INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Hongqian Zhang,Feng Ding,Zongwei Zhu,Qian Sun,Chuanxu Yang
Small interfering RNA (siRNA) mediating specific gene silencing provides a promising strategy for anti-inflammatory therapy. However, the development of potent carriers for anti-inflammatory siRNA to macrophages remains challenging. With the aim of realizing potent delivery of siRNA to macrophages, we engineered ionizable lipid nanoparticles (LNPs) with the key component of synthetic lipid-like materials. By varying the amine molecules in the structure of synthetic lipid-like materials, a potent LNP (1O 14 -LNP) was identified, which exhibited efficient transfection of macrophages by facilitating efficient internalization and endosomal escape. The 1O 14 -LNP successfully delivered anti-inflammatory siRNA against interleukin-1β (siIL-1β) with more than 90% downregulation of IL-1β expression in LPS-activated macrophages. From in vivo studies, systemic administrated 1O 14 -LNP/siRNA mainly distributed in liver and efficiently captured by hepatic macrophages without notable sign of toxicity. Furthermore, LPS/ d -GalN-induced acute liver injury model treated with 1O 14 -LNP/siIL-1β resulted in significant suppression of IL-1β expression and amelioration of liver tissue damage. These results demonstrate that the engineered ionizable LNP provides a powerful tool for siRNA delivery to macrophages and that the strategy of silencing of pro-inflammatory cytokines holds great potential for treating inflammatory diseases .
研究领域:
药理学
·
分子生物学
·
治疗学
·
炎症
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2017
·
IF 3.649
Tingting Meng,Binbin Lu,Shihong Shao,Ming Yuan,Xuan Liu,Hong Yuan,Xuan Huang,Fuqiang Hu
P-glycoprotein (P-gp) is a major efflux transporter overexpressed on multidrug resistant tumor cells and responsible for pumping drugs out. If anti-tumor drugs are given when P-gp level is low, satisfactory treatment efficiency may be achieved. Thus, a P-gp down-regulating siRNA (siMDR1) and doxorubicin (DOX) were applied to eliminate multidrug resistant breast cancer cells (MCF-7/ADR). A redox-responsive glucolipid conjugate (CSO-ss-SA) was used to condense siRNA (CSO-ss-SA/siRNA) and encapsulate DOX (CSO-ss-SA/DOX) separately. They responded to the high reducing environment of tumor cells and fast released the payload. CSO-ss-SA/siMDR1 silenced MDR1 gene and resulted in a transient decrease of P-gp. Sequentially, DOX formulation (CSO-ss-SA/DOX or DOX·HCl) was delivered when P-gp was reduced to the lowest level. After pretreatment by CSO-ss-SA/siMDR1, cytotoxicity of CSO-ss-SA/DOX and DOX·HCl against MCF-7/ADR cells were 6.4 or 3.4-fold respectively of that treated by DOX·HCl alone, which exhibited increased cytotoxin sensitivity of drug resistant cells and maximized therapeutic outcomes. These results revealed that the sequential treatment strategy of CSO-ss-SA/siRNA and CSO-ss-SA/DOX hold potential in achieving an optimal overcoming multidrug resistance efficiency.
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
ADVANCED FUNCTIONAL MATERIALS
·
2017
·Vol. 28
·期 6
·1703207
·
IF 12.124
Jia Feng,Shun Chen,Xuemei Ge,Fei Wu,Guang Bai,Tuo Jin
A synthetic carrier of small interfering RNA (siRNA) with customizable size, pH-responsive degradability and optimized surface population of cell-targeting agents is constructed precisely through a series of interlocked thermodynamically self-regulated processes. This system consists of a unimolecular polyplex core formed from each individual molecule of networked cationic polymer and a multi-functional shell assembled from a rationally designed triblock copolymer. The core-forming polymer of defined size is synthesized via Zeta potential-regulated condensation of branched and linear multi-amine bearing oligomers through pH-responding imidazole conjugated imine linkages. The shell-forming copolymer consists of a multi-carboxyl saccharide end block to guide to the surface assembly, a hydrophobic central block to form an encapsulating layer, and a poly(ethylene glycol) end block equipped with a highly selective active ester for “hooking” various cell-targeting agents. Animal assays confirm the flexibility and convenience of this system to equip with selected functional components for systemic delivery of siRNA.
