Nanoscale
·
2018
·Vol. 10
·期 22
·10514-10527
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IF 7.233
Hang Hu,Jiangling Wan,Xuetao Huang,Yuxiang Tang,Chen Xiao,Huibi Xu,Xiangliang Yang,Zifu Li
Herein, reduction-responsive disintegratable nanoclusters (NCs) were prepared as a novel nanovehicle for targeted drug delivery. The NCs, with a diameter of ∼170 nm, were self-assembled from hydrophobically modified and iRGD decorated hydroxyethyl starch (iRGD-HES-SS-C18). DOX was loaded into the NCs as a model drug. DOX@iRGD-HES-SS-C18 NCs can disintegrate into smaller ones and release DOX under reduction stimuli. Due to the ligand–receptor binding interactions between iRGD and integrin αV, DOX@iRGD-HES-SS-C18 NCs can specifically bind to the cell membranes of HepG-2 and 4T1 cells (integrin αV positive), resulting in enhanced cellular uptake as compared to DOX@HES-SS-C18 NCs. After cellular internalization, the NCs were transported to endosomes/lysosomes in which the reductive environment triggered the disintegration and DOX release. As a consequence, DOX@iRGD-HES-SS-C18 NCs exhibited an enhanced antitumor effect as compared to DOX@HES-SS-C18 NCs and free DOX, in an in vitro antitumor activity study. The reduction-responsive disintegratable NCs reported here were proved to be a safe and efficient nanoplatform, holding significant translation potential for tumor-targeted drug delivery.
研究领域:
药剂学
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肿瘤学
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生物材料科学
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产品关联
DOI
PubMed
高影响因子
Nano Research
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2020
·Vol. 13
·期 10
·2706-2715
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IF 8.183
Yan Jing,Zhu Rongying,Wu Fan,Zhao Ziyin,Ye Huan,Hou Mengying,Liu Yong,Yin Lichen
Insufficient intratumoral penetration greatly hurdles the anticancer performance of nanomedicine. To realize highly efficient tumor penetration in a precisely and spatiotemporally controlled manner, far-red light-responsive nanoclusters (NCs) capable of size shrinkage and charge conversion were developed and co-administered with iRGD to synergistically improve the intratumoral penetration and the anticancer efficacy. The NCs were constructed using the singlet oxygen-sensitive (SOS) polyethylene glycolpolyurethane-polyethylene glycol (PEG-( 1 O 2 )PU-PEG) triblock copolymer to encapsulate the doxorubicin (DOX)-loaded, chlorin e6 (Ce6)-conjugated polyamindoamine (PAMAM) dendrimer (DCD) via the double-emulsion method. Co-administration of iRGD notably increased the permeability of NCs within tumor vasculature and tumor tissues. In addition, upon far-red light irradiation (660 nm) of tumors at low optical density (10 mW/cm 2 ), the generated 1 O 2 could disintegrate the NCs and release the DCD with positive surface charge and ultra-small size (∼5 nm), which synergized with iRGD to enable deep intratumoral penetration. Consequently, the local 1 O 2 at lethal concentrations along with the released DOX efficiently and cooperatively eradicated tumor cells. This study provides a convenient approach to spatiotemporally promote the intratumoral penetration of nanomedicine and mediate programmed anticancer therapy.
研究领域:
药剂学
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肿瘤学
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生物材料学
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DOI
高影响因子
JOURNAL OF DRUG TARGETING
·
2017
·
IF 3.068
Chang Liu,Sen Yao,Xuqian Li,Feng Wang,Yanyan Jiang
iRGD (internalizing RGD) with high affinity to αν integrins was reported to enhance tumor penetrability by binding to neuropilin-1 (NRP-1). Based on our previous study, chitosan surface-modified poly (lactide-co-glycolides) nanoparticles (PLGA/CS NPs), loaded with carmustine (BCNU) and its sensitizer (O6-benzylguanine, BG) showed stronger anti-tumor effect than free drugs. In present study, PLGA/CS NPs (NPs) with core-shell structure were prepared and modified with iRGD or mPEG. F98, C6 or U87 cell lines with different receptors levels were selected for in vitro and in vivo studies. After administration of iRGD-mediated NPs, including iRGD-modified NPs (iRGD-NPs) and co-administration of iRGD and NPs (iRGD + NPs), their effects on glioma were compared with NPs. iRGD-NPs showed stronger cytotoxicity and cellular uptake than other groups. iRGD-NPs and iRGD + NPs displayed deeper tumor penetration and stronger anti-invasion effect on three dimensional (3D) glioma spheroids than NPs. On F98 glioma-bearing mice model, iRGD-mediated NPs showed enhanced crossing BBB ability and brain tumor accumulation levels. Correspondingly, the median survival time of iRGD + NPs, iRGD-NPs and NPs groups were 58, 49 and 34.5 days, respectively. Present studies supported the iRGD-mediated strategy to improve the efficacy of antitumor drug delivery system. Importantly, co-administration of iRGD may be a greater way over the conjugation of iRGD.
