Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 15
·3016-3027
·
IF 5.344
Qian Wu,Kaipeng Wang,Xichao Wang,Guohai Liang,Jinming Li
Controlling and detecting cell differentiation in human mesenchymal stem cells (hMSCs) for regenerative medicine remain challenging at present. Here, we developed multifunctional gold nanoparticles (AuNPs) to control and detect osteogenic differentiation in human mesenchymal stem cells (hMSCs) in real-time. The polyethyleneimine (PEI) capped AuNPs (Au-PEI) were synthesized first and were then conjugated with a matrix metalloproteinase 13 (MMP13)-sensitive peptide-FITC group (EGPLGVRGKG-FITC) to obtain multifunctional AuNPs (AuNP-PEI-peptide-FITC). AuNP-PEI-peptide-FITC could bind siRNA with PEI by electrostatic interactions to form the AuNP-PEI-peptide-FITC/siRNA nanocomplexes, allowing efficient siRNA delivery in hMSCs. The adipogenic-related gene peroxisome proliferator-activated receptor γ (PPARγ) was targeted for silencing by the AuNP-PEI-peptide-FITC/siRNA nanocomplexes to control osteogenic differentiation in hMSCs. After demonstrating that the AuNP nanocomplexes could control cell differentiation, the versatility of this tool was illustrated by showing that it can be used as a nanoprobe for real time detection of the osteogenic differentiation of hMSCs. This was done by measuring the activity of the MMP13 enzyme (produced during osteogenic differentiation) through the recovery of FITC fluorescence. This multifunctional AuNP showed a robust new methodology for controlling cell fate and simultaneously detecting cell differentiation in real-time for hMSCs, which is promising for multiple applications in regenerative medicine.
研究领域:
纳米技术
·
干细胞生物学
·
再生医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Hezhi Wang,Ye Yuan,Lu Qin,Mengmeng Yue,Jingwen Xue,Zhixiang Cui,Xuanguang Zhan,Jiayi Gai,Xin Zhang,Jian Guan,Shirui Mao
Faced with the threat of lung cancer-related deaths worldwide, small interfering RNA (siRNA) can silence tumor related messenger RNA (mRNA) to tackle the issue of drug resistance with enhanced anti-tumor effects. However, how to increase lung tumor targeting and penetration with enhanced gene silencing are the issues to be addressed. Thus, the objective of this study is to explore the feasibility of designing non-viral siRNA vectors for enhanced lung tumor therapy via inhalation. Here, shell-core based polymer-lipid hybrid nanoparticles (HNPs) were prepared via microfluidics by coating PLGA on siRNA-loaded cationic liposomes (Lipoplexes). Transmission electron microscopy and energy dispersive spectroscopy study demonstrated that HNP consists of a PLGA shell and a lipid core. Atomic force microscopy study indicated that the rigidity of HNPs could be well tuned by changing thickness of the PLGA shell. The designed HNPs were muco-inert with increased stability in mucus and BALF, good safety, enhanced mucus penetration and cellular uptake. Crucially, HNP1 with the thinnest PLGA shell exhibited superior transfection efficiency (84.83%) in A549 cells, which was comparable to that of lipoplexes and Lipofectamine 2000, and its tumor permeability was 1.88 times that of lipoplexes in A549-3T3 tumor spheroids. After internalization of the HNPs, not only endosomal escape but also lysosomal exocytosis was observed. The transfection efficiency of HNP1 (39.33%) was 2.26 times that of lipoplexes in A549-3T3 tumor spheroids. Moreover, HNPs exhibited excellent stability during nebulization via soft mist inhaler. In conclusion, our study reveals the great potential of HNP1 in siRNA delivery for lung cancer therapy via inhalation.
