ACS Nano
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2024
·
IF 15.8
Di Liu,Na Lu,Fengchao Zang,Mingze Lu,Jingyue Zhang,Ying Zhao,Hao Wan,Mengjun Wang,Qian-Qian Li,Fei Wang,Shouhua Luo,Ming Ma,Fangfang Shi,Haoan Wu,Jing Tu,Yu Zhang
Even though the enhanced permeability and retention (EPR) effect is applicable for the passive targeting of solid tumors, many nanodrugs have failed to achieve meaningful clinical outcomes due to the heterogeneity of EPR effect. Therefore, understanding the mechanism of the EPR effect is crucial to overcome the obstacles nanomedicines face in clinical translation. The aim of this study was to establish a reliable method to increase awareness of the critical influencing factors of nanoparticle (NP) transport into tumors based on the EPR effect using a combined radiogenomics and clinical magnetic resonance imaging (MRI) technique and gene set pathway enrichment analysis. Employing poly(lactic-co-glycolic acid) (PLGA)-coated Fe3O4 NPs as the contrast agent, the monolayer and multilayer distribution of the NPs were observed and quantitatively analyzed by MRI, improving the accuracy of evaluating vascular permeability by MRI. By performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of genes and pathways, we identified a variety of genes affecting vascular permeability, such as Cldn1, Dlg2, Bves, Prkag3, Cldn10, and Cldn8, which are related to tight junctions and control the permeability of blood vessels in tumors. The method presented here provides an MRI-supported approach to increase the breadth of data collected from genetic screens, reveals genetic evidence of the presence of NPs in tumors and lays a foundation for clinical patient stratification and personalized treatment.
研究领域:
医学影像学
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肿瘤学
·
基因组学
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产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2016
·Vol. 9
·期 1
·314-325
·
IF 7.76
Lijia Li,Wei Sun,Lian Li,Yuanyuan Liu,Lei Wu,Fengling Wang,Zhou Zhou,Zhirong Zhang,Yuan Huang
Cationic materials have been reported as promising tools for targeting to mitochondria which are the “power houses” and “metabolic garbage keepers” of cells. However, their positive nature also restricts their in vivo application due to the quick clearance. Herein, we fabricated a nanohybrid consisting of the pH-responsive N-(2-hydroxypropyl)methacrylamide (HPMA) co-polymer (R-P) shells and positive mesoporous silica nanoparticle cores via electrostatic interaction. The anticancer drug, docetaxel (DTX), was encapsulated in the positive MSN cores (MSN–DTX). Once concealed by the anionic R-P shield, the assembled nanohybrid R-P@MSN–DTX will achieve prolonged blood circulation thereby leading to an enhanced EPR effect. At mildly acidic tumor environmental pH, first-stage charge reversion took place due to the hydrolysis of the amide bond on HPMA co-polymers. The de-attachment of the HPMA co-polymer occurred because of the positive charge repulsion and partial exposure of the positively charged MSN core promoted the cell internalization. The second-stage pH-responsiveness in the endo/lysosomes with a more acidic environment accelerates the disassembly of the nanohybrid and the leakage of the core facilitated the endo/lysosome escape and mitochondrial targeting with the help of intracellular compartmental acidity. Gathering up the characteristics of neutralized charge and stepwise pH-responsiveness, the R-P@MSN–DTX acquired a good tumor inhibition rate of 72.6% on nude mice. Our report provided a reference for systemic mitochondrial targeting achieved by the union of “assembly–disassembly”.
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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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2018
·Vol. 7
·期 24
·1801094
·
IF 5.609
Guoqing Wei,Yi Wang,Xuehui Huang,Guang Yang,Jingya Zhao,Shaobing Zhou
The accumulation of nanoparticles in tumors by the enhanced permeability and retention (EPR) effect is effective and well known. However, how to maximize accumulation is still a bottleneck in the development of nanomedicine. Herein, a tumor vascular-targeted hybrid polymeric micelle, which has a great capacity to selectively augment the EPR effect of nanoparticles by dilating tumor blood vessels via the activity of nitric oxide (NO), is presented. Under neutral conditions, the micelle is stable, with a long blood circulation half-life due to the carboxylated poly(ethylene glycol) (PEG) layer; in mildly acidic tumor tissues, the micelle can selectively target the tumor blood vessels by the exposed cyclic Arg-Gly-Asp peptide (cRGD) peptides, which is realized with a pH-dependent hydrolysis of the monomethoxy PEG layer. Simultaneously, exposed copper ions catalyze the decomposition of endogenous NO donors, which generates NO in situ, leading to vasodilation and increased tumor vascular permeability. As a result, the accumulation of nanoparticles is significantly enhanced, and a high accumulation of doxorubicin in tumors is achieved at 48 h after injection. This high dose of therapeutic agent produces a large inhibition of tumor growth (94%) in cancer treatment, and shows no general toxicity, with 100% of the mice surviving the treatment regimen.
