Journal of Pharmaceutical Analysis
·
2025
·
IF 8.9
Liyin Wang,Milad Ashrafizadeh,Gautam Sethi,Xinjia Zhou
Suboptimal treatment of laryngeal squamous cell carcinoma (LSCC) reduces survival rate. The poor bioavailability and resistance to cetuximab (Cet) and the instability of small interfering RNA (siRNA) limit their therapeutic efficacy in LSCC. This study aimed to develop a Cet and focal adhesion kinase (FAK) siRNA (siFAK) co-delivery nanosystem. Zeolitic imidazolate framework-8 (ZIF-8), with its large specific surface area and pH-responsive properties, is an ideal delivery carrier that allows controlled drug release in the acidic tumor microenvironment. Therefore, Cet was loaded onto ZIF-8 and encapsulated in a TU177 cell membrane (TCM) after the electrostatic adsorption of siFAK. Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), scanning electron microscopy (SEM), zeta potential, X-ray diffraction, and particle size analyses were used to characterize Cet/siFAK@ZIF-8@TCM. TU177 cells and subcutaneously transplanted tumor-bearing nude mice were used to evaluate the intracellular uptake, cytotoxicity, in vivo biocompatibility, biodistribution, biosafety, pH responsiveness, and anti-LSCC efficacy of Cet/siFAK@ZIF-8@TCM. After ZIF-8@TCM were loaded with Cet and siFAK, alterations in their physical and crystal structures, particle size, and zeta potential were observed. Meanwhile, the co-delivery system increased the loading of Cet through the electrostatic adsorption of siFAK to Cet-loaded ZIF-8. The intracellular uptake of Cet/siFAK@ZIF-8@TCM also protected siFAK from degradation, effectively reducing the messenger RNA (mRNA) and protein expression levels of FAK in LSCC cells. The ZIF-8@TCM nanosystem for co-delivery of Cet and siFAK exhibited pH-responsiveness and tumor-targeting capabilities, thereby exerting anti-LSCC effects. Co-delivery of Cet and siFAK via the pH-responsive ZIF-8@TCM system enabled the targeted release of the chemotherapeutic and gene, in turn maximizing their anti-LSCC effect while ensuring biosafety.
研究领域:
肿瘤学
·
药剂学
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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
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yanan Chen,Zhonghao Jiang,Zhuo Yan,Jierong Liu,Yilin Lai,Li Li,Xiao Lin,Jiantao Lin
Sorafenib (SF) is a first-line drug for the treatment of hepatocellular carcinoma (HCC) in clinical practice. However, acquired drug resistance tremendously limits the clinical efficacy of sorafenib in treating HCC, which has attracted great attention. PDL1 plays a crucial role in the drug resistance of HCC. Here, a codelivery system based on poly-SS-lysine modified chitosan (TAT-C-SS-P) was established and was applied to deliver sorafenib and PDL1-siRNA for synergetic HCC therapy. The successful synthesis of TAT-C-SS-P was confirmed by 1 H NMR. Additionally, sorafenib and PDL1-siRNA were successfully transported into the cells as the decreased expression of VEGF and PD-L1 by administrated with TAT-C-SS-P@SF@ PDL1-siRNA. Simultaneously, the expression of pro-apoptosis proteins cyt-c and Bax was prominently augmented, whereas the expression of anti-apoptosis protein Bcl-2 was decreased. The reduced expression of PDL1 resulted in the downregulation of P-GP and MRP1, which contributed to more sorafenib aggregation in tumor cells. Moreover, TAT-C-SS-P@PDL1-siRNA@SF efficiently promotes apoptosis of HepG2-SI cells, as the apoptosis rate rised to 73 %. A sorafenib-insensitive model was established to evaluate in vivo antitumor effect of TAT-C-SS-P@PDL1-siRNA@SF. TAT-C-SS-P@PDL1-siRNA@SF showed a tumor inhibition rate of 90.2 ± 3.5 % and no significant decrease in body weight. Taken together, our study provided compelling evidence that TAT-C-SS-P@PDL1-siRNA@SF has great potential application in the treatment of HCC clinically.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2018
·
IF 3.862
Wenyi Ruan,Yuanhao Zhai,Kaiyue Yu,Chuanbin Wu,Yuehong Xu