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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生物医学工程
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Qing Hu,Jiayi Yao,Xiaoqin Wang,Yanfang Wang,Xiaoling Fu,Ju Ma,Han Lin,Jiaqi Xu,Longhua Shen,Xiangbin Yu
Chemoimmunotherapy can synergistically enhance the therapeutic effects and decrease the side effects by a combined method. However, the effective targeted codelivery of various chemotherapeutic agents and siRNAs remains challenging. Although nanomedicine-based chemoimmunotherapy has shown great potential in cancer treatment in recent years, further effort is needed to simplify the nanocarrier designs and maintain their effective functions. Here, we report a simple but robust multifunctional liposomal nanocarrier that contains a pH-sensitive liposome (LP) shell and a dendritic core for tumor-targeted codelivery of programmed cell death ligand 1 (PD-L1) siRNA and doxorubicin (DOX) (siPD-L1@PM/DOX/LPs). siPD-L1@PM/DOX/LPs had a suitable particle size and zeta potential, excellent stability in serum, and pH-sensitive drug release in vitro. They exhibited significant cell proliferation inhibition compared to free DOX and DOX-loaded LPs and could escape endosomes, effectively release siRNA into the cytoplasm of MCF-7 cells, and significantly reduce the PD-L1 expression on tumor cells. In vivo imaging confirmed high accumulation of siPD-L1@PM/DOX/LPs at the tumor site. More importantly, compared with siPD-L1@PM/LPs or DOX alone, siPD-L1@PM/DOX/LPs were more effective in inhibiting tumor growth and activating cytotoxic T cells in vivo. In conclusion, this nanocarrier may hold promise as a codelivery nanoplatform to improve the treatment of various solid tumors.
研究领域:
癌症研究
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药学
·
纳米技术
·
分子生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 27
·5903-5911
·
IF 5.344
Qingfei Zhang,Gaizhen Kuang,Dongfang Zhou,Yanxin Qi,Mingzhe Wang,Xiaoyuan Li,Yubin Huang
Endo/lysosomal escape and the subsequent controllable/precise release of drugs and genes are key challenges for efficient synergistic cancer therapy. Herein, we report a photoactivated polyprodrug nanoparticle system (PPNPsiRNA) centered on effective light-controlled codelivery of Pt(IV) prodrug and siRNA for synergistic cancer therapy. Under green-light irradiation, PPNPsiRNA can sustainedly generate oxygen-independent azidyl radicals to facilitate endo/lysosomal escape through the photochemical internalization (PCI) mechanism. Besides, concurrent Pt(II) release and siRNA unpacking could occur in a controllable manner after the decomposition of Pt(IV), main chain shattering of photoactivated polyprodrug and the PPNPsiRNA disassociation. Based on these innovative features, excellent synergistic therapeutic efficacy of chemo- and RNAi therapies of PPNPsiBcl-2 could be achieved on ovarian cancer cells under light irradiation. The facile synthesized and prepared photoactivatable polyprodrug nanoparticle system provides a new strategy for effective gene/drug codelivery, where controllable endo/lysosomal escape and the subsequent drug/gene release/unpacking play vital roles, which could be adopted as a versatile codelivery nanoplatform for the treatment of various cancers.
研究领域:
纳米技术
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癌症治疗
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药物递送系统
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药学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2015
·Vol. 3
·期 10
·2215-2228
·
IF 4.726
Minghui Xu,Junmin Qian,Aili Suo,Ning Cui,Yu Yao,Weijun Xu,Ting Liu,Hongjie Wang
Combined treatment of chemotherapeutics and small interfering RNAs (siRNAs) is a promising therapy strategy for breast carcinoma via their synergetic effects. In this study, to improve the therapeutic effect of doxorubicin (DOX), novel triblock copolymers, folate/methoxy-poly(ethylene glycol)-block-poly(L-glutamate-hydrazide)-block-poly(N,N-dimethylaminopropyl methacrylamide) (FA/m-PEG-b-P(LG-Hyd)-b-PDMAPMA), were synthesized and used as a vehicle for the co-delivery of DOX and P-glycoprotein (P-gp) siRNA into breast cancer cells. The triblock copolymers were synthesized by a combination of ring-opening polymerization of γ-benzyl-L-glutamate-N-carboxyanhydride using cystamine-terminated heterotelechelic PEG derivatives possessing folate or methoxy end groups (FA/m-PEG-Cys) as initiators and reversible addition–fragmentation chain transfer polymerization of N,N-dimethylaminopropyl methacrylamide followed by hydrazinolysis. The successful synthesis of the copolymers was confirmed by 1H NMR and gel permeation chromatography. DOX was covalently conjugated onto the poly(L-glutamate-hydrazide) blocks via a pH-labile hydrazone linkage, and the DOX-conjugated triblock copolymers could self-assemble into nanoparticles in aqueous solutions. P-glycoprotein (P-gp) siRNA was then bound to the cationic poly(N,N-dimethylaminopropyl methacrylamide) (PDMAPMA) blocks through an electrostatic interaction, resulting in the formation of spherical nanocomplexes with an average diameter of 196.8 nm and a zeta potential of +28.3 mV. The in vitro release behaviors of DOX and siRNA from the nanocomplexes were pH- and reduction-dependent, and the release rates were much faster under a reductive acidic condition (pH 5.0, glutathione: 10 mM) simulating the intracellular endo-lysosomal environment of cancer cells compared to physiological conditions. The fast payload release rates were closely related to both the glutathione-triggered detachment of PEG blocks from the nanocomplex surface and the pH-sensitive cleavage of hydrazone linkages. FA-decorated nanocomplexes showed higher cellular uptake efficiency and cytotoxicity against MCF-7 cells than FA-free nanocomplexes, as confirmed by confocal laser scanning microscopy, transmission electron microscopy, MTT and flow cytometry analyses. Our results demonstrated that the multifunctional triblock copolymer-mediated co-delivery of DOX and P-gp siRNA might be a new promising therapeutic strategy for breast cancer treatment.
