SAUDI PHARMACEUTICAL JOURNAL
·
2024
·
IF 3
Yao Yao,Qian Zhao,Feng Xu,Tingting Yao
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Sorafenib (Sf) is currently the first-line treatment for HCC. However, due to the side effects and unsatisfied efficiency of Sf, it is urgent to combine different therapeutic agents to inhibit HCC progression and increase the therapeutic efficacy. Here, our study constructed a Sf and KIAA1199-siRNA co-loaded liposome Sf-Lp-KIAA, which was prepared by electrostatic interaction of KIAA1199-siRNA and Sf loaded liposome (Sf-Lp). The particle size, zeta potential, the in vitro cumulative release was investigated. The physical and chemical properties were characterized, and the inhibition of HepG2 growth and metastasis in vitro was investigated. The cellular uptake of the co-loaded liposome was significantly higher than that of free siRNA, and the drug/siRNA could be co-delivered to the target cells. Sf-Lp-KIAA could significantly inhibit the growth, migration, invasion and down-regulate KIAA1199 expression of HepG2 cells in vitro than that of single Sf treated group. In addition, the co-delivery liposome accumulated in the HepG2 subcutaneous tumor model and suppress tumor growth after systemic administration without induce obvious toxicity. The present study implied that the co-delivery of Sf and KIAA1199-siRNA through the co-loaded liposomes exerted synergistic antitumor effects on HCC, which would lay a foundation for HCC therapy in the future.
研究领域:
肿瘤学
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药学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2022
·Vol. 10
·期 22
·6601-6613
·
IF 7.59
Jie Xu,Tianbao Chen,Tingting Sun,Chunyang Yu,Deyue Yan,Lijuan Zhu
The combination of gene therapy and chemotherapy is emerging as a promising strategy for multidrug-resistant (MDR) cancer treatment. However, due to the significant differences in the physicochemical properties between macromolecular oligonucleotides and chemodrugs, the co-delivery of different drug combos makes for a great challenge. Moreover, the biosafety of the carriers and poor lysosomal escape of oligonucleotides are the main concerns for combination therapy. Herein, we developed a facile carrier-free strategy to co-deliver small interfering RNA (siRNA) and positive-charged chemodrugs (termed cationic amphiphilic chemodrugs, CACDs), in which CACDs interact with negative-charged anti P-glycoprotein siRNA (siPgp) without extra carriers and self-assemble into siPgp/CACDs nanoparticles (NPs[siPgp/CACDs]). Meanwhile, the CACDs also play an important role in the lysosomal escape of siRNA. Both molecular dynamics simulations and experimental characterization demonstrate that CACDs and siRNA can self-assemble into nanoparticles. Furthermore, red blood cell membrane (RBCm) was used to camouflage the NPs[siPgp/CACDs] to enhance their physiological stability and prolong the circulation time. Both in vitro and in vivo assessments reveal their excellent performance for drug-resistant cancer treatment. This strategy provides a safe and efficient pathway for gene and chemo combination therapy for MDR cancers.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
ChemNanoMat
·
2022
·Vol. 8
·期 3
·e202100453
·
IF 3.82
Qing Chang,Chenghao Liu,Zhiquan Xie,Qingfeng Shu,Yijun Xie,Qianqian Su,Xiaoyong Deng
Graphical An ultrasmall mesoporous silica delivery system (∼8 nm) with PEG and PEI dual-modification (FMSNs-PEG@PEI) was developed for loading negatively charged siRNA through electrostatic interaction. FMSNs-PEG@PEI can efficiently deliver siRNA into 293T cells and protect siRNA from being degraded. In addition, when GAPDH related gene was delivered by FMSNS-PEG@PEI, we observed a lower expression in GAPDH gene knockdown cells. This study offers new possibilities for advanced gene delivery research and gene therapy by using ultra-small mesoporous silica nanoparticles with minor cellular toxicity. Small interfering RNA (siRNA) for gene therapy has attracted great attention. However, due to easy degradation and inaccessibility to the cells, the gene silencing efficiency is not always satisfactory. To overcome this hurdle, developing an excellent nanocarrier to deliver siRNA into cancer cells is crucial. Fluorescent mesoporous silica nanoparticles are considered to be a superb nanocarrier for siRNA delivery systems because of its negligible toxicity and good biocompatibility. Herein, we developed an efficient fluorescent ultrasmall mesoporous silica nanocarrier for siRNA loading and delivery. The ultrasmall nanocarriers with polyethylenimine coating have a uniform size of about 10 nm. We find that the amino groups on polyethylenimine can protect siRNA from being degraded. Based on the fluorescence observation, we show that polyethylenimine-coated mesoporous silica nanocarrier loaded with siRNA can be uptake by 293T cells. Importantly, we also prove that siRNA can be delivered into 293T cells by our nanocarrier and subsequently inhibit the expression of related genes. The study provides insights into the development of nonviral fluorescence nanocarriers for siRNA delivery, which have important implications for targeted cancer therapy.