BRAF is the most frequently mutated gene in skin melanoma . Applying BRAF siRNA (siBraf) to silencing BRAF gene is a current frontline therapy for melanoma. However, delivery of macromolecular siRNA into the tumor site and introduction of siRNA into the tumor cells remain as challenges. In this study, we for the first time developed a siBraf delivery system based on cell penetrating peptide octaarginine (R8) nanocomplexes combined with coated microneedles (MNs), i.e. R8/siBraf coated MNs, for targeted anti–melanoma treatment. The R8/siBraf nanocomplexes were optimized based on the internalization of siBraf by A375 cells. In vitro A375 cell experiments presented that R8/siBraf can enhance siBraf transfection, silence BRAF gene, and inhibit tumor cells growth, comparable to polyethylenimine (PEI)/siBraf. R8/siBraf coated MNs can effectively deliver R8/siBraf into the disease site. In vivo anti-melanoma experiments indicated that R8/siBraf coated MNs can significantly inhibit the melanoma development, induce the tumor cells apoptosis , and suppress their proliferation. The BRAF gene in tumor were also significantly silenced in vivo. SiBraf intradermal delivery via combining MNs and R8 nanocomplexes is a promising approach for skin melanoma treatment, which exploited both virtues of MNs and cell penetrating peptide to obtain the targeting inhibition efficacy on skin melanoma.
研究领域:
癌症治疗
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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
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2021
·
IF 5.268
Yufeng Zhang,Yanliang Dong,Junhui Zhou,Wenjun Huang,Yidi Wu,Shuyue Zhao,Yongli Shi,Suping Bai,Chunhui Li,Yuanyu Huang,Anjie Dong
Optimal combination of hydrophobic-hydrophilic balance, proton buffering and electrostatic interaction is the key issue for designing polycations as efficient gene vectors and antibacterial agents . Herein, we screened a series of pH-sensitive quaternary ammonium-based amphiphilic triblock copolymers , mPEG 2k -P(DPA a /DMA b )-PQA c (TDDE-x), which had different pKa values and proton buffering capacities. Significantly, we found that both the highest siRNA intracellular delivery efficiency and the strongest antibacterial capacity occurred on TDDE-3 micelles with the segment structure of mPEG 2k -P(DPA 50 /DMA 56 )-PQA 55 . The TDDE-3/siRNA complex achieved 67% silencing efficiency on H9C2 cells (N/P = 5, 50 nM siRNA), higher than the advanced commercial transfection reagents RNAiMAX (58%) and Lipo2000 (30%). Moreover, TDDE-3 micelles showed quite low MICs of 32 μg/mL and 8 μg/mL against E. coli and S. aureus , respectively. Further studies on the structure-function relationship indicated that TDDE-3 micelles could mediate robust endosome escape and siRNA cytosolic release, and strong bacterial cell membrane-destabilizing function. Undoubtedly, this work reveals the possibility for double optimization of siRNA intracellular delivery efficiency and antibacterial activity of amphiphilic polycations by reasonable structure design, which is significant for low-cost development and clinical translation of efficient multifunctional polycations.
研究领域:
生物材料学
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基因治疗
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抗菌研究
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产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2024
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IF 5.3
Shaojun Yu,Jinrong Zheng,Haiting Xie,Qun Deng,Jianwei Wang,Jian Chen,Haitao Zhou,Jun Wang
Although the significance of the curative effect has been recognized, ideal nanocarriers with the properties of lysosomal escape and biocompatibility are still lacking for the development of siRNA-based cancer gene therapy. In this work, a lysosomal escaped and redox-responsive polyacrylamide nanohydrogel (cRGD-9R-PAss) was constructed for STAT3 siRNA delivery. The functional groups, including tumor-targeting peptide cRGD, cell-penetrating and lysosome-escaping peptide 9R, and a redox-responsive disulfide bond, were introduced to the polyacrylamide nanohydrogel to attain enhanced transfection efficiency and biocompatibility. The synthesized cRGD-9R-PAss(siRNA) was dispersed as core–shell nanoparticles in water with an average size of 48 nm. cRGD-9R-PAss(siRNA) could prevent lysosomal phagocytosis and responsive release STAT3 siRNA into C26 tumor cells, thus promoting STAT3 gene silencing and inhibiting the proliferation of cancer cells in vitro and in vivo. Our results demonstrate that cRGD-9R-PAss hydrogel nanospheres constitute a potential candidate vector for siRNA-based colon cancer gene therapy.