研究领域:
药学
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肿瘤学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2019
·
IF 10.273
Yanbing Wang,Zhuo Wang,Caina Xu,Huayu Tian,Xuesi Chen
Despite multifunctional nanoparticles using for photothermal therapy can efficiently kill cancer cells, their further application is still hindered by the intrinsic high uptake in the reticuloendothelial system (RES) organs, causing the slow elimination from the body and potential toxicity to the body. Therefore, it is ideal to develop multifunctional nanoparticles which process the ability to effectively accumulate in tumors, while the nanoparticles can be rapidly excreted from the body via renal clearance after effective treatment. Herein, we report the multifunctional nanoparticles (FeTNPs) based on the coordination interaction of phenolic group and metal iron, which are composed of ferric iron, tannic acid (TA) and poly (glutamic acid)- graft -methoxypoly (ethylene glycol) (PLG- g -mPEG). FeTNPs exhibit the following highlighted features: (1) The effective accumulation in the tumor tissue is achieved based on EPR effect. (2) The dual photoacoustic (PA)/magnetic resonance (MR) imaging capacity can provide guidance for the photothermal therapy (PTT). (3) FeTNPs can be dynamically disassembled by deferoxamine mesylate (DFO) to accelerate elimination of the nanoparticles, thus reducing the potential toxicity for the body. The DFO triggered dynamic disassembling strategy may open a new avenue to overcome the dilemma between EPR effect and renal clearance.
研究领域:
生物医学工程
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癌症治疗
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纳米医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF RADIOANALYTICAL AND NUCLEAR CHEMISTRY
·
2018
·Vol. 316
·期 2
·685-690
·
IF 1.181
Song Hu,Wang Yunhan,Wang Jing,Wang Guanquan,He Jiaheng,Wei Hongyuan,Luo Shunzhong
For the superiority of graphene quantum dots (GQDs) in bioimaging and drug delivery carrier, GQDs bring new opportunities for theranostics of diseases. In this study, GQDs were successfully prepared and labeled with 131 I. The in vitro properties, biodistribution and SPECT imaging of 131 I-GQDs were investigated. The uptake of 131 I-GQDs at tumor sites can be clearly observed via SPECT imaging and T/B and T/M ratios increase with increasing time, which can contribute to enhanced permeability and retention (EPR) effect.
研究领域:
核医学
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放射学
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材料科学
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生物医学工程
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产品关联
DOI
高影响因子
RSC Advances
·
2016
·Vol. 6
·期 17
·13698-13709
·
IF 3.289
Ying Hao,YiXing Huang,YunQi He,JinRong Peng,LiJuan Chen,Xun Hu,ZhiYong Qian
In this study, we successfully prepared MPEG–PDLLA polymer micelles with two different particle sizes, A and B. DLS and TEM assays demonstrated that the particle sizes of the polymer micelles A and polymer micelles B were about 25 nm and 150 nm respectively. The stability of the MPEG–PDLLA polymer micelles in vitro revealed that the free Cy5.5 dye had been successfully loaded into the polymer micelles as a fluorescence marker and the fluorescence wasn’t quenched until 72 h. The cellular uptake of the polymer micelles was time-dependent and micelles A (particle size 25 nm) showed a higher efficiency to be internalized into the cytoplasm of MCF-7 cells than micelles B (particle size 150 nm). Furthermore, in vivo and in vitro biodistribution and tumor-targeting of polymer micelles MPEG–PDLLA were investigated in female MCF-7 tumor-bearing balb/cA-nu mice with an IVIS imaging system. The results showed that polymer micelles A (particle size 25 nm) had a time dependent biodistribution and tumor site accumulation in mice bearing MCF-7 tumors. Meanwhile, the NIR fluorescence intensity of polymer micelles B (particle size 150 nm) in tumor sites showed a pattern of a rise, a peak and then a decline. What’s more, the distribution of the polymer micelles in the tissue slices demonstrated the same results. Consequently, the results indicated that the micelles with a smaller particle size (25 nm) could be more efficiently internalized into cells and increase the enhanced permeation and retention (EPR) effect in tumor tissue. Therefore, a reasonable small size of micelles may be a key factor for a high-performance anti-cancer drug delivery system.