研究领域:
药剂学
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肿瘤学
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神经科学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2023
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IF 8
Dinghu Zhang,Yanhong Chu,Hanqing Qian,Lingyu Qian,Jie Shao,Qiuping Xu,Lixia Yu,Rutian Li,Quanan Zhang,Fenglei Wu,Baorui Liu,Qin Liu
Introduction Gambogic acid (GA) is proved to have anti-tumor effects on gastric cancer. Due to poor solubility, non-specific biological distribution, toxicity to normal tissues and short half-life, it is hard to be applied into the clinic. To overcome these issues, we developed a thermosensitive and injectable hydrogel composed of hydroxypropyl cellulose, silk fibroin and glycerol, with short gelling time, good compatibility and sustained release, and demonstrated that the hydrogel packaged with gambogic acid nanoparticles (GA-NPs) and tumor-penetrating peptide iRGD could improve the anti-tumor activity.Methods The Gelling time and micropore size of the hydrogels were regulated through different concentrations of glycerol. Controlled release characteristics of the hydrogels were evaluated with a real-time near-infrared fluorescence imaging system. Location of nanoparticles from different carriers was traced by confocal laser scanning microscopy. The in vivo antitumor activity of the hydrogels packaging GA-NPs and iRGD was evaluated by investigating tumor volume and tumor size.Results The thermo-sensitive properties of hydrogels were characterized by 3–4 min, 37°C, when glycerol concentration was 20%. The hydrogels physically packaged with GA-NPs and iRGD showed higher fluorescence intensity than other groups. The in vivo study indicated that the co-administration of GA-NPs and iRGD by hydrogels had higher antitumor activity than the GA-loaded hydrogels and free GA combining with iRGD. Free GA group showed few antitumor effects. Compared with the control group, the body weight in other groups had no obvious change, and the count of leukocytes and hemoglobin was slightly decreased.Discussion The hydrogel constructed iRGD and GA-NPs exerted an effective anti-tumor effect possibly due to retention effect, local administration and continuous sustained release of iRGD promoting the penetration of nanoparticles into a deep part of tumors. The delivery system showed little systemic toxicity and would provide a promising strategy to improve anti-gastric cancer efficacy.
研究领域:
肿瘤学
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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
DRUG DEVELOPMENT RESEARCH
·
2019
·Vol. 80
·期 8
·1080-1088
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IF 1.742
Hang Hu,Bin Wang,Chao Lai,Xiangjian Xu,Zihan Zhen,Huan Zhou,Defeng Xu
Paclitaxel (PTX) is a chemotherapeutic agent which shows antitumor activities against a broad spectrum of cancers. Yet, the current formulation of PTX used in clinic may cause a number of adverse reactions, which significantly limit its application. To obtain better clinical use of PTX, we report, for the first time, iRGD-PTX conjugate nanoparticles (NPs) for targeted PTX delivery. iRGD-PTX conjugate was synthesized from thiolated iRGD and 6-maleimidocaproic acid-PTX through Michael addition reaction. iRGD-PTX NPs with hydrodynamic diameter of ~110 nm were self-assembled from iRGD-PTX conjugate in deionized water. The as-prepared iRGD-PTX NPs exhibit good stability in phosphate buffered saline (PBS) buffer and fetal bovine serum containing PBS buffer. iRGD-PTX NPs exhibit sustained drug release behaviors. The in vitro studies show that iRGD-PTX NPs can be internalized by 4T1 cells by integrin αV-mediated endocytosis, resulting in better in vitro antitumor activity as compared to free PTX. The in vivo studies demonstrate that iRGD-PTX NPs exhibit enhanced tumor accumulation. The iRGD-PTX NPs reported here represent a novel PTX nanoplatform to achieve targeted PTX delivery.