研究领域:
纳米技术
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生物医学工程
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分子生物学
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基因治疗
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产品关联
DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2017
·
IF 0
Zhili Yu,Junxiao Ye,Xing Pei,Lu Sun,Ergang Liu,Jianxin Wang,Yongzhuo Huang,Seung Jin Lee,Huining He
RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular weight and strong anionic charge. Considering their remarkable functions in vivo and features that are often desired in drug delivery carriers, biomimetic systems for siRNA delivery become an effective and promising strategy. Based on this, covalent attachment of synthetic cell penetrating peptides (CPP) to siRNA has become of great interest. We developed a monomeric covalent conjugate of low molecular weight protamine (LMWP, a well-established CPP) and siRNA via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Results showed that the conjugates didn't generate coagulation, and exhibited much better RNAi potency and intracellular delivery compared with the conventional charge-complexed CPP/siRNA aggregates. Three different synthetic and purification methods were compared in order to optimize synthesis efficiency and product yield. The methodology using hetero-bifunctional NHS–PEG–OPSS as a crosslinker to synthesize LMWP–siRNA simplified the synthesis and purification process and produced the highest yield. These results pave the way towards siRNA biomimetic delivery and future clinical translation.
研究领域:
药学
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分子生物学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Sunlong Li,Siyu Hu,Yifeng Shi,Yeheng Huang,Yuli Chen,Yan Chen,Fengyu Zhang,Zhan Gao,Shuqing Jin,Qiwei Zhou,Shu Yang,Haibo Liang,Lianggao Yu,Shuhao Zhang,Chongan Huang,Chenglong Xie,Zaher Meftah,Aimin Wu,Xiaolei Zhang,Xiangyang Wang
Ferroptosis is a major contributor to intervertebral disc degeneration (IVDD) and represents a promising therapeutic target; however, effective medications that specifically target ferroptosis are still lacking. Consequently, strategies aimed at suppressing the expression of ferroptosis-related genes, such as small interfering RNA (siRNA) targeting activating transcription factor 3 (ATF3), appear to be a feasible therapeutic approach for IVDD. Zeolitic imidazolate framework-8 (ZIF-8) exhibits exceptionally high binding affinity for nucleic acids, including siRNA. Nevertheless, its practical application is hindered by challenges such as limited siRNA encapsulation and potential toxicity arising from Zn 2 ⁺ ion release during degradation. In the current study, a novel siRNA delivery system is designed with low toxicity, high encapsulation efficiency, and sustained release by hybridizing classical ZIF-8 with histidine (H-ZIF-8) through defect engineering. In vitro functional studies demonstrated that H-ZIF-8 significantly enhances the delivery efficiency of siATF3 in nucleus pulposus cells (NPCs), and effectively suppresses ferroptosis and extracellular matrix (ECM) degradation. Furthermore, the incorporation of histidine into ZIF-8 may improve its biocompatibility by reducing the proportion of Zn 2 ⁺ ions present. In vivo, siATF3@H-ZIF-8 significantly inhibited ferroptosis and alleviated intervertebral disc degeneration (IVDD) in a rat model through sustaining ATF3 knockdown. This research suggests that histidine-modified ZIF-8 may serve as a novel system for siRNA delivery and an effective gene therapy method for diseases, including IVDD.