研究领域:
药学
·
纳米技术
·
生物医学工程
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Materials Today Bio
·
2024
·
IF 8.7
Diyu Wang,Subin Lin,Tuanwei Li,Xiaohu Yang,Xiang Zhong,Qian Chen,Guoqin Jiang,Chunyan Li
ABSTRACT Radiotherapy plays a critical role in the clinical treatment of breast cancer. However, the efficacy of traditional X-ray radiotherapy is greatly limited by its low tumor specificity and treatment tolerance mediated by the tumor microenvironment. Herein, we proposed a novel nano-radiotherapy sensitization strategy to design and construct a cancer cell membrane-coated siRNA-decorated Au/MnO 2 nanosensitizer (R&F@Au/MnO 2 -CM) to synergistically enhance radio-immunotherapy for breast cancer. In the integrated nanosensitizer, the cancer cell membrane (CM) derived from 4T1 breast cancer cells is utilized for targeted functionality, while Au/MnO 2 is designed to improve X-ray absorption and alleviate tumor hypoxia. Additionally, PD-L1 siRNA (R) is used to downregulate PD-L1 expression in tumor cells. In an in situ mouse model of 4T1 breast cancer, R&F@Au/MnO 2 -CM demonstrated accurate tumor identification via CM-mediated homologous targeting after intravenous injection, which was monitored in real-time through NIR-II fluorescence imaging of NIR-935 (F). Subsequently, the radiotherapy sensitivity was achieved due to the strong radiation absorption properties and oxygen generation through catalysis of Au/MnO 2 upon X-ray irradiation. Furthermore, the immunosuppressive microenvironment of the tumor is improved by downregulating PD-L1, enhancing synergistic anti-tumor effect. Our findings demonstrate a promising approach for tumor treatment by combining targeted enhanced radiotherapy with immune activation.
研究领域:
纳米技术
·
癌症研究
·
诊疗学
·
放射生物学
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免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2021
·Vol. 11
·期 52
·32549-32558
·
IF 3.361
Hai Xiao,Shuqin Han,Huricha Baigude
The pro-inflammatory polarization of microglia after stroke is one of the major causes of secondary brain injury. Downregulation of the gene involved in canonical inflammatory pathways in glial cells can exert neuroprotective effects via inhibiting the release of pro-inflammatory factors. In this study, we functionalized DoGo lipids with mannose, the ligand of the mannose receptor (MR) that is expressed in microglia, and evaluated the MR-mediated cellular internalization of DoGo lipid nanoparticles (denote M3) carrying siRNA against TLR4 in BV2 cells in vitro. We confirmed that siTLR4/M3 complexes were specifically internalized by BV2 cells in a MR-dependent manner, and the treatment of oxygen glucose deprivation (OGD)-treated BV2 cells with siTLR4/M3 complexes resulted in remarkable silencing of TLR4, and induced downregulated M1 polarization and upregulated M2 polarization markers. Collectively, our data suggest that the M3 lipoplex is a promising microglia-targeting siRNA delivery agent.