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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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2016
·
IF 7.145
Shengnan Ma,Jie Zhou,Yuxin Zhang,Yiyan He,Qian Jiang,Dong Yue,Xianghui Xu,Zhongwei Gu
The stability dilemma and limited tumor penetration of nanocarriers in cancer chemotherapy remain two predominant challenges for their successful clinical translation. Herein, the pH-sensitive fluorocarbon-functionalized nanocarriers (SFNs) with a tumor-homing and penetrating peptide iRGD are reported to overcome the stability dilemma and enhance tumor accumulation and penetration in an orthotopic breast cancer. The highly stable SFNs with a low critical association concentration provide a safe and spacious harbor for hydrophobic drugs. Furthermore, the stimulus-responsive evaluation and in vitro drug release study show that the SFNs can balance intracellular dissociation for drug release and extracellular stability in the blood circulation. Additionally, the tumor penetration capacity has been dramatically enhanced in 3D multicellular spheroids, effectively affecting cells far from the periphery. This can be ascribed to the coadministration of iRGD having tumor-penetrating ability and fluorocarbon chains having good cell membrane permeability. The combination of SFNs and iRGD is a viable approach to assist drugs’ effective accumulation in primary and metastasized tumor sites, significantly inhibiting the breast tumor growth and curbing lung and liver metastases in an orthotopic-tumor-bearing mouse model. Taken together, this pH-sensitive fluorinated nanosystem having excellent stability and tumor accumulation and penetration properties paves the way to combat cancer.
研究领域:
肿瘤学
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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 Nanomedicine
·
2023
·
IF 8
Xianchuang Liu,Xinyang Zhu,Xun Qi,Xianwei Meng,Ke Xu
Purpose Hepatocellular carcinoma (HCC) is one of the most common fatal cancers, with no curative therapy available. The concept of ferroptosis is attracting increasing attention in cancer research. Herein, we describe the use of a nanodevice as an effective strategy for inducing ferroptosis to manage HCC.Methods To improve ferroptosis-induced treatment of HCC, we constructed sorafenib (sor)-loaded MIL-101(Fe) nanoparticles (NPs) [MIL-101(Fe)@sor] and evaluated the efficacy of ferroptosis-based HCC therapy after co-administration with the iRGD peptide both in vitro and in vivo.Results The prepared MIL-101(Fe) NPs have several promising characteristics including drug-loading, controllable release, peroxidase activity, biocompatibility, and T2 magnetic resonance imaging ability. MIL-101(Fe)@sor NPs significantly induced ferroptosis in HepG2 cells, increased the levels of lipid peroxidation and malondialdehyde, and reduced those of glutathione and glutathione peroxidase 4 (GPX-4). The in vivo results showed that the MIL-101(Fe)@sor NPs significantly inhibited tumor progression and decreased GPX-4 expression levels, with negligible long-term toxicity. Meanwhile, co-administration of MIL-101(Fe)@sor NPs with iRGD significantly accelerated ferroptosis.Conclusion Our findings suggest that MIL-101(Fe)@sor NPs co-administered with iRGD are a promising strategy for inducing HCC ferroptosis.
研究领域:
肿瘤学
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药理学
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纳米医学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2023
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IF 8
Jiejian Chen,Qiyao Yang,Minchen Liu,Mengting Lin,Tiantian Wang,Zhentao Zhang,Xincheng Zhong,Ningning Guo,Yiying Lu,Jing Xu,Changsheng Wang,Min Han,Qichun Wei
Purpose Boron neutron capture therapy (BNCT) is an emerging binary radiotherapy, which is limited for application due to the challenge of targeted delivery into tumor nowadays. Here, we propose the use of iRGD-modified polymeric nanoparticles for active targeted delivery of boron and doxorubicin (DOX) in BNCT.Methods 10B-enriched BSH was covalently grafted to PEG-PCCL to prepare 10B-polymer, then surface-modified with iRGD. And, DOX was physically incorporated into polymers afterwards. Characterization of prepared polymers and in vitro release profile of DOX from polymers were determined by several methods. Cellular uptake of DOX was observed by confocal microscope. Accumulation of boron in cells and tissues was analyzed by ICP-MS. Biodistribution of DOX was studied by ex vivo fluorescence imaging and quantitative measurement. Tumor vascular normalization of Endostar for promoting delivery efficiency of boron on refractory B16F10 tumor was also studied.Results The polymers were monodisperse and spheroidal in water with an average diameter of 24.97 nm, which were relatively stable at physiological pH and showed a sustained release of DOX, especially at endolysosomal pH. Enhanced cellular delivery of DOX was found in iRGD-modified polymer group. Cellular boron uptake of iRGD-modified polymers in A549 cells was remarkably raised fivefold (209.83 ng 10B/106 cells) compared with BSH. The polymers represented prolonged blood circulation, enhanced tumor accumulation of 10B against BSH, and favorable tumor:normal tissue boron concentration ratios (tumor:blood = 14.11, tumor:muscle = 19.49) in A549 tumor-bearing mice 24 hrs after injection. Both fluorescence imaging and quantitative measurement showed the highest tumor accumulation of DOX at 24 hrs after injecting of iRGD-modified polymers. Improvement of vascular integrity and reduction of vascular mimicries were found after Endostar injection, and raised tumor accumulation of boron as well.Conclusion The developed nanoparticle is an inspiring candidate for the safe clinical application for BNCT.
