jia-Liang Zhang,Mei Zhang,Yu-Jing He,Jin-Yuan Lyu,Jian-Bin Qiao,Bao-An Chen,Hu-Lin Jiang
The mitochondria-mediated apoptosis pathway is an effective option for cancer therapy due to the presence of cell-suicide weapons in mitochondria. However, anti-apoptotic proteins that are over-expressed in the mitochondria of many malignant tumors, such as Bcl-2 protein, could allow the cancer cells to evade apoptosis, greatly reducing the efficacy of this type of chemotherapy. Here, we constructed a hierarchical targeted delivery system that can deliver siRNA and chemotherapeutic agents sequentially to tumor cells and mitochondria. In detail, the copolymer TPP-CP-LND (TCPL) was synthesized by the mitochondria-targeting ligand triphenylphosphine (TPP) and therapeutic drug lonidamine (LND) conjugated to the polyethyleneimine in chitosan- graft -PEI (CP), and then complexed with siRNA. Followed, the complexes were coated with poly(acrylic acid)-polyethylene glycol-folic acid (PPF) copolymer to form a hierarchical targeted co-delivery system (TCPL/siRNA/PPF NPs). The TCPL/siRNA/PPF NPs had a neutral surface charge, were stable in plasma and exhibited pH-responsive shell separation. Remarkably, the TCPL/siRNA/PPF NPs simultaneously released siBcl-2 into the cytoplasm and delivered LND to mitochondria in the same cancer cell after FA-directed internalization, and even synergistically activated mitochondria apoptosis pathway. This work demonstrated the potential of RNA-interference and mitochondria-targeted chemotherapeutics to collaboratively stimulate the mitochondria apoptosis pathway for cancer therapy.
研究领域:
药理学
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纳米技术
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Cheng Zeng,Xiaojing Chen,Mingxi Lin,Yizi Jin,Qing Guo,Teng Zhou,Xingang Wang,Yiping Li,Xinghui Wang,Yongming Han,Ling Du,Qianyun Tang,Peifeng Liu,Jian Zhang
The extracellular matrix (ECM) of solid tumor constitutes a formidable physical barrier that impedes immune cell infiltration, contributing to immunotherapy resistance. Breast cancer, particularly triple-negative breast cancer (TNBC), is characterized by a collagen-rich tumor microenvironment, which is associated with T cell exclusion and poor therapeutic outcomes. Discoidin domain receptor 2 (DDR2) and integrins, key ECM regulatory receptors on cancer cells, play pivotal role in maintaining this barrier. In this study, we developed a dual-receptor-targeted strategy using metal-organic frameworks (MOFs) to deliver DDR2-specific siRNA (siDDR2) and ITGAV-specific siRNA (siITGAV) to disrupt the ECM barrier. siDDR2 modulates immune infiltration by regulating collagen–cell interactions, while siITGAV suppresses TGF-β1 activation. The MOF@siDDR2+siITGAV complex significantly reduced collagen deposition, enhanced CD8+ T cell infiltration, and downregulated programmed cell death ligand 1 (PD-L1) expression in TNBC. Consequently, this approach markedly inhibited tumor growth. Our findings demonstrate that dual-receptor-targeted MOF-based nanocarriers (MOF@siDDR2+siITGAV) can effectively reprogram the tumor ECM to enhance immune cell access, offering a promising prospect for synergistic cancer immunotherapy. Statement of significance A dual-receptor-targeted MOF nanocarrier is developed to improve immune accessibility in tumors. Concurrent blockade of DDR2 and ITGAV effectively decreases collagen deposition, increases CD8+ T cell infiltration, and suppresses PD-L1 expression. Modulating the mechanical properties of the extracellular matrix (ECM) to enhance immune accessibility offers an innovative strategy for cancer treatment.