研究领域:
生物医学工程
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基因治疗
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材料科学
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骨科
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产品关联
DOI
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 5
·964
·
IF 6.525
Yingying Zhang,Hongxia Duan,Heming Zhao,Lingling Qi,Yanhong Liu,Zheao Zhang,Chao Liu,Liqing Chen,Mingji Jin,Youyan Guan,Zhonggao Gao,Wei Huang
Primary prostate cancer (PC) progresses to castration-resistant PC (CRPC) during androgen deprivation therapy (ADR) in early stages of prostate cancer. Thus, rather than blocking the androgen-related pathway further, docetaxel (DTX)-based therapy has become the most effective and standard first-line chemotherapy for CRPC. Although the therapy is successful in prolonging the survival of patients with CRPC, chemotherapy resistance develops due to the abnormal activation of the androgen receptor (AR) signaling pathway. Thus, to optimize DTX efficacy, continued maximum suppression of androgen levels and AR signaling is required. Here, we designed a prostate-specific membrane antigen (PSMA)-targeted nanosystem to carry both DTX and AR siRNA (Di-PP/AR-siRNA/DTX) for CRPC treatment. Specifically, DTX was encapsulated into the hydrophobic inner layer, and the AR siRNA was then condensed with the cationic PEI block in the hydrophilic outer layer of the PEI-PLGA polymeric micelles. The micelles were further coated with PSMA-targeted anionic polyethylene glycol-polyaspartic acid (Di-PEG-PLD). In vitro and in vivo results demonstrated that the resulting Di-PP/AR-siRNA/DTX exhibited prolonged blood circulation, selective targeting, and enhanced antitumor effects. Consequently, Di-PP/AR-siRNA/DTX holds great potential for efficient CRPC treatment by combining chemotherapy and siRNA silencing of androgen-related signaling pathways.Keywords:prostate cancer;androgen receptor;siRNA delivery;docetaxel;PSMA targeting
研究领域:
肿瘤学
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药学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2024
·Vol. 16
·期 7
·936
·
IF 4.9
Peng Chen,Zhihui Wang,Xinmo Wang,Junni Gong,Ju Sheng,Yufei Pan,Dandan Zhu,Xiaoxuan Liu
Small interfering RNA (siRNA) therapeutics, characterized by high specificity, potency, and durability, hold great promise in the treatment of cancer and other diseases. However, the clinic implementation of siRNA therapeutics critically depends on the safe and on–demand delivery of siRNA to the target cells. Here, we reported a family of ferrocenyl amphiphilic dendrimers (Fc-AmDs) for on–demand delivery of siRNA in response to the high ROS content in cancer cells. These dendrimers bear ROS–sensitive ferrocene moieties in the hydrophobic components and positively chargeable poly(amidoamine) dendrons as the hydrophilic entities, possessing favorable safety profiles and ROS responsive properties. One of these ferrocenyl amphiphilic dendrimers,Fc-C8-AmD 8A, outperforms in siRNA delivery, benefiting from its optimal balance of hydrophobicity and hydrophilicity. Its ROS feature facilitates specific and efficient disassembly of its complex with siRNA in ROS–rich cancer cells for effective siRNA delivery and gene silencing. Moreover,Fc-C8-AmD 8Aalso integrates the features and beneficial properties of both lipid and dendrimer vectors. Therefore, it represents a novel on–demand delivery system for cancer cell–specific siRNA delivery. This work opens new perspectives for designing self–assembly nanosystems for on–demand drug delivery.