研究领域:
癌症治疗
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纳米技术
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药学
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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
RSC Advances
·
2016
·Vol. 6
·期 34
·28331-28342
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IF 3.289
Lu Wang,Xi Xie,Di Liu,Xiao-Bin Fang,Peng Li,Jian-Bo Wan,Cheng-Wei He,Mei-Wan Chen
Reduction-sensitive micelles with crosslinked cores were developed to load the lipophilic chemotherapeutic drug docetaxel (DTX) in order to overcome the issues of toxicity, water insolubility, and rapid metabolism of DTX. These DTX-loaded micelles (MM(DTX/Crosslink)) provide efficient incorporation and sustained release of DTX. Using independently synthesized LA–PLGA–TPGS and DSPE–PEG polymers as vehicles, MM(DTX/Crosslink) was found to be reduction-responsive, and possessed desirable drug entrapment efficiency (84.17 ± 1.15%) and drug loading efficiency (6.21 ± 0.07%). The MM(DTX/Crosslink) quickly dissociated under reduction conditions that mimicked the reductive intracellular environment, suggesting that it can rapidly release the encapsulated DTX in vitro. Furthermore, to target MM(DTX/Crosslink) to tumors for cancer therapy, iRGD was conjugated to the surface of MM(DTX/Crosslink). The iRGD-MM(DTX/Crosslink) micelles significantly increased the cellular uptake of DTX and inhibited cell proliferation, compared to the micelles without iRGD modification. Moreover, the iRGD-MM(DTX/Crosslink) micelles presented enhanced antitumor effects based on the analyses of apoptosis and cell cycle arrest. The micelles developed in this work may constitute a stable, efficient, and powerful system to deliver DTX into cancer cells.
研究领域:
药剂学
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肿瘤学
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生物材料学
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产品关联
DOI
高影响因子
Theranostics
·
2020
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IF 8.579
Haohan Wu,Yanni He,Hao Wu,Meijun Zhou,Zhili Xu,Ran Xiong,Fei Yan,Hongmei Liu
Rheumatoid arthritis (RA), a common inflammatory disorder of the joints characterized by synovitis and pannus formation, often results in irreversible joint erosion and disability. Methotrexate (MTX) is the first-line drug against RA, but the therapeutic effects are sub-optimal due to its poor retention at the target sites and systemic side effects. Multifunctional nanoparticles are highly promising agents for minimally invasive, traceable and effective targeted therapy. Methods: This study developed iRGD peptide-functionalized echogenic liposomes (iELPs) which encapsulates MTX and indocyanine green (ICG) fluorescent probe through the thin film-hydration method. Results: The resulting iELPs showed high affinity for endothelial cells overexpressing αvβ3 integrin, favorable acoustic response and fluorescence tracking properties. Also, near-infrared (NIR) fluorescence imaging of iELPs and ultrasound-triggered drug release of MTX were proved in a mouse RA model, greatly improving the therapeutic efficacy and reducing MTX side effects. Histological assessment of the articular tissues further revealed significantly lower inflammatory cell infiltration and angiogenesis in the iELPs-treated and sonicated mice. Conclusion: Our study provides a promising nanoplatform for integrating ultrasound-controlled drug release and NIR fluorescence imaging for RA treatment.