研究领域:
纳米技术
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基因治疗
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癌症研究
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药学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Jinyan Tan,Fan Liu,Xiaoxue He,Lin Gao,Linsheng Wu,Xianbao Shi,Jing Li,Yanfei Chen,Yanhua Liu,Yongbing Sun,Zhixiao Zhang,Zhonggui He,Qikun Jiang,Jin Sun
Lipid nanoparticles (LNPs) have been utilized to deliver small interfering RNA (siRNA) to treat acute liver injury. However, LNPs exhibit suboptimal lysosomal escape capabilities and biodegradability. To address these limitations, we have designed triglyceride-mimetic ionizable lipids by conjugating N,N-dimethyl tertiary amine head groups to the sn-2 position of triglyceride (TG) through ester bonds. These ionizable lipids were abbreviated as 2C-TG, 3C-TG, and 4C-TG, with N,N-dimethyl tertiary amine head groups located in the β-, γ-, and δ-positions of the ester linkage bond, respectively. The uniform-size LNPs were prepared by using the ethanol dilution method. Notably, the position of the tertiary amine head group within the carbon chain of triglyceride-mimetic ionizable lipids is found to significantly influence critical parameters, including the encapsulation rate, pKa, cellular uptake, lysosomal escape, lipase release, and gene silencing efficiency. Our findings hold promise for improving the efficacy and safety of LNP-based siRNA therapeutics.
研究领域:
分子生物学
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药物递送系统
·
生物化学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Jinsheng Huang,Huiling Huang,Yiyao Wang,Bin Xu,Minzhao Lin,Shisong Han,Yuanyuan Yuan,Yong Wang,Xintao Shuai
Activated hepatic stellate cell (aHSC) is mainly responsible for deposition of extracellular collagen matrix that causes liver fibrosis. Although several siRNAs adequately inhibited HSC activation in vitro, they were demonstrated poor RNAi efficiency in vivo. Developing HSC-targeting and cytoplasmic delivery nanocarrier is highly essential to acquire a desirable siRNA therapeutic index for anti-liver fibrosis. Here, we developed a unique crosslinking nanopolyplex (called T-C-siRNA) modified by vitamin A (VA) with the well-designed natures, including the negative charge, retinol-binding protein (RBP) hijacking, and cytoplasmic siRNA release in response to ROS and cis diol molecules. The nanopolyplex was given a yolk-shell-like shape, camouflage ability in blood, and HSC-targeting capability by hijacking the endogenous ligand RBP via surface VA. PDGFR- β siRNA (siPDGFR- β ) supplied via T-C-siPDGFR- β nanopolyplex dramatically reduced HSC activation and its production of pro-fibrogenic proteins in vitro and in vivo. Furthermore, T-C-siPDGFR- β nanopolyplex effectively alleviated CCl 4 -induced liver injury, decreased hepatic collagen sediment, and recovered liver function in mice. This study provides a sophisticated method for HSC-targeting cytoplasmic RNA delivery using endogenous ligand hijacking and dual sensitivity of ROS and cis diol compounds.