研究领域:
药学
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纳米技术
·
癌症研究
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Shudan Zheng,Zhenghao Zhou,Jie Ji,Yuxin Liu,Xiaodan Jiao,Xiaoyang Li,Yi Shen,Hao Hong,Xiaodong Han
Idiopathic pulmonary fibrosis (IPF) exhibits extremely high mortality rates. Targeted therapy, which utilizes specific drugs or other substances to identify and attack specific molecular targets in the lesion, holds promise as a potent means of treating IPF. M2 macrophages have been shown to express high levels of osteopontin (OPN) early in the onset of IPF and sustain this high expression to promote the progression of IPF. Intervention in OPN expression can effectively impede the development of fibrosis. While the technology for targeting proteins with siRNA has become increasingly mature, the targeted delivery of siRNA to resident M2 macrophages in the lungs remains challenging. In this study, we developed an engineered self-assembling OPN siRNA carrier complex based on a metal-polyphenol network (luteolin-Zr) and PEG conjugated with an M2 macrophage-targeting peptide (Pery-PEG-M2), termed siOPN@LuZ-M2, for the treatment of pulmonary fibrosis. Consequently, significant therapeutic effects were observed in both bleomycin-induced pulmonary fibrosis mouse models and human precision-cut lung slices (hPCLS) models. Importantly, luteolin, which is slowly released from siOPN@LuZ-M2 within cells, can gradually accumulate in fibrotic lung tissue, exerting an anti-inflammatory effect and further enhancing the treatment of IPF. It is worth mentioning that siOPN@LuZ-M2 can be labeled with 89 Zr, allowing for the detection of its in vivo distribution and metabolic behavior via PET-CT. This study presents a promising new image-guided molecular targeting strategy for the treatment of fibrosis.
研究领域:
药理学
·
分子生物学
·
医学影像学
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产品关联
DOI
PubMed
高影响因子
MACROMOLECULAR BIOSCIENCE
·
2021
·Vol. 21
·期 5
·2100025
·
IF 4.979
Qinping Yang,Yanliang Dong,Xuanyu Wang,Zhihao Lin,Mingyu Yan,Weiwei Wang,Anjie Dong,Jianhua Zhang,Pingsheng Huang,Changrong Wang
pH-sensitive polyelectrolytes provide enormous opportunity for siRNA delivery. Especially, their tertiary amine structures can not only bind genes but also act as pH-sensitive hydrophobic structure to control genes release. However, the influence of molecular structures on siRNA delivery still remains elusive, especially for the asymmetric alkyl substituents of the tertiary amine groups. Herein, a library of N -methyl- N -alkyl aminoethyl methacrylate monomers (MsAM) with asymmetric alkyl substituents on the tertiary amine group is synthesized and used to prepare a series of tri-block polycationic copolymers poly(aminoethyl methacrylate)-block-poly ( N -methyl- N -alkyl aminoethyl methacrylate)-block-poly(ethylene glycol methacrylate) (PAMA-PMsMA-PEG). And the properties of these polycations and their self-assembled micelles are characterized, including molecular structure, proton buffering capacity, pH-sensitivity, size, and zeta potential. With the length increase of one alkyl substituent, the proton buffering capacity of both monomers and polycations is demonstrated to be narrowed down. The siRNA delivery efficiency and cytotoxicity of these micelles are also evaluated on HepG2 cells. In particular, poly(aminoethyl methacrylate)-block-poly( N -methyl- N -ethyl aminoethyl methacrylate)-block-poly(ethylene glycol methacrylate) (PAMA-PMEMA-PEG) elicited the best luciferase knockdown efficiency and low cytotoxicity. Besides, PAMA-PMEMA-PEG/siRRM2 also induced significant anti-tumor activity in vitro. These results indicated PAMA-PMEMA-PEG has potential for further use in the design of gene vehicles with the improved efficiency of siRNA delivery.
