International Journal of Nanomedicine
·
2023
·
IF 8
Wen-jing Zhu,Shu-di Yang,Chen-xi Qu,Qiao-ling Zhu,Wei-liang Chen,Fang Li,Zhi-qiang Yuan,Yang Liu,Ben-gang You,Xue-nong Zhang
Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new “binary polymer” low-density lipoprotein–N-succinyl chitosan–cystamine–urocanic acid (LDL–NSC–SS–UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA–PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA–PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy.
研究领域:
药学
·
生物医学工程
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Yurong Xiang,Qiang Liu,Kang Liu,Liuxian Chen,Fengjiao Chen,Tao Li,Siqi Li,Qiang Yu,Quan Lv,Zheng Xiang
Multi-drug combination therapy is one of the most effective strategies for the treatment of drug-resistant and advanced tumors. Modern nanodrug delivery systems are crucial for multi-drug combination therapy and gene therapy. However, research on direct injection of RNAi has not yielded significant results. Artificial vectors are emerging as promising delivery systemts for RNA for gene therapy. In this study, a multi-drug therapy system was built based on a biodegradable exosome nano-platform exploiting the protective and low immunogenic properties of exosomes for RNA. This work aimed to accomplish the co-delivery of siRNA and 3-Bromopyruvic acid (3BP) on an exosome nanoplatform, enhancing targeting by coupling cetuximab (CTX) to exosome membranes, resulting in a new nanomedicine Exo@siRNA/3BP-CTX (ERBC) engineered exosomes. The synthesis conditions were optimized to obtain stable, safe, and effective nanomedicines. Successful targeting of tumors with CTX inhibited KRAS oncogene expression and significantly reduced glucose uptake by cancer cells. This enhanced the starvation therapy effect of the energy deprivation agent 3BP, thus promoting excessive autophagy activation in cells and doubling apoptosis. However, ERBC combined with CTX therapy restored cellular chemosensitivity to CTX. These findings indicate that engineered exosomes with dual therapeutic activities is a promising approach for treating refractory KRAS-mutant cancers.
研究领域:
肿瘤学
·
基因治疗
·
纳米医学
✓ 已验证
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2022
·
IF 10.633
Mengying Hou,Xuejie Wu,Ziyin Zhao,Qiurong Deng,Yongbing Chen,Lichen Yin
Neutrophils serve as a key contributor to the pathophysiology of myocardial ischemia reperfusion injury (MIRI), because the unregulated activation and infiltration of neutrophils lead to overwhelming inflammation in the myocardium to cause tissue damage. Herein, endothelial cell-targeting and reactive oxygen species (ROS)-ultrasensitive nanocomplexes (NCs) were developed to mediate efficient co-delivery of VCAM-1 siRNA (siVCAM-1) and dexamethasone (DXM), which cooperatively inhibited neutrophil recruitment by impeding neutrophil migration and adhesion. RPPT was first synthesized via crosslinking of PEI 600 with ditellurium followed by modification with PEG and the endothelial cell-targeting peptide cRGD. RPPT was allowed to envelope the DXM-loaded PLGA nanoparticles and condense the siVCAM-1. After systemic administration in rats experiencing MIRI, the cRGD-modified NCs efficiently targeted and entered the inflamed endothelial cells, wherein RPPT was sensitively degraded by over-produced ROS to trigger intracellular siVCAM-1 release and potentiate the VCAM-1 silencing efficiency. As a consequence of the complementary function of DXM and siVCAM-1, the NCs notably mitigated neutrophil infiltration into ischemic myocardium, provoking potent anti-inflammatory efficacy to reduce MIRI and recover cardiac function. The present study offers an effective approach for the controlled co-delivery of siRNA and drug cargoes, and it also highlights the importance of multi-dimensional manipulation of neutrophils in anti-inflammatory treatment. Statement of significance The unregulated activation and infiltration of neutrophils lead to overwhelming inflammation in the myocardium after myocardial ischemia reperfusion injury (MIRI). Here, endothelial cell-targeting and ROS-ultrasensitive nanocomplexes (NCs), comprised of PLGA NPs decorated with cRGD-poly(ethylene glycol) (PEG)-modified, ditellurium-crosslinked PEI (RPPT), were developed to mediate efficient co-delivery of VCAM-1 siRNA (siVCAM-1) and dexamethasone (DXM). DXM and siVCAM-1 with complementary functions inhibited both the migration and adhesion of neutrophils, efficiently interventing the neutrophil recruitment and interrupting the self-amplified inflammation cascade in the injured myocardium. The molecular design of RPPT renders an effective example for constructing polymeric materials with high ROS sensitivity, and it resolves the critical dilemma related to polycation-mediated siRNA delivery, such as siRNA encapsulation versus release, and transfection efficiency versus toxicity.