研究领域:
肿瘤学
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分子生物学
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IET Nanobiotechnology
·
2023
·
IF 2.3
Xiu Han,Yan Lu,Zhaoluo Xu,Yanan Chu,Xueping Ma,Haiping Wu,Bingjie Zou,Guohua Zhou
Currently, organic solvents are necessary for the preparation of anionic liposomes for siRNA delivery. The removal of organic solvent is time-consuming and the residual organic solvent is not only a hidden danger, but also affects the stability of anionic liposomes. Glycerol, which is physiologically compatible and does not need to be removed, is used to promote the dispersion of lipids and the formation of anionic liposomes. Additionally, the preparation process is simple and not time-consuming. The results showed that anionic liposomes, which were typically spherical with a particle size of 188.9 nm were successfully prepared with glycerol. And with the help of Ca 2+ , siRNA was encapsulated in anionic liposomes. The highest encapsulation efficiency at 2.4 mM Ca 2+ reached 91%. And the formation of calcium phosphate could promote the endosomal escape of siRNA effectively. The results from cell viability showed that the anionic liposomes had no obvious cytotoxicity. It was also verified that anionic liposomes could improve the resistance of siRNA against degradation. Additionally, siRNA delivered by anionic liposomes could play an effective role in knockout. Therefore, anionic liposomes prepared with glycerol will be a safe and effective delivery platform for siRNA and even other nucleic acid drugs.
研究领域:
药剂学
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纳米技术
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药物递送系统
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2016
·
IF 3.994
Zhongjuan Wang,Haijuan Zou,Zirui Wang,Jiamin Wu,Zhongsheng Xia,Min Feng
RNA interfere (RNAi)-based technology holds great promise in cancer treatment. The use of small interfering RNA (siRNA), however, is hampered by its low delivery efficiency in vivo when they are diluted in blood biofluids and in the presence of serum and salt. In this study, we developed the polyglutamate derivative polymer brush, poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (mPEG-b-PG-g-spermine, PPGS), which could efficiently deliver survivin-siRNA under ultra-high dilution and in the presence of salt (NaCl 150 mM) and serum (10% FBS), most likely due to its PEG-shelled polymer brush structure. On the contrary, aggregation occurred when PEI/siRNA polyplex dispersed in saline and serum-containing media and PEI polyplex dissociated after making a 256-fold dilution. PPGS/si-survivin polyplex exhibited high cellular uptake efficiency and efficiently down-regulated the expression of survivin mRNA in the cisplatin-resistance of non-small cell human lung adenocarcinoma (A549/DDP) cells in the presence of serum. However, either PEI polyplex or Lipofectmine 2000 complex was unstable in serum and salt-containing media and at high dilution rates, which resulted in their dramatical decrease of cellular uptake and gene-silencing efficiency in these conditions. The PPGS/si-survivin polyplex also exhibited synergistic effects of killing the cancer cells by combination treatment with cisplatin . Therefore, the PPGS gene carrier showed great potential in systemic siRNA delivery, and its combination with chemotherapeutic drug is promising in treating drug resistant cancers.
研究领域:
药学
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肿瘤学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2025
·
IF 5.5
Suixin Xing,Xu Zhang,Haizhen Guo,Shitian Jia,Shujing Xu,Yongxin Liu,Xue Li,Yuewei Li,Sheng Wang
Ferroptosis has become an emerging paradigm in tumor therapy characterized by the accumulation of lipid peroxides (LPO). However, intracellular glutathione peroxidase 4 (GPX4) will lead to the clearance of LPO, weakening the therapeutic effect based on ferroptosis. Herein, the integration of the Fenton reaction amplifier and GPX4-targeted siRNA (si-GPX4) was proposed. A polyprodrug-siGPX4 nanoparticle (denoted as si-PDAFH NP) was prepared. On one hand, the si-PDAFH NP can respond to tumor microenvironment, leading to structural degradation of the NPs and release of therapeutic components. The released cinnamaldehyde and ferrocene can amplify the Fenton reaction to produce •OH, oxidizing unsaturated fatty acids to generate LPO. On the other hand, the expression of the GPX4 protein can be knocked down by si-GPX4, preventing the clearance of LPO. The results showed that the si-PDAFH NPs can significantly affect the tumor redox status related to ferroptosis and suppress tumor growth. Therefore, this study provides a new avenue to enhance ferroptosis for cancer treatment.