研究领域:
神经科学
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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
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Jiamin Wu,Zhi Li,Zeping Yang,Ling Guo,Ye Zhang,Huihui Deng,Cuifeng Wang,Min Feng
It is not efficient enough using the current approaches for tumor-selective drug delivery based on the EPR effect and ligand–receptor interactions, and they have largely failed to translate into the clinic. Therefore, it is urgent to explore an enhanced strategy for effective delivery of anticancer agents. Clinically, many cancers require large amounts of glutamine for their continued growth and survival, resulting in circulating glutamine extraction by the tumor being much greater than that for any organs, behaving as a “glutamine trap”. In the present study, we sought to elucidate whether the glutamine-trap effect could be exploited to deliver therapeutic agents to selectively kill cancer cells. Here, a macromolecular glutamine analogue, glutamine-functionalized branched polyethylenimine (GPI), was constructed as the carrier to deliver anti-CD47 siRNA for the blockage of CD47 “don’t eat me” signals on cancer cells. The GPI/siRNA glutamine-rich polyplexes exhibited remarkably high levels of cellular uptake by glutamine-dependent lung cancer cells, wild-type A549 cells (A549WT), and its cisplatin-resistant cells (A549DDP), specifically under glutamine-depleted conditions. It was noted that the glutamine transporter ASCT2 was highly expressed both on A549WT and A549DDP but with almost no expression in normal human lung fibroblasts cells. Inhibition of ASCT2 significantly prevented the internalization of GPI polyplexes. These findings raised the intriguing possibility that the glutamine-rich GPI polyplexes utilize the ASCT2 pathway to selectively facilitate their cellular uptake by cancer cells. GPI further delivered anti-CD47 siRNA efficiently both in vitro and in vivo to downregulate the intratumoral mRNA and protein expression levels of CD47. CD47 functions as a “don’t eat me” signal and binds to the immunoreceptor SIRPα inducing evasion of phagocytic clearance. GPI/anti-CD47 siRNA polyplexes achieved significant antitumor activities both on A549WT and A549DDP tumor-bearing nude mice. Notably, it had no adverse effect on CD47-expressing red blood cells and platelets, likely because of selective delivery. Therefore, the glutamine-rich carrier GPI driven by the glutamine-trap effect provides a promising new strategy for designing anticancer drug delivery systems.
研究领域:
肿瘤学
·
药学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2020
·
IF 8.758
Tingjie Yin,Yanqi Liu,Mengnan Yang,Lei Wang,Jianping Zhou,Meirong Huo
Despite the great potential of combination therapy based on siRNA and chemotherapeutics, an efficient vehicle with abilities of well drug co-loading, synchronizing in vivo trafficking, and target-specific co-burst release remains elusive, which results in a suboptimal synergistic potency. Herein, a novel chitosan amphiphile (PEI-ss-HECS-ss-OA, HSPO) with glutathione (GSH)-reversible cationization and hydrophobicization by polyethylenimine (PEI) and octylamine (OA), respectively, was developed for this purpose. HSPO spontaneously assembled in aqueous solution to be a micellar system and effectively co-encapsulated the two drugs with an adjustable dosage ratio. With a surface charge inversion strategy by hyaluronic acid (HA) coating, the HA(HSPO) co-delivery micelles with a negative surface charge (−21.45 ± 1.44 mV) and suitable size (192.52 ± 7.41 nm) selectively accumulated into CD44 overexpressed A549 tumors through a combination of passive and active targeting mechanism. Then, tumor cytoplasm-selective co-burst release was obtained through GSH triggered collapse of the amphiphilic assembly alongside a decrease of positive charge condensation, finally leading to an enhanced synergistic antitumor effect with a superior inhibition ratio of 86.63%. Overall, this study validated the great promise of HSPO as an efficient site-specific rapid co-trafficking vehicle of siRNA and chemotherapeutics for a remarkable synergistic tumor inhibition.
研究领域:
药剂学
·
癌症研究
·
纳米医学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2017
·Vol. 16
·期 2
·1383-1388
·
IF 1.692
Tao Liu,Xidong Wu,Yigang Wang,Xiongjun Hou,Gang Jiang,Ting Wu,Huifen Xie,Minqiang Xie
The co-delivery of a drug and a target gene has become a primary strategy in cancer therapy. Based on our previous study, a synthesized star‑shaped co‑polymer consisting of β‑cyclodextrin (CD) and a poly(L‑lysine) dendron (PLLD) was used to co-deliver docetaxel (DOC) and matrix metalloproteinase 9 (MMP‑9) small interfering RNA, via CD‑PLLD/DOC/MMP‑9 complexes, into mice implanted with HNE‑1 human nasopharyngeal carcinoma (NPC) tumor cells in vivo. Unlike the commonly used amphiphilic co‑polymer micelles, the obtained CD derivative may be used directly for a combined delivery of nucleic acid and hydrophobic DOC without a complicated micellization process. In vivo assays demonstrated that CD‑PLLD/DOC/MMP‑9 inhibited HNE‑1 tumor growth and decreased proliferating cell nuclear antigen expression levels, indicating a potential strategy for NPC therapy. In addition, the distribution of DOC and MMP‑9 was investigated; CD‑PLLD/DOC/MMP‑9 complexes were phagocytized in reticuloendothelial systems, including the liver and spleen, which requires further study. Furthermore, the complexes did not cross the blood‑brain barrier due to their large molecular size, suggesting they may be relatively safe. Additionally, the complexes mediated increased DOC concentrations with prolonged blood circulation and EGFP expression in HNE‑1 tumors. These results suggest the future potential application of CD-PLLD/DOC/MMP-9 for NPC therapy.