研究领域:
药剂学
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肿瘤学
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生物医学工程
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产品关联
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-18
·
IF 10.435
Zhao Bonan,Dong Zhipeng,Liu Weixing,Lou Fangning,Wang Qiyan,Hong Hao,Wang Yue
Background According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC. Results In this study, the use of poly( l -Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects—enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models. Conclusions We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment. Graphic abstract
研究领域:
肿瘤学
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药学
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免疫疗法
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产品关联
DOI
PubMed
高影响因子
Cancer Nanotechnology
·
2024
·Vol. 15
·期 1
·1-16
·
IF 4.5
Jiang Qiping,Yao Fengjiao,An Yacong,Lai Xialian,Li Xundou,Yu Zhen,Yang Xian-Da
Background PD-1/PD-L1 blockade plays a crucial role in cancer immunotherapy. Exploration of new technologies to further enhance the efficacy of PD-1/PD-L1 blockade is therefore of potential medical importance. Nanotherapeutics can accumulate in tumor tissues due to enhanced permeability and retention (EPR) effects. In this study, a novel nanotherapeutic for cancer immunotherapy was implemented with albumin nanoparticles functionalized by both PD-1 and PD-L1 aptamers.Results Albumin nanoparticles (NP) were functionalized with either PD-1 aptamers (PD1-NP), PD-L1 aptamers (PDL1-NP), or both types of aptamers (PD1-NP-PDL1). Average sizes of PD1-NP, PDL1-NP, and PD1-NP-PDL1 were 141.8 nm, 141.8 nm, and 164.2 nm, respectively. PD1-NP had good affinity for activated T cells that expresses PD-1. Similarly, PDL1-NP could bind with MDA-MB-231 or CT26 tumor cells that express PD-L1. Moreover, the bispecific PD1-NP-PDL1 could bind with both the activated T cells and the PD-L1-expressing tumor cells, and tether the two type of cells together. Functionally, aptamer-modified nanoparticles exhibited stronger immune-stimulating effects vs. free aptamers. Specifically, PD1-NP or PDL1-NP induced stronger lymphocyte-mediated cytotoxicity against PD-L1-expressing tumor cells in vitro vs. free PD-1 or PD-L1 aptamers. Animal studies also showed that PD1-NP or PDL1-NP significantly improved antitumor efficacy against CT26 colon cancer in vivo vs. free PD-1 or PD-L1 aptamers. Importantly, the bispecific PD1-NP-PDL1 further boosted the in vivo antitumor efficacy compared with PD1-NP or PDL1-NP, without raising systemic toxicity.Conclusion The results suggest that the bispecific PD1-NP-PDL1 is a promising nanotherapeutic to improve the efficacy of PD-1/PD-L1 blockade, and may have application potential in colon cancer treatment.
研究领域:
肿瘤学
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纳米医学
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免疫学
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DOI
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Hong Liu,Shuya Wang,Qiaohui Chen,Xiaoyue Ge,Huang Ning,Yanzi Guo,Di Wang,Kelong Ai,Changping Hu
Pulmonary hypertension (PH) is a disease of pulmonary artery stenosis and blockage caused by abnormal pulmonary artery smooth muscle cells (PASMCs), with high morbidity and mortality. High levels of reactive oxygen species (ROS) in pulmonary arteries play a crucial role in inducing phenotypic switch and abnormal proliferation of PASMCs. However, antioxidants are rarely approved for the treatment of PH because of a lack of targeting and low bioavailability. In this study, the presence of an enhanced permeability and retention effect (EPR)-like effect in the pulmonary arteries of PH is revealed by tissue transmission electron microscopy (TEM). Subsequently, for the first time, tungsten-based polyoxometalate nanodots (WNDs) are developed with potent elimination of multiple ROS for efficient treatment of PH thanks to the high proportion of reduced W 5+ . WNDs are effectively enriched in the pulmonary artery by intravenous injection because of the EPR-like effect of PH, and significantly prevent the abnormal proliferation of PASMCs, greatly improve the remodeling of pulmonary arteries, and ultimately improve right heart function. In conclusion, this work provides a novel and effective solution to the dilemma of targeting ROS for the treatment of PH.
