Scientific Reports
·
2024
·Vol. 14
·期 1
·1-10
·
IF 3.8
Tong Luqing,Ye Ke,Chen Qun,Wang Xiaoxi,Hu Chi,Xu Qingsheng,Zhou Lihui,Zhan Renya,Tong Ying
Gamma knife radiosurgery (GKRS) is recommended as the first-line treatment for brain metastases of lung adenocarcinoma (LUAD) in many guidelines, but its specific mechanism is unclear. We aimed to study the changes in the proteome of brain metastases of LUAD in response to the hyperacute phase of GKRS and further explore the mechanism of differentially expressed proteins (DEPs). Cancer tissues were collected from a clinical trial for neoadjuvant stereotactic radiosurgery before surgical resection of large brain metastases (ChiCTR2000038995). Five brain metastasis tissues of LUAD were collected within 24 h after GKRS. Five brain metastasis tissues without radiotherapy were collected as control samples. Proteomics analysis showed that 163 proteins were upregulated and 25 proteins were downregulated. GO and KEGG enrichment analyses showed that the DEPs were closely related to ribosomes. Fifty-three of 70 ribosomal proteins were significantly overexpressed, while none of them were underexpressed. The risk score constructed from 7 upregulated ribosomal proteins (RPL4, RPS19, RPS16, RPLP0, RPS2, RPS26 and RPS25) was an independent risk factor for the survival time of LUAD patients. Overexpression of ribosomal proteins may represent a desperate response to lethal radiotherapy. We propose that targeted inhibition of these ribosomal proteins may enhance the efficacy of GKRS.
研究领域:
肿瘤学
·
放射肿瘤学
·
蛋白质组学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2024
·
IF 5.5
Zhipeng Yang,Yanjie Liu,Haoyuan Li,Qisheng Tang,Biao Yang,Zhifeng Shi,Ying Mao
The blood–brain barrier (BBB) and drug resistance present challenges for chemotherapy of glioblastoma (GBM). A microneedle (MN) patch with excellent biocompatibility and biodegradability was designed to bypass the BBB and release temozolomide (TMZ) and PLCG1-siRNA directly into the tumor site for synergistic treatment of GBM. The codelivery of TMZ and PLCG1-siRNA enhanced DNA damage and apoptosis. The potential mechanism behind this enhancement is to knockdown of PLCG1 expression, which positively regulates the expression of signal transducer and activator of transcription 3 genes, thereby preventing DNA repair and enhancing the sensitivity of GBM to TMZ. The MN patch enables long-term sustainable drug release through in situ implantation and increases local drug concentrations in diseased areas, significantly extending mouse survival time compared to other drug treatment groups. MN drug delivery provides a platform for the combination treatment of GBM and other central nervous system diseases.
研究领域:
药学
·
神经科学
·
癌症研究
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2024
·
IF 4.5
Yumin Li,Lianghao Huang,Sifeng Zhu,Xiaoyao Ma,Zimin Cai,Zhao Yang,Cheng Wang,Wei Wang
Influenza A viruses (IAVs) necessitate urgently development of novel treatment approaches due to their high variability and widespread drug resistance. Penindolone (PND), distinct from anti-IAVs drugs on the market, is a promising IAVs inhibitor specifically targeting both HA1 and HA2 subunits of virus hemagglutinin. However, its clinical utility is hindered by poor water solubility and inadequate oral bioavailability. This study was for the first time to propose a practical and potent delivery approach for PND against IAVs. Inhalable PND-loaded nanoparticles (PND-NPs) were obtained through hydrophobic interactions of PND and monomethoxy poly(ethylene glycol)-poly(D, l -lactide) copolymer, realizing efficient loading of PND. The in vitro experiments demonstrated that PND-NPs exhibited lower cytotoxicity and more potent antiviral activity against IAVs than free PND (IC 50 2.5 μM vs. 42.9 μM for A/Virginia/ATCC1/2009 and 11 μM vs. 73 μM for A/Puerto Rico/8/3 (PR/8)), thus expanding the therapeutic window. In the PR/8 infected mice model, the local delivery of PND-NPs via aerosolized inhalation demonstrated that PND-NPs, superior to the effects of the clinical drug oseltamivir, effectively reduced viral load and pro-inflammatory cytokines in the lungs, and significantly prolonged the survival time of mice (twice as long as the oseltamivir treatment group). Overall, non-invasive inhalation therapy with PND-NPs holds significant promise for clinical application in the antiviral domain.