研究领域:
医学
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纳米技术
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药理学
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影像学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Xuefeng Hou,Qi Chen,Ying Fang,Li Zhang,Shuoheng Huang,Minjie Xu,Yaning Ren,Zhansen Shi,Yan Wei,Lihua Li
Background Breast cancer presents significant challenges due to the limited effectiveness of available treatments and the high likelihood of recurrence. iRGD possesses both RGD sequence and C-terminal sequence and has dual functions of targeting and membrane penetration. iRGD-modified nanocarriers can enhance drug targeting of tumor vascular endothelial cells and penetration of new microvessels, increasing drug concentration in tumor tissues.Methods The amidation reaction was carried out between SiO2/AuNCs and iRGD/PTX, yielding a conjugated drug delivery system (SiO2/AuNCs-iRGD/PTX, SAIP@NPs). The assessment encompassed the characterization of the morphology, particle size distribution, physicochemical properties, in vitro release profile, cytotoxicity, and cellular uptake of SAIP@NPs. The tumor targeting and anti-tumor efficacy of SAIP@NPs were assessed using a small animal in vivo imaging system and a tumor-bearing nude mice model, respectively. The tumor targeting and anti-tumor efficacy of SAIP@NPs were assessed utilizing a small animal in vivo imaging system and an in situ nude mice breast cancer xenograft model, respectively.Results The prepared SAIP@NPs exhibited decent stability and a certain slow-release effect in phosphate buffer (PBS, pH 7.4). In vitro studies had shown that, due to the dual functions of transmembrane and targeting of iRGD peptide, SAIP@NPs exhibited strong binding to integrin αvβ3, which was highly expressed on the membrane of MDA-MB-231 cells, improving the uptake capacity of tumor cells, inhibiting the rapid growth of tumor cells, and promoting tumor cell apoptosis. The results of animal experiments further proved that SAIP@NPs had longer residence time in tumor sites, stronger anti-tumor effect, and no obvious toxicity to major organs of experimental animals.Conclusion The engineered SAIP@NPs exhibited superior functionalities including efficient membrane permeability, precise tumor targeting, and imaging, thereby significantly augmenting the therapeutic efficacy against breast cancer with a favorable safety profile.
研究领域:
纳米技术
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癌症研究
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药学
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生物医学工程
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分子生物学
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2018
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IF 4.37
Zhen Zhang,Hanqing Qian,Jie Huang,Huizi Sha,Hang Zhang,Lixia Yu,Baorui Liu,Dong Hua,Xiaoping Qian
Background Red blood cell membrane-coated nanoparticle (RBCm-NP) platform, which consist of natural RBCm and synthetic polymeric core, can extend circulation time in vivo with an improved biocompatibility and stability of this biomimetic nanocarrier. To achieve better bioavailability of antitumor drugs that were loaded in RBCm-NPs, the functionalization of coated RBCm with specific targeting ability is essential. Bispecific recombinant protein anti-EGFR-iRGD, containing both tumor penetrating peptide (internalizing RGD peptide) and EGFR single-domain antibody (sdAb), seems to be an optimal targeting ligand for RBCm-NPs in the treatment of multiple tumors, especially colorectal cancer with high EGFR expression. Materials and methods We modified the anti-EGFR-iRGD recombinant protein on the surface of RBCm-NPs by lipid insertion method to construct iE–RBCm–PLGA NPs and confirmed the presentation of active tumor-targeting ability in colorectal cancer models with high EGFR expression when compared with RBCm–PLGA NPs. In addition, potential anti-tumor drug gambogic acid (GA) was loaded into the NPs to endow the antitumor efficiency of iE–RBCm–GA/PLGA NPs. It was simultaneously evaluated whether GA can reach better biocompatibility benefiting from the improved antitumor efficiency of iE–RBCm–GA/PLGA NPs in colorectal cancer models. Results We successfully modified anti-EGFR-iRGD proteins on the surface of biomimetic NPs with integrated and stable “shell–core” structure. iE–RBCm–PLGA NPs showed its improved targeting ability in vitro (multicellular spheroids [MCS]) and in vivo (nude mice bearing tumors). Besides, no matter on short-term cell apoptosis at tumor site (terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]) and long-term tumor inhibition, iE–RBCm–GA/PLGA NPs achieved better antitumor efficacy than free GA in spite of the similar effects of cytotoxicity and apoptosis to GA in vitro. Conclusion We expect that the bispecific biomimetic nanocarrier can extend the clinical application of many other potential antitumor drugs similar to GA and become a novel drug carrier in the colorectal cancer treatment.
研究领域:
纳米技术
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药学
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肿瘤学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）