研究领域:
聚合物化学
·
分子生物学
·
基因治疗
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Song Shen,Yue Zhang,Kai-Ge Chen,Ying-Li Luo,Jun Wang
Accumulating evidence has confirmed that malignant tumors have a complex microenvironment, which consists of a heterogeneous collection of tumor cells and other cell subsets (including the full gamut of immune cells). Tumor-associated macrophages (TAMs), derived from circulating Ly6Chi monocytes, constitute the most substantial fraction of tumor-infiltrating immune cells in nearly all cancer types and contribute to tumor progression, vascularization, metastasis, immunosuppression, and therapeutic resistance. Interrupting monocyte recruitment to tumor tissues by disturbing pivotal signaling pathways (such as CCL2-CCR2) is viewed as one of the most promising avenues for tumor microenvironment manipulation and cancer therapy. One critical issue for monocyte-based therapy is to deliver therapeutic agents into monocytes efficiently. In the present study, we systematically investigated the relationship between the surface potential and the biodistribution of polymeric nanoparticles in monocytes in vivo, aiming to screen and identify an appropriate delivery system for monocyte targeting, and we found that cationic nanoparticles have a higher propensity to accumulate in monocytes compared with their neutral counterparts. We further demonstrated that siCCR2-encapsulated cationic nanoparticle (CNP/siCCR2) could modify immunosuppressive tumor microenvironment more efficiently and exhibit superior antitumor effect in an orthotopic murine breast cancer model.
研究领域:
纳米技术
·
肿瘤学
·
免疫疗法
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
STAR Protocols
·
2023
·
IF 0
Yunfei Yi,Chan Feng,Mian Yu,Lin Mei,Meiying Wu,Wei Tao
Summary Efficient gene delivery in an integrated drug delivery system is urgent for multimodal antitumor therapy. Herein, we describe a protocol for constructing a peptide-based siRNA delivery system to achieve tumor vascular normalization and gene silencing in 4T1 cells. We highlighted four major steps, including (1) synthesis of the chimeric peptide, (2) preparation and characterization of P A7R @siRNA micelleplexes, (3) in vitro tube formation assay and transwell cell migration assay, and (4) siRNA transfection in 4T1 cells. This delivery system is expected to be used to silence gene expression, normalize tumor vasculature, and perform other treatments based on the different peptide segments. For complete details on the use and execution of this protocol, please refer to Yi et al. (2022). 1
研究领域:
癌症生物学
·
分子生物学
·
药学
·
生物技术
✓ 已验证
DOI
PubMed
Journal of Materials Chemistry B
·
2018
·Vol. 7
·期 4
·586-597
·
IF 4.776
Yanan Liu,Meng Xu,Yingyu Zhao,Xu Chen,Xufeng Zhu,Chunfang Wei,Shuang Zhao,Jie Liu,Xiuying Qin
Due to the anti-apoptotic effect employed by cells to protect themselves, recent research shows that photothermal therapy (PTT) can lead to heat shock response, thus reducing the effect of treatment on cancer cells. Small interfering RNA (siRNA), as an effective carrier of RNA interference, can silence the expression of heat shock protein, HSPs or BAG3 genes by inhibiting the expression of specific genes, and thereby inhibiting heat shock response and making cancer cells more sensitive to PTT. In this study, flower-like gold nanoparticles were used as a core for a layer-by-layer strategy to produce a safe and biodegradable nanoparticle platform for gene silencing and photothermal therapy. The results showed that when the mass ratio of the GNFs and siRNA was 20 : 1, the loading efficiency was above 90%, which can effectively silence the expression of BAG3 siRNA. We demonstrated that the GNFs–siRNA still had a good photothermal effect after siRNA modification. In vitro, the GNFs–siRNA showed good biocompatibility and effectively tumor killing properties after laser irradiation. Furthermore, the GNFs–siRNA with laser treatment significantly decreased the expression of BAG3 and remarkably inhibited tumor growth in vivo. This nanosystem establishes an optimized platform for future gene delivery and photothermal therapy.
研究领域:
纳米技术
·
癌症研究
·
治疗学
·
分子生物学
✓ 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）