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
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Yudong Song,Cui Tang,Chunhua Yin
Given that vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), over-expressed in breast cancer cells and M2-like tumor-associated macrophages (M2-TAMs) within tumor microenvironment (TME), work synergistically and independently in mediating tumor progression and immunosuppression, combinatorial immune-based approaches targeting them are expected to be a potent therapeutic modality for patients. Here, polyethylene glycol (PEG) and mannose doubly modified trimethyl chitosan (PEG = MT) along with citraconic anhydride grafted poly (allylamine hydrochloride) (PC)-based nanoparticles (NPs) (PEG = MT/PC NPs) with dual pH-responsiveness were developed to deliver VEGF siRNA (siVEGF)/PIGF siRNA (siPIGF) to both M2-TAMs and breast cancer cells for antitumor immunotherapy. With prolonged blood circulation and intelligent pH-sensitivity, PEG = MT/PC NPs were highly accumulated in tumor tissues and then internalized in M2-TAMs and breast cancer cells via mannose-mediated active targeting and passive targeting, respectively. With the charge-reversal of PC, PEG = MT/PC NPs presented effective endosomal/lysosomal escape and intracellular siRNA release, resulting in efficient gene silencing. Due to the synergism between siVEGF and siPIGF in anti-proliferation of tumor cells and reversal of the TME from pro-oncogenic to anti-tumoral, PEG = MT/PC/siVEGF/siPIGF NPs (PEG = MT/PC/siV-P NPs) exerted robust suppression of breast tumor growth and lung metastasis. This combination strategy may provide a promising alternative for breast cancer therapy.
研究领域:
癌症生物学
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药学
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纳米技术
·
免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Xiaochen Ma,Yubo Cui,Min Zhang,Qinghua Lyu,Jun Zhao
Introduction Oxidant stress, abnormal angiogenesis, and inflammation are three key factors contributing to the development of ocular neovascular diseases (ONDs). This study aims to develop a multifunctional nanodrug, DEX@MPDA-Arg@Si (DMAS), which integrates mesoporous polydopamine, vascular endothelial growth factor (VEGF)-siRNA, and dexamethasone (DEX) to address these therapeutic targets.Methods Physicochemical properties of DMAS were measured using transmission electron microscopy and a nanoparticle size analyzer. The encapsulation efficiency and drug loading capacity of DMAS were measured using a UV-visible spectrophotometer. The in vivo therapeutic efficacy and ocular safety of DMAS were evaluated using three established mouse models, including the alkali burn-induced corneal neovascularization (CoNV) model, the oxygen-induced retinopathy (OIR) model, and the laser-induced choroidal neovascularization (CNV) model.Results The DMAS nanoparticles demonstrated a uniform bowl-like shape with an average size of 264.9 ± 2.5 nm and a zeta potential of −28.2 ± 4.2 mV. They exhibited high drug-loading efficiency (36.04 ± 3.60% for DEX) and excellent biocompatibility. In vitro studies confirmed its potent antioxidant, anti-inflammatory, and anti-apoptotic properties. In vivo, DMAS treatment led to significant therapeutic effects across all models. It effectively inhibited CoNV, promoted corneal repair, and modulated inflammation in the alkali burn model. In the OIR model, DMAS reduced retinal neovascularization by decreasing VEGF expression. In the laser-induced CNV model, it significantly reduced the CNV area and lesion thickness.Conclusion This research developed a multifunctional nanodrug, DMAS, capable of co-delivering VEGF-siRNA and DEX, offering synergistic therapeutic benefits for treating ONDs. The DMAS nanodrug demonstrates promising anti-inflammatory, antioxidative, and anti-angiogenic effects, highlighting its potential as a versatile and effective treatment for multiple ocular conditions.