研究领域:
药学
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分子生物学
·
纳米技术
·
肝病学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2022
·
IF 7.419
Huixiao Yuan,Xin Huang,Qingqing Li,Cici Luo,Chenyu Lin,Shuxian Zhang,Yaguang Zhang,Zhilin Yan,Ning Du,Zhongmin Liu,Hua Jiang,Bingdi Chen
Novel functions and involvement of circFARSA have not been reported in pancreatic cancer; in addition, its inhibitor screening has not yet been conducted. The purpose of this study was to (1) verify circFARSA as a novel anti-cancer target for pancreatic cancer and (2) to prepare a novel anti-pancreatic cancer agent targeting circFARSA. In this study, we designed and synthesized a small interfering RNA (siRNA, named siRNA-circFARSA), which specifically inhibits circFARSA expression. Using liposomes and porous silicon nanoparticles (pSiNPs) as siRNA delivery system, we prepared liposome-siRNA-circFARSA and pSiNP-PEI-siRNA-circFARSA and investigated their anti-cancer mechanism by quantitative real-time PCR and western blotting. Cell proliferation curves and transwell migration assays were performed to investigate the effect of siRNAs proliferation and migration capabilities of cancer cells. Patient-derived tumor xenograft mouse models were used to investigate the anti-cancer effects in vivo . The data showed that both liposome-siRNA-circFARSA and pSiNP-PEI-siRNA-circFARSA (Si: 0.7 µg/mL) significantly inhibited the proliferation and migration of pancreatic cancer cells in vitro . However, the biological safety and in vivo anti-cancer effects of pSiNP-PEI-siRNA-circFARSA (Si: 22.4 µg/mL) were higher than those of liposome-siRNA-circFARSA. The results showed that siRNA-circFARSA could inhibit the expression of circFARSA and then BCL-2 protein expression, thereby leading to pancreatic cancer cell apoptosis after transportation into pancreatic cancer cells. Therefore, this study provides tools for pancreatic cancer treatment in the future, as it (1) verified circFARSA as a novel target for pancreatic cancer treatment, and (2) prepared a novel anti-pancreatic cancer agent (pSiNP-PEI-siRNA-circFARSA).
研究领域:
肿瘤学
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分子生物学
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纳米技术
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Yuwen Song,Tingting Xu,Hao Li,Jing Liu,Shumin Cao,Yichen Yang,Nianlu Li,Peiwen Lv,Min Han,Haohan Sun,Guangfu Dang,Jianxin Li,Hao Sun,Tao Xin,Huitang Xia,CanWei Zhang
Corneal neovascularization (CoNV) is a leading cause of visual impairment worldwide. However, CoNV remains challenging to cure clinically because of the limitations of current drugs. New and more effective therapeutic formulations for CoNV treatment are therefore urgently needed. Antisense oligonucleotide drugs hold great promise for the treatment of neovascular diseases, and ionizable cationic lipid nanoparticles (icLNPs) have shown excellent performance for nucleic acid delivery, with high encapsulation, good cellular uptake, and effective endosomal escape. In the present study, we identified integrin β1 ( Itgb1 ) as a key gene involved in angiogenesis and revealed the significant upregulation of Flt1 in vascular endothelial cells and pericytes in CoNV using single-cell sequencing. Itgb1 knockdown significantly inhibited the proliferation and migration of vascular endothelial cells and CoNV in mice. Based on these findings, we developed Itgb1 -small interfering RNA (siRNA)-loaded icLNPs, and conjugated anti-Flt1 peptide to their surface to improve CoNV targeting. Furthermore, because lipid nanoparticles reportedly trigger immune responses by upregulating pro-inflammatory cytokine expression, which may promote neovascularization, we modified triptolide (a compound with anti-inflammatory properties) into the icLNPs. The triptolide-modified, anti-Flt1 peptide-conjugated, and Itgb1 -siRNA-loaded icLNPs ( Itgb1 -siRNA@TPL) effectively inhibited the proliferation and migration of vascular endothelial cells in vitro and CoNV in mice after eye drop administration. These effects occurred via downregulation of the PI3K/AKT and NF-κB signaling pathways. Finally, the biosafety of Itgb1 -siRNA@TPL was tested, and the results revealed that it was not toxic to the cornea or major organs and had no impact on corneal epithelial healing. In conclusion, Itgb1 -siRNA@TPL represent a novel, noninvasive, and effective approach for the treatment of CoNV.