研究领域:
药学
·
纳米技术
·
心血管研究
·
分子生物学
·
炎症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2020
·
IF 7.242
Yihang Wu,Ling Wang,Yue Xiong,Quanming Zhou,Linxian Li,Guanyu Chen,Yulei Ping,Gary Davidson,Pavel A. Levkin,Liqian Gao,Wenbin Deng
Development of non-viral gene vectors which can efficiently and safely transfect plasmid DNA and siRNA into cells is of great importance for gene therapy. Despite lots of efforts spent, it is still imperative to develop suitable gene vectors with better transfection efficiency and low cytotoxicity. To this end, we successfully designed, synthesized and screened a library of 120 polymers ( via nucleophilic substitution reaction between dihalides and amines). With cell-based transfection screening assays, 120 polymers were tested to evaluate their transfection efficiency of transporting DNA and siRNA into cells. Our results indicated that hydrophobic modification could greatly enhance cationic polymers’ transfection efficiency, and polymers with long linkers usually showed better transfection performance, especially for polymers with the linker of 1, 12-dibromododecane (L3 linker). Besides, polyalkylamines exhibited better transfection efficiency with the polymer particle size around 200 nm and the zeta potential in the range of + 40 mV to +50 mV. Interestingly, polymer particles made from N15HL3 not only exhibited better DNA transfection efficiency in HEK 293T cells but also showed higher siRNA transfection efficiency in U87 Luc-GFP cells together with low cell toxicity than Lipofectamine 2000 (one of commercial transfection reagents). Therefore, it is hoped that our study here not only provides promising gene vector candidates for further evaluation in gene therapy, but also provides valuable insights for better understanding of the relationship between the chemical structures and gene transfection efficiency to rationally design better non-viral gene vectors for gene therapy in the future.
研究领域:
基因治疗
·
药学
·
生物技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2021
·Vol. 13
·期 19
·8998-9008
·
IF 7.79
Xupeng Mu,Meng Zhang,Anhui Wei,Fei Yin,Yan Wang,Kebang Hu,Jinlan Jiang
Programmed cell death ligand 1 (PD-L1) blockade has achieved great success in cancer immunotherapy. PD-L1 siRNA can restore the immune anti-tumor activity of T cells by downregulating the level of PD-L1 on tumor cells, but the efficiency of PD-1/PD-L1 monotherapy is relatively low. Doxorubicin (DOX) can induce tumor cell apoptosis, and then increase the release of tumor antigen. But the expression of PD-L1 in tumor tissues treated with DOX will be enhanced adaptively. Therefore, DOX combination with PD-L1 siRNA can produce a good synergistic anti-tumor effect. In this study, stem cell membrane (SCM) camouflaged polydopamine nanoparticles carrying DOX and PD-L1 siRNA (PDA–DOX/siPD-L1@SCM) were constructed for targeting prostate cancer (PCa) bone metastases. PDA–DOX/siPD-L1@SCM NPs could effectively enhance blood retention and improve accumulation at tumor sites. In vitro and in vivo studies demonstrated that PDA–DOX/siPD-L1@SCM NPs showed excellent performance in synergistic chemoimmunotherapy for PCa bone metastases. Hence, this study provided an effective strategy for developing biomimetic multifunctional nanoparticles for PCa bone metastasis treatment.
研究领域:
癌症研究
·
纳米技术
·
药学
·
免疫治疗
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2023
·
IF 13.3
Yunshu Lu,Fenfen Gu,Yuwei Ma,Ruonan Li,Yi Luo,Xianhong Da,Lan Jiang,Xiang Li,Yan Liu
Triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer, currently lacks a targeted therapy and has a high clinical recurrence rate. The present study reports an engineered magnetic nanodrug based on Fe 3 O 4 vortex nanorods coated with a macrophage membrane loaded with doxorubicin (DOX) and Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) siRNA. This novel nanodrug displays excellent tissue penetration and preferential tumor accumulation. More importantly, it significantly increases tumor suppression compared to chemotherapy, suggesting the synergistic activity of the combination of doxorubicin and EZH2-inhibition. Importantly, owing to tumor-targeted delivery, nanomedicine shows an excellent safety profile after systemic delivery, unlike conventional chemotherapy. In summary, chemotherapy and gene therapy are combined into a novel magnetic nanodrug carrying doxorubicin and EZH2 siRNA, which shows promising clinical application potential in TNBC therapy.