研究领域:
肿瘤学
·
药学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2019
·
IF 6.638
Zhenqiang Wang,Liucan Wang,Neeraj Prabhakar,Yuxin Xing,Jessica M. Rosenholm,Jixi Zhang,Kaiyong Cai
Combined photothermal and gene therapy provides a promising modality toward cancer treatment, yet facile integration and controlled codelivery of gene payloads and photothermal conversion agents (PTCAs) remains a great challenge. Inspired by the robust wet adhesion of marine mussels, we present a rationally designed nanosystem constructed by using hybrid mesoporous polydopamine nanoparticles (MPDA) with sub-100 nm sizes and a high photothermal conversion efficiency of 37%. The surface of the particles were modified with tertiary amines by the facile Michael addition/Schiff base reactions of PDA to realize high siRNA loading capacity (10 wt%). Moreover, a successful calcium phosphate (CaP) coating via biomineralization was constructed on the cationic nanoparticle to prohibit premature release of siRNA. The CaP coating underwent biodegradation in weakly-acidic subcellular conditions (lysosomes). The synergistic integration of tertiary amines and catechol moieties on the subsequently exposed surfaces was demonstrated to feature the destabilization/disruption ability toward model cellular membranes via the greatly enhanced interfacial adhesion and interactions. Consequently, sufficient permeability of lysosomal membranes, and in turn, a high lysosomal escape efficiency, was realized, which then resulted in high gene silencing efficiencies via sufficient cytosolic delivery of siRNA. When an efficient knocking down (65%) of survivin (an inhibitor of apoptosis proteins) was combined with a subsequent photothermal ablation, remarkably higher therapeutic efficiencies were observed both in vitro and in vivo , as compared with monotherapy. The system may help to pave a new avenue on the utilization of bio-adhesive surfaces for handling the obstacles of combined photothermal and gene therapy. Statement of Significance Polydopamine (PDA) based porous photothermal-conversion agent (PTCA) with sufficiently high conversion efficiency was employed to deliver photothermal/gene therapy modalities towards cancer treatment. CaP coating via PDA-induced biomineralization was constructed to prohibit premature release of siRNA loaded in the pore space of the nanocarriers. Responsive degradation of CaP also led to the exposure of membrane-lytic surfaces built through the synergistic integration of tertiary amines and catechol moieties, and in turn the significantly enhanced lysosomal escape and cytosol siRNA delivery. Therapeutic targeting of survivin was successfully applied for activation of apoptosis and programmed cell death. Combined photothermal and gene therapy improved therapeutic effectiveness.