研究领域:
药学
·
纳米技术
·
眼科
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Zide Wang,Huimin Geng,Yuqi Zhang,Yingzhao Shao,Dongchen Li,Zhiwei Li,Yuan Ma,Yulin Zhang,Kaiyan Xi,Zhiwei Xue,Guangpan Sun,Hanlin Zhong,Gang Li,Xingang Li,Ran Wang,Shilei Ni
Glioblastoma multiforme (GBM) is a refractory malignant tumor of the central nervous system; treating GBM remains challenging because many drugs cannot cross the blood–brain barrier (BBB). The presence of meningeal lymphatic vessels indicates significant potential for treating GBM with immunotherapy. However, limited immune cell numbers and immunosuppressive tumor microenvironment present additional challenges. Lymph nodes (LNs) play crucial roles in antitumor immunity, including roles in facilitating cellular interactions and lymphocyte expansion. Inspired by LN functions, we constructed an acid-responsive hydrogel to enhance local immune therapy efficacy. Local injection of this hydrogel into the tumor surgical cavity bypassed the BBB and reversed the adenosine-induced immunosuppressive tumor microenvironment by delivering small interfering RNA (siRNA) to knockdown ecto-5′-nucleotidase. Antigen release induced by doxorubicin, with imidazoquinoline, established a local inflammatory microenvironment to promote cellular interaction and lymphocyte expansion, significantly improving tumor clearance. Overall, this study presents a novel approach for GBM immunotherapy that is inspired by LN functions and demonstrates promising clinical translational value for future treatments.
研究领域:
肿瘤学
·
神经科学
·
免疫学
·
生物医学工程
·
药学
✓ 已验证
DOI
高影响因子
Nanoscale
·
2022
·Vol. 14
·期 17
·6449-6464
·
IF 8.307
Ziwei Yuan,Bin Wang,Yilong Teng,William Ho,Bin Hu,Kofi Oti Boakye-Yiadom,Xiaoyang Xu,Xue-Qing Zhang
Gene therapy holds tremendous potential for the treatment of incurable brain diseases including Alzheimer's disease (AD), stroke, glioma, and Parkinson's disease. The main challenge is the lack of effective gene delivery systems traversing the blood–brain barrier (BBB), due to the complex microvessels present in the brain which restrict substances from the circulating blood passing through. Recently, increasing efforts have been made to develop promising gene carriers for brain-related disease therapies. One such development is the self-assembled heavy chain ferritin (HFn) nanoparticles (NPs). HFn NPs have a unique hollow spherical structure that can encapsulate nucleic acid drugs (NADs) and specifically bind to cancer cells and BBB endothelial cells (BBB ECs) via interactions with the transferrin receptor 1 (TfR1) overexpressed on their surfaces, which increases uptake through the BBB. However, the gene-loading capacity of HFn is restricted by its limited interior volume and negatively charged inner surface; therefore, these drawbacks have prompted the demand for strategies to remould the structure of HFn. In this work, we analyzed the three-dimensional (3D) structure of HFn using Chimera software (v 1.14) and developed a class of internally cationic HFn variants (HFn+ NPs) through arginine mutation on the lumenal surface of HFn. These HFn+ NPs presented powerful electrostatic forces in their cavities, and exhibited higher gene encapsulation efficacy than naive HFn. The top-performing candidate, HFn2, effectively delivered siRNA to glioma cells after traversing the BBB and achieved the highest silencing efficacy among HFn+ NPs. Overall, our findings demonstrate that HFn+ NPs obtained by this genetic engineering method provide critical insights into the future development of nucleic acid delivery carriers with BBB-crossing ability.