研究领域:
肿瘤学
·
纳米技术
·
药学
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2017
·
IF 8.402
Qin Wang,Hao Jiang,Yan Li,Wenfei Chen,Hanmei Li,Ke Peng,Zhirong Zhang,Xun Sun
The transcription factor NF-kB plays a pivotal role in the pathogenesis of rheumatoid arthritis. Here we attempt to slow arthritis progression by co-delivering the glucocorticoid dexamethasone (Dex) and small-interfering RNA targeting NF-kB p65 using our previously developed polymeric hybrid micelle system. These micelles contain two similar amphiphilic copolymers : polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethyleneglycol (PCL-PEG). The hybrid micelles loaded with Dex and siRNA effectively inhibited NF-kB signaling in murine macrophages more efficiently than micelles containing either Dex or siRNA on their own. In addition, the co-delivery system was able to switch macrophages from the M1 to M2 state. Injecting hybrid micelles containing Dex and siRNA into mice with collagen-induced arthritis led the therapeutic agents to accumulate in inflamed joints and reduce inflammation, without damaging renal or liver function. Thus, blocking NF-kB activation in inflammatory tissue using micelle-based co-delivery may provide a new approach for treating inflammatory disease.
研究领域:
药理学
·
纳米技术
·
风湿病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2014
·
IF 8.312
Qiao-ling Zhu,Yi Zhou,Min Guan,Xiao-feng Zhou,Shu-di Yang,Yang Liu,Wei-liang Chen,Chun-ge Zhang,Zhi-qiang Yuan,Chun Liu,Ai-jun Zhu,Xue-nong Zhang
Developing safe and effective carriers of small interference RNA (siRNA) is a significant demand for the systemic delivery of siRNA. In this study, low-density lipoprotein (LDL) was isolated from human plasma and loaded with cholesterol-conjugated siRNA to silence the multidrug resistant gene of tumors. Chol-siRNA/LDL-coupled N-succinyl chitosan nanoparticles loaded with doxorubicin (Dox-siRNA/LDL-SCS-NPs) were then prepared and characterised. The Dox-siRNA/LDL-SCS-NPs had average particle size of 206.4 ± 9.2 nm, entrapment efficiency of 71.06% ± 1.42%, and drug-loading amount of 12.35% ± 0.87%. In vitro antitumor activity revealed that cell growth was significantly inhibited. The accumulation of Dox by fluorescence microscopy and flow cytometry showed that LDL-coupled nanoparticles were more easily taken up than Dox-SCS-NPs. Results of confocal microscopy and reverse transcription-PCR revealed the highly efficient uptake of siRNA and the decrease in mdr1 mRNA expression. LDL-coupled nanoparticles protected siRNA from macrophage phagocytosis by dynamic observation using live cell station. In vivo tumor-targeting suggested that Cy7-labelled Dox-LDL-SCS-NPs were markedly accumulated in an analyzed in situ liver tumor model. Results indicated that LDL-SCS-NPs were effective tumor-targeting vectors and that the preparation form may provide a new strategy for co-delivering siRNA and antitumor drugs.
研究领域:
药学
·
纳米技术
·
癌症研究
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2014
·
IF 8.312
Tinghui Yin,Ping Wang,Jingguo Li,Yiru Wang,Bowen Zheng,Rongqin Zheng,Du Cheng,Xintao Shuai
Drug resistance is a big problem in systemic chemotherapy of hepatocellular carcinoma (HCC), and nanomedicines loaded with both chemotherapeutic agents (e.g. paclitaxel, PTX) and siRNA's targeting antiapoptosis genes (e.g. BCL-2) possess the advantages to simultaneously overcome the efflux pump-mediated drug resistance and antiapoptosis-related drug resistance. However, tumor-penetrating drug delivery with this type of nanomedicines is extremely difficult due to their relatively big size compared to the single drug-loaded nanomedicines. Aiming at address this problem, US-responsive nanobubbles encapsulating both anti-cancer drug paclitaxel (PTX) and siRNA (PTX–NBs/siRNA) for HCC treatment were developed by hetero-assembly of polymeric micelles and liposomes in the present study. Utilizing an external low-frequency US force imposed to the tumor site, effective tumor-penetrating codelivery of siRNA and PTX was achieved via tail vein injection of PTX–NBs/siRNA into nude mice bearing human HepG2 xerografts. Consequently, the PTX treatment-inducible antiapoptosis in HepG2 cells was effectively suppressed by the codelivered siRNA targeting an antiapoptosis gene (BCL-2 siRNA) during chemotherapy. Owing to the synergistic anti-cancer effect of two therapeutic agents, tumor growth was completely inhibited using low-dose PTX in animal study. Our results highlight the great potential of this type of US-responsive hetero-assemblies carrying both anti-cancer drug and siRNA as an effective nanomedicinal system for HCC therapy.