研究领域:
纳米技术
·
生物医学工程
·
药学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Research
·
2019
·Vol. 12
·期 3
·659-667
·
IF 8.515
Xu Xin,Yang Weijing,Liang Qiujun,Shi Yanan,Zhang Wenxin,Wang Xiao,Meng Fenghua,Zhong Zhiyuan,Yin Lichen
Co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical challenge against their utilization. We herein developed macrophage-targeting, reversibly crosslinked polymersomes (TKPR-RCP) based on the TKPR-modified, poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) triblock copolymer, which could efficiently encapsulate TNF-α siRNA and dexamethasone sodium phosphate (DSP) in their hydrophilic core. The cationic PEI segments provided additional electrostatic interactions with cargo molecules to promote the encapsulation, and disulfide crosslinking of the polymersome membrane endowed the TKPR-RCP with high colloidal stability. Because the cationic PEI was embedded in the hydrophilic core, the polymersomes displayed neutral surface charge and thus possessed high serum stability. The TKPR-RCP co-encapsulating TNF-α siRNA and DSP could be efficiently internalized by macrophages (∼ 98%) and undergo redox-responsive membrane de-crosslinking to accelerate cargo release in the cytoplasm, thus inducing efficient gene silencing and anti-inflammatory effect. Intravenous injection of the co-delivery TKPR-RCP mediated potent and cooperative anti-inflammatory effect in inflamed colons of UC mice, and significantly prevented animals from colonic injury. This study therefore provides a promising approach for the co-delivery of hydrophilic drug/siRNA toward the treatment of inflammatory bowel diseases.
研究领域:
药学
·
生物医学工程
·
炎症性肠病
✓ 已验证
产品关联
DOI
高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
·
2022
·
IF 6.458
Qiming Yin,Xiang Song,Peng Yang,Wen Yang,Xinyu Li,Xuejun Wang,Shengqi Wang
Liver injury caused by hepatitis is the pathological basis of varied hepatic diseases with high morbidity and mortality. Although siRNA appears promising in therapeutics of hepatitis, efficient and safe delivery remains a challenge. In this study, we developed a new strategy of incorporating glycyrrhizic acid (GA) and polyene phosphatidylcholine (PPC) into lipid nanoparticles (GA/PPC-modified LNPs), which was capable of promoting cellular uptake, enhancing gene-silencing, reducing cytotoxicity and improving siRNA stability. GA/PPC-modified LNP and siRNA lipoplex targeting NF-κB, a key mediator of inflammation, mitigates acute liver injury, as assessed by liver histology , hematological and pro-inflammatory cytokine analysis. Furthermore, GA/PPC-modified LNPs reveal efficiently intracellular delivery of antisense oligonucleotides (ASOs) and mRNA inhibiting viral infection. In conclusion, GA/PPC-modified LNPs could be used as a promising delivery system for nucleic acid-based therapy.
研究领域:
药理学
·
分子生物学
·
纳米技术
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Qiaoxuan Wang,Qi Cheng,Ding Huang,Kefei Zhao,Qiaoju Hu,Min Liang,Yifan Xie,Huaxiang Wu,Changyou Gao
The inefficient lysosomal escape of small interfering RNA (siRNA) from immune cells remains a major barrier to therapeutic efficacy. To address this challenge, an innovative pH-triggered aggregation nanoplatform for enhanced siRNA delivery is developed. By using adamantane (Ad)-modified hyperbranched poly-L-lysine (HBPL-Ad) as a backbone, this nanoplatform incorporated acetalated β-cyclodextrin (β-ACD) as a pH-sensitive “gatekeeper”, together with siRNA to prepare physiologically stable aggregated nanoparticles (ANPs). Triggered by the acidic lysosomal microenvironment, the β-ACD hydrolysis exposed β-CD cavities to enable strong host-guest (β-CD/Ad) binding. This binding caused nanoparticle aggregation and subsequent mild lysosomal membrane permeabilization (LMP), facilitating efficient siRNA escape independent of the proton sponge effect. The ANPs demonstrated superior cellular uptake and significantly enhanced TNF-α silencing across macrophages, dendritic cells, and Jurkat immune cells in vitro. Intraperitoneal administration of ANPs loaded with TNF-α siRNA in a collagen-induced arthritis (CIA) model achieved 93% mRNA reduction and 95% protein reduction in joint TNF-α levels, significantly outperforming Lipo2000 (56% mRNA and 60% protein reduction), effectively attenuating synovitis and cartilage erosion without detectable systemic toxicity. This work establishes pH-triggered programmable aggregation as a potent and transformative strategy for overcoming immune cell delivery barriers, offering a promising clinically viable platform for RNAi-based immunotherapy.
研究领域:
纳米技术
·
RNA干扰
·
免疫治疗
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）