研究领域:
医学
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分子生物学
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药剂学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2018
·
IF 3.909
Shuyun Wu,Na Li,Chuan Yang,Li Yan,Xuan Liang,Meng Ren,Liqun Yang
The cationic branched tea polysaccharide (CTPSA) derivative bearing N -acylurea and 3-(dimethylamino)-1-propylamine residues was synthesized and characterized using FTIR and 1 H NMR spectroscopy. A nonspecific siRNA (NsiRNA) was used as a model molecule of functional siRNA that could downregulate over-expressed glycometabolism enzymes in the liver. The result from the agarose gel electrophoresis confirmed that the CTPSA and NsiRNA could form stable complexes when their weight ratio was larger than 18. The zeta potentials and sizes of the complexes were in the range of +8–+15 mv and 120–150 nm, respectively. The CTPSA/NsiRNA complex was observed as nanoparticles with a spherical shape of approximately 100 nm using scanning electron microscopy. The CTPSA derivative and the CTPSA/NsiRNA complexes exhibited lower cytotoxicity in HL-7702 cells when compared with the branched PEI (bPEI) and bPEI/NsiRNA complexes assessed by the Cell Counting Kit-8 assay. The results of flow cytometric analysis and laser confocal microscopy indicated that the CTPSA derivative could effectively target the transfer of the NsiRNA to HL-7702 cells. This work provides a potential approach to promote the CTPSA derivative as a nonviral vector for targeted delivery of functional siRNA to hepatocytes.
研究领域:
药理学
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分子生物学
·
生物技术
·
基因治疗
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
·
2019
·
IF 3.131
Chuanmin Zhang,Shubiao Zhang,Defu Zhi,Yinan Zhao,Shaohui Cui,Jingnan Cui
This work designed a new delivery system (L-PTX-PSur), which could efficiently co-deliver paclitaxel (PTX) and survivin siRNA (Sur) to overcome the dose-limiting toxicity by effectively accumulating PTX in tumor and obtain enhanced therapy by synergistic effect. In this co-delivery system, protamine was selected to condense siRNA into a compacted ‘core’, and a carbamate-linked cationic lipid was used to develop PTX-loaded liposome to entrap the core. L-PTX-PSur with protamine could facilitate Sur entry into NCI-H460 cells and exhibited high encapsulation efficiency of PTX. In vitro studies on the NCI-H460 lung cancer cells revealed that L-PTX-PSur offered significant advantages over the control groups, and it had the highest cellular uptake, the lowest cell viability and the strongest apoptosis. Western blot result showed that survivin protein expression could be noticeably suppressed by L-PTX-PSur in NCI-H460 cells. And the down-regulation of survivin protein could lower the apoptotic threshold of cancer cells and render PTX more effective with low doses. Collectively, L-PTX-PSur with a low dose of PTX could induce a synergistic inhibitory effect on cancer cells growth by the collaboration of PTX and Sur. This work provides a promising strategy for the treatment of lung cancer.
研究领域:
肿瘤学
·
药学
·
分子生物学
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产品关联
DOI
高影响因子
Journal of Materials Chemistry B
·
2015
·Vol. 4
·期 2
·273-281
·
IF 4.726
Lei Wang,Weimin Wu,Jingshuai Wang,Jianjun Wang,Xiaowen Tong,Qiaoling Hu,Lifeng Qi
Malignant bowel obstruction (MBO) is a serious complication which causes high death rate and low quality of life (QOL) for patients diagnosed at an advanced stage of ovarian cancer. RNA interference (RNAi) could be a promising method for the treatment of ovarian cancer and could decrease the morbidity of MBO. Gab2 gene is overexpressed in ovarian cancer compared with normal ovarian tissue, and regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells. Here, chitosan–polyethyleneimine (PEI, Mw 1800) copolymer nanoparticles were synthesized as nanocarriers to deliver Gab2 siRNA into SKOV3 cells. The silencing effects against the Gab2 gene and the antitumor effects by the chitosan–PEI–Gab2 siRNA nanoparticles (chitosan–PEI–Gab2 NPs) were studied. Results showed that highly efficient silencing effects against Gab2 expression and its downstream effector, AKT protein, at more than 90% deregulation were obtained by chitosan–PEI NP mediated Gab2 siRNA delivery, so as to exhibit obvious antitumor effects against SKOV3 cells with low cytotoxicity, and induce cell apoptosis in early and late stages. The study will provide novel strategies to overcome MBO in ovarian cancer by the efficient knockdown of Gab2 expression.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
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）