研究领域:
药理学
·
肿瘤学
·
纳米技术
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2015
·Vol. 5
·期 27
·20890-20899
·
IF 3.84
Minghui Xu,Junmin Qian,Aili Suo,Weijun Xu,Rongrong Liu,Hongjie Wang
Combination of chemotherapy and small interfering RNA (siRNA)-based therapy has emerged as a promising approach for cancer treatment with the synergistic effect. In this study, a novel terpolymer methoxy poly(ethylene glycol)-block-poly(N,N-dimethylaminopropyl methacrylamide)-block-poly(acrylhydrazine) (mPEG-b-PDMAPMA-b-PAH) with a disulfide linkage between mPEG and PDMAPMA blocks was developed for the intracellular targeted co-delivery of adriamycin and P-gp siRNA. The terpolymer was synthesized by sequential reversible addition–fragmentation chain transfer (RAFT) polymerization of N,N-dimethylaminopropyl methacrylamide and N-tert-butoxycarbonyl-N′-acryl hydrazine (Boc-acrylhydrazine) in the presence of a PEGylated macro-RAFT agent, followed by Boc-deprotection. The terpolymer could chemically conjugate adriamycin via an acid-cleavable hydrazone bond and simultaneously condense the negatively charged siRNA through electrostatic interactions at an N/P ratio of 2. The resultant adriamycin-conjugated nanoparticles/siRNA complexes (ADR-NPs/siRNA complexes) showed a spherical morphology and had an average diameter of 186 nm. The release profiles of the two payloads from the ADR-NPs/siRNA complexes exhibited a pH/reduction dual-dependent sustained release behavior. The ADR-NPs/siRNA complexes could simultaneously deliver adriamycin and siRNA efficiently into MCF-7/ADR cells and significantly inhibit their growth in a synergistic fashion. All the results indicated that the terpolymer mPEG-b-PDMAPMA-b-PAH could serve as a potential vehicle for the combination of chemotherapy and gene therapy.
研究领域:
药学
·
纳米技术
·
癌症研究
·
聚合物化学
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2020
·
IF 5.162
Biyun Lan,Junfeng Wu,Na Li,Chenglin Pan,Li Yan,Chuan Yang,Liming Zhang,Liqun Yang,Meng Ren
Gene vectors are important for successful siRNA delivery. Four types of hyperbranched cationic polysaccharide derivatives (HCP) were synthesized by conjuncting 1,2-ethylenediamine (EDA) and diethylenetriamine (DETA) with glycogen or amylopectin respectively and named as G-EDA, G-DETA, A-EDA and A-DETA. The efficiency and safety of these HCPs to deliver siRNA were explored in vitro and in vivo . Our results showed that HCPs could form complexes with siRNA. All HCP/siRNA exhibited negligible cytotoxicity. Compared with A-EDA and A-DETA, G-EDA and G-DETA could carry much more siRNA into cells and then escape from endosomes. The delivery of MMP-9 siRNA (siMMP-9) by G-EDA and G-DETA significantly inhibited MMP-9 in HaCaT cells. Wound models in diabetic rats demonstrated that treatment of G-EDA/siMMP-9 could potently knock down MMP-9 of skin wound tissues and then enhanced wound healing. In summary, this study provided an effective and safe approach for siRNA delivery in vitro and in vivo .
研究领域:
药学科学
·
生物技术
·
伤口愈合
·
糖尿病研究
·
纳米技术
·
基因治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Pei-Yao Xu,Ranjith Kumar Kankala,Yu-Jing Pan,Hui Yuan,Shi-Bin Wang,Ai-Zheng Chen
Background In recent times, the co-delivery therapeutics have garnered enormous interest from researchers in the treatment of cancers with multidrug resistance (MDR) due to their efficient delivery of multiple agents, which result in synergistic effects and capable of overcoming all the obstacles of MDR in cancer. However, an efficient delivery platform is required for the conveyance of diverse agents that can successfully devastate MDR in cancer.Methods Initially, short-interfering RNA-loaded chitosan (siRNA-CS) nanoparticles were synthesized using the ionic gelation method. Further, the siRNA-CS nanoparticles and doxorubicin hydrochloride (DOX) were co-loaded in poly-L-lactide porous microparticles (PLLA PMs) (nano-embedded porous microparticles, [NEPMs]) by the supercritical anti-solvent (SAS) process.Results and discussion The NEPM formulation exhibited an excellent aerodynamic performance and sustained release of DOX, which displayed higher anticancer efficacy in drug-resistant cells (human small cell lung cancer, H69AR cell line) than those treated with either free DOX and DOX-PLLA PMs due to the siRNA from CS nanoparticles silenced the MDR gene to DOX therapy.Conclusion This eco-friendly process provides a convenient way to fabricate such innovative NEPMs co-loaded with a chemotherapeutic agent and a gene, which can devastate MDR in cancer through the co-delivery system.
研究领域:
药学
·
纳米技术
·
癌症研究
·
药物递送系统
·
生物医学工程
✓ 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）