研究领域:
药理学
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纳米技术
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心血管疾病
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Yunyan Chen,Ziwei Zhang,Zhilei Qian,Rui Ma,Minna Luan,Yu Sun
Background A sequential release co-delivery system is an effective strategy to improve anti-cancer efficacy. Herein, multicomponent-based liposomes (TET-CTM/L) loaded with tetrandrine (TET) and celastrol (CEL)-loaded coix seed oil microemulsion (CTM) were fabricated, which showed synergistic anti-liver cancer activities. By virtue of Enhanced Permeability and Retention (EPR) effect, TET-CTM/L can achieve efficient accumulation at the tumor site. TET was released initially to repair abnormal vessels and decrease the fibroblasts, and CTM was released subsequently for eradication of tumor tissue.Methods TEM (transmission electron microscopy) and DLS (dynamic light scattering) were adopted to characterize the TET-CTM/L. Flow cytometry was adopted to examine the cellular uptake and cytotoxicity of HepG2 cells. The HepG2 xenograft nude mice were adopted to evaluate the anti-tumor efficacy and systemic safety of TET-CTM/L.Results TEM images of TET-CTM/L showed the structure of small particle size of CTM within large-size liposomes, indicating that CTM can be encapsulated in liposomes by film dispersion method. In in vitro studies, TET-CTM/L induced massive apoptosis toward HepG2 cells, indicating synergistic cytotoxicity against HepG2 cells. In in vivo studies, TET-CTM/L displayed diminished systemic toxicity compared to celastrol or TET used alone. TET-CTM/L showed the excellent potential for tumor-targeting ability in a biodistribution study.Conclusion Our study provides a new strategy for combining anti-cancer therapy that has good potential not only in the treatment of liver cancer but also can be applied to the treatment of other solid tumors.
研究领域:
药学
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肿瘤学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2018
·
IF 3.466
Yan Xiao,Cheng Xu,Hui Xiong,Shi Du,Jianping Zhou,Lifang Yin,Jing Yao
Curcumin (CUR) is a natural diketone with diverse bioactivities of inhibiting angiogenesis and tumor growth. However, its clinical application for cancer treatment was severely hindered by poor aqueous solubility and chemical instability. To overcome these drawbacks and achieve enhanced antitumor efficiency, low molecular weight heparin (LMWH) was conjugated to CUR via the one-step esterification reaction to yield LMWH-CUR (LCU) nanodrugs with the size of 180 nm , which exhibited enhanced accumulation within tumor site by EPR effect and long circulating capacity by LMWH hydrophilic shell. The solubility of conjugated CUR was increased to 0.12 mg/mL (equivalent of CUR) in comparison with 0.006 mg/mL of free CUR. The bioactivities of CUR were guaranteed because of the improved stability of LCU nanodrugs in low pH condition. Moreover, the stronger anti-angiogenesis efficacy of LCU nanodrugs than LMWH monotherapy was also verified. Notably, at a rather low dose of equivalent LMWH (5 mg/kg) and CUR (0.3 mg/kg), the tumor inhibition rate of LCU nanodrugs were much higher than that of LMWH (10 times) and LMWH plus CUR mixture (3.8 times) respectively, indicating its excellent in vivo antitumor efficacy. Overall, our study managed to obtain the novel nanodrugs with potent anti-angiogenesis and antitumor effects whereas avoiding tedious and complicated synthetic procedures. These results also suggested that LCU nanodrugs could be considered as a promising targeted delivery system for cancer treatment.
研究领域:
药学
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纳米技术
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癌症研究
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2018
·
IF 3.997
Jing Zhang,Biao Shen,Liqun Chen,Lingdong Chen,Yangsheng Meng,Jie Feng
A multifunctional envelope-type mesoporous silica nanoparticle (MSN) was delicately designed for subcellular co-delivery of drug and therapeutic peptide to tumor cells. Firstly, a kind of cell apoptosis peptide (KLAKLAK) 2 (KLA) was anchored on surface of MSN via disulfide bond to obtain MSN-SS-KLA. Subsequently, anticancer drug doxorubicin hydrochloride (DOX) was loaded into the pores of MSN-SS-KLA. Then, the drug loaded MSN-SS-KLA (DOX@MSN-SS-KLA) was further coated with bovine serum albumin (BSA) to obtain a biological media stable MSN based drug delivery system (DDS), DOX@MSN-SS-KLA/BSA, for cancer synergetic therapy. The results show that stability of the DOX@MSN-SS-KLA/BSA is much better than that of DOX@MSN-SS-KLA and it could keep well dispersed in serum for more than 24 h. After accumulating at tumor site by EPR effect, the DOX@MSN-SS-KLA/BSA could be effectively phagocytosed by HeLa cells and release apoptotic peptide KLA as well as DOX simultaneously responding to reductive stimulus inside the cells. In vitro cell experiment results show that the DOX@MSN-SS-KLA/BSA complex exhibits much better inhibition on HeLa cells compared with pure DOX, indicating that co-delivery of KLA and DOX is expected to achieve synergetic therapy of cancer.
研究领域:
纳米技术
·
药学
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癌症研究
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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）