研究领域:
生物化学
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肿瘤学
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纳米医学
✓ 已验证
产品关联
DOI
高影响因子
Biomedicines
·
2025
·Vol. 13
·期 2
·486
·
IF 3.9
Chunli Zhu,Yiheng Cheng,Lei Yang,Yifu Lyu,Jingjing Li,Pengbo Zhao,Ying Zhu,Xiaofei Xin,Lifang Yin
Background and Objectives: As a key mechanism of metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis, inflammation triggered by chronic liver injury and immune cells with macrophages enables MASLD to progress to an advanced stage with irreversible processes such as fibrosis, cell necrosis, and cancer in the liver. The complexity of MASLD, including crosstalk between multiple organs and the liver, makes developing a new drug for MASLD challenging, especially in single-drug therapy. It was reported that upregulation of Notch1 is closely associated with the function of pro-inflammatory macrophages. To leverage this signaling pathway in treating MASLD, we developed a combination therapy.Materials and Methods: We chose Notch1 siRNA (siNotch1) to block the Notch pathway so that phenotypic regulation and functional recovery can be achieved in macrophages, combining with small molecule drug AMD3100. AMD3100 can cut off the migration of inflammatory cells to the liver to impede the development of inflammation and inhibit the CXCL12/CXCR4 biological axis in liver fibrosis to protect against the activation of HSCs. Then, we investigated the efficacy of the combination therapy on resolving inflammation and MASLD.Results: We demonstrated that in liver cells, siNotch1 combined with AMD3100 not only directly modulated macrophages by downregulating multiple pathways downstream of Notch, exerting anti-inflammatory, anti-migration, and switch of macrophage phenotype, but also modulated macrophage phenotypes through inhibiting NET release. The restored macrophages further regulate HSC and neutrophils. In in vivo pharmacodynamic studies, combination therapy exhibits a superior therapeutical effect over monotherapy in MASLD models.Conclusions: These results constitute an siRNA therapeutical approach combined with a small molecule drug against inflammation and liver injury in MASLD, offering a promising therapeutic intervention for MASLD.
研究领域:
医学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2015
·
IF 7.705
HongYan Zhu,ShengYu Zhang,Yong Ling,GuoLiang Meng,Yu Yang,Wei Zhang
Hypoxia is a characteristic of cancer and plays a key role in tumorigenesis, angiogenesis and resistance to cancer therapies. SiRNA treatment is effective against hypoxic tumors by gene silencing. However, siRNA delivery to the hypoxic regions of solid tumors still presents a challenge due to the distance from blood vessels and the increased presence of efflux transporters. Therefore, tumor therapies would be improved through the immediate development of an effective siRNA delivery system to hypoxic regions. To this end, we synthesized a system to deliver HIF-1α siRNA into hypoxic tumor cells. The system consists of a functional shell composed of 2-deoxyglucose (DG)-polyethylene glycol (PEG) connected with the compound of lipoic acid , lysine and 9-poly- d -arginine (LA–Lys–9R) by a hydrazone bond and a core of CdTe quantum dots (QDs). The molecular structure of DG–PEG–LA–Lys–9R was confirmed by liquid chromatography–mass spectrometry (LC–MS), nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The multifunctional CdTe QDs measured approximately 200 nm and showed excellent biocompatibility , perfect siRNA binding capability and enhanced hypoxic tumor targeting. Importantly, the system described here is pH-responsive with a hydrazone bond; therefore, it avoids GLUT1 receptor-mediated endocytic recycling, resulting in irreversible delivery of the siRNA. We used Western blots to confirm the superior gene silencing efficiency induced by the DG–PEG–LA–Lys–9R with hydrazone modified CdTe QDs. Here, we demonstrate high efficacy of the siRNA tumor delivery system using in vitro and in vivo experiments. In addition, these studies demonstrate that pH-responsive hybrid quantum dots show improved antitumor efficacy with decreased organ toxicity , indicating a promising siRNA delivery system for hypoxic cancer therapy.
研究领域:
癌症治疗
·
纳米技术
·
分子生物学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2019
·
IF 6.044
Xia Wang,Yuxuan Qi,Lixia Liu,Tsogzolmaa Ganbold,Huricha Baigude,Jingfen Han
A long-anticipated cancer therapy would deliver the right type of therapeutic agents to the target in control with minimal systemic toxicity. The purpose of this study was to prepare lactosylated curdlan-triornithine nanocarriers (CTOLs), and target deliver gene to hepatoma cells. Structures and biophysical properties had been elucidated with physical and chemical methods. The results revealed that those functionalized polymers can completely condense the gene into spherical nanoparticles. Cytotoxicity assay, GFP-pDNA and siRNA transfection in vitro were implemented successively. Observations showed that CTOL 20% with the highest lactose acid substitution degree targeted delivered gene into HepG2 cells over expressing ASGPR receptors and had pretty gene knockdown efficiency over 70%. Meanwhile, the carriers showed excellent biocompatibility. Our studies demonstrated that CTOLs with lower toxicity and higher gene binding capacity may serve as a potential valuable platform that can be tailored to target the liver cancer cells for therapeutic gene.
研究领域:
生物化学
·
分子生物学
·
药剂学
✓ 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）