研究领域:
生物医学工程
·
分子生物学
·
神经科学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Lingjiao Li,Chengyao Feng,Wenchao Zhang,Lin Qi,Binfeng Liu,Hua Wang,Chenbei Li,Zhihong Li,Chao Tu,Wenhu Zhou
Cisplatin, a frontline chemotherapeutic agent against cancer, faces challenges in clinical application due to significant toxicities and suboptimal efficacy. Renal toxicity, a dose-limiting factor of cisplatin, results from multifactorial processes including cisplatin-induced cellular pyroptosis, oxidative damage, and inflammatory responses. Our findings reveal that Tea Polyphenols Nanoparticles (TPNs) derived from Epigallocatechin gallate (EGCG) effectively could address these diverse mechanisms, comprehensively alleviating cisplatin-induced nephrotoxicity. Leveraging TPNs as carriers, chemical conjugation enables the encapsulation of tetravalent cisplatin prodrug, extending its systemic half-life, enhancing tumor tissue accumulation, while simultaneously mitigating renal toxicity. Concurrently, employing a CRISPR/Cas9 kinase library, we identified CSNK2A1 as a target sensitizing tumor cells to cisplatin, enabling specific siRNA sequences to augment cisplatin susceptibility, thereby minimizing the dosage requirement. Benefiting from the versatile carrier properties of TPNs to codeliver cisplatin prodrug and anti-CSNK2A1 siRNA, we developed a codelivery system, Pt-TPNs/siRNA. Pt-TPNs/siRNA not only enhances the anticancer effects but also mitigates cisplatin-induced renal toxicity, achieving efficacy while reducing toxicity. Mechanistic and safety assessments of these nanoparticles were conducted at both cellular and animal levels, opening new avenues for improved clinical utilization of cisplatin.
研究领域:
肿瘤学
·
药理学
·
纳米技术
·
分子生物学
·
毒理学
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Bin Gu,Xianyan Zeng,Ming Gong,Xiangyu Li,Qian Yu,Zhengzong Tan,Zheqi Lou,Tinghui Jiang,Yu Che,Yiran Ao,Yong Zhu
Glioblastoma multiforme (GBM) is the most aggressive and common adult brain tumor. Current therapies primarily involve surgical resection, followed by chemotherapy and radiotherapy. However, the low survival rate due to high toxicity, side effects, and poor targeting necessitates novel treatments. Post-transcriptional regulation pathways, particularly the regulation of alternative polyadenylation based on the mRNA 3′UTR, play a critical role in cell growth and development and the progression of tumors. Targeting tumor cells and reprogramming the 3′UTR of tumor suppressor genes to achieve post-transcriptional regulation is expected to be a new channel for GBM therapy. Herein, a novel siRNA delivery system is developed based on mesoporous silica nanoparticles: siRNA composite nanoparticles (siRNA CNP). Encapsulation in MSNs overcomes siRNA degradation and cellular entry issues, while lipid bilayer coating improves biocompatibility and stability. Surface-modified nucleic acid aptamer SL1 (Apt-SL1) significantly enhances GBM targeting, offering therapeutic potential. The findings show that siRNA CNP effectively silences the promoter CFIm25 of distal poly(A) in tumor cells, inducing gene reprogramming, inhibiting tumor growth, and promoting apoptosis in nude mice. The siRNA CNP demonstrates a significant effect in reprogramming tumor suppressor genes and treating GBM. It offers a novel and promising therapeutic avenue for GBM.
研究领域:
肿瘤学
·
纳米技术
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2017
·
IF 3.671
Ling Yi,Yisi Wang,Guanliang Lin,Danling Lin,Wenliang Chen,Yugang Huang,Guodong Ye
Ring-opening polymerization of S -propargyl-cysteine -N -carboxyanhydride has been used to synthesize conformation switchable poly( S -propargyl-cysteine) starting with l -cysteine, d l - and d -cysteine. Then cationic polypeptides with different backbone chirality are obtained by nearly 100% side-chain grafting of cysteamine via thiol-yne click chemistry. The cationic polypeptides containing mixed conformations of β-sheets, β-turns and random coils are stable against pH, salt and temperature variations. The cationic polypeptides can condense siRNA at a low polypeptide/siRNA weight ratio to form nanoparticles with size depending on the backbone chirality. The cationic polypeptides derived from poly( S -propargyl- l or d -cysteine) are non-cytotoxic to HeLa and HepG2 cells, but interrupting the backbone chirality enhances the cytotoxicity sharply. The cationic polypeptides used for siRNA delivery show good transfection efficiency, but cell internalization process depends on the backbone chirality. The cationic polypeptide derived from the poly( S -propargyl- l -cysteine) is an appropriate siRNA vector with advantages of non-cytotoxicity and high transfection efficiency.
研究领域:
高分子化学
·
纳米技术
·
生物医学工程
·
分子生物学
·
药学
✓ 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）