研究领域:
药理学
·
病毒学
·
纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
DRUG DELIVERY
·
2018
·
IF 3.095
Liuxiang Chu,Aiping Wang,Ling Ni,Xiuju Yan,Yina Song,Mingyu Zhao,Kaoxiang Sun,Hongjie Mu,Sha Liu,Zimei Wu,Chunyan Zhang
Glioblastoma is the most common malignant brain tumor. Efficient delivery of drugs targeting glioblastomas remains a challenge. Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified polylactide-co-glycolide (PLGA) nanoparticles (NPs) were developed to target glioblastoma via nose-to-brain delivery. Anti-EPHA3-modified, TBE-loaded NPs were prepared using an emulsion-solvent evaporation method, showed a sustained in vitro release profile up to 48 h and a mean particle size of 145.9 ± 8.7 nm. The cellular uptake of anti-EPHA3-modified NPs by C6 cells was significantly enhanced compared to that of nontargeting NPs (p < .01). In vivo imaging and distribution studies on the glioma-bearing rats showed that anti-EPHA3-modified NPs exhibited high fluorescence intensity in the brain and effectively accumulated to glioma tissues, indicating the targeting effect of anti-EPHA3. Glioma-bearing rats treated with anti-EPHA3-modified NPs resulted in significantly higher tumor cell apoptosis (p < .01) than that observed with other formulations and prolonged the median survival time of glioma-bearing rats to 26 days, which was 1.37-fold longer than that of PLGA NPs. The above results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.
研究领域:
神经学
·
药剂学
·
肿瘤学
·
纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pathogens
·
2025
·Vol. 14
·期 2
·131
·
IF 3.3
Jingjing Zhang,Mengfei Wang,Dan Wang,Xiangyi Zhang,Yue Ma,Els Pardon,Jan Steyaert,Romany Abskharon,Fei Wang,Jiyan Ma
Prion diseases are fatal neurodegenerative disorders affecting humans and animals, and the central pathogenic event is the conversion of normal prion protein (PrPC) into the pathogenic PrPScisoform. Previous studies have identified nanobodies that specifically recognize PrPCand inhibit the PrPCto PrPScconversion in vitro. In this study, we investigated the potential for in vivo expression of anti-PrPCnanobodies and evaluated their impact on prion disease. The coding sequences of three nanobodies were packaged into recombinant adeno-associated virus (rAAV) and were administered via intracerebroventricular (ICV) injection in newborn mice. We found that the expression of these nanobodies remained robust for over 180 days, with no observed detrimental effects. To assess their therapeutic potential, we performed ICV injections of nanobody-expressing rAAVs in newborn mice, followed by intracerebral prion inoculation at 5–6 weeks of age. One nanobody exhibited a small yet statistically significant therapeutic effect, extending survival time from 176 days to 184 days. Analyses of diseased brains revealed that the nanobodies did not alter the pathological changes. Our findings suggest that high levels of anti-PrPCnanobodies are necessary to delay disease progression. Further optimization of the nanobodies, AAV vectors, or delivery methods is essential to achieve a significant therapeutic effect.
研究领域:
神经科学
·
分子生物学
·
病毒学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Polymer Chemistry
·
2018
·Vol. 10
·期 4
·512-525
·
IF 4.927
Yanan Tan,Xiqin Yang,Suhuan Dai,Keke Lian,Lijuan Wen,Yun Zhu,Tingting Meng,Xuan Liu,Hong Yuan,Fuqiang Hu
The selective delivery of DOX into tumor mitochondria in vitro and in vivo, which can be achieved with the aid of a skeletal polymer with positively charged and lipophilic character, may significantly promote its antitumor efficiency as well as eliminate its severe cardiotoxicity. In this study, we developed a polycationic glycolipid polymer (CSOSA) as a skeletal nanomaterial, which was further modified with lipophilic (4-carboxybutyl) triphenylphosphonium bromide (CTPP) cations to form the mitochondria-targeted polymer C-P-CSOSA. In vitro, C-P-CSOSA polymer micelles were internalized more by tumor cells than normal cells and exhibited rapid lysosomal escape capability due to their strong proton buffering ability. When loaded with DOX, the C-P-CSOSA/DOX micelles could selectively target mitochondria in tumor cells and remarkably activate the mitochondrial apoptosis signaling pathway. Importantly, the C-P-CSOSA polymer exhibited significant mitochondrial co-localization in vivo. Moreover, C-P-CSOSA/DOX demonstrated the highest tumor-inhibition rate (75.0%), when compared with CSOSA/DOX (44.8%) and DOX·HCl (55.0%). Meaningfully, C-P-CSOSA/DOX did not cause obvious organ damage and exhibited the longest survival time, indicating the low toxicity of this polymer. This study opens up new avenues for the future clinical translation of mitochondrial-targeted drug delivery systems.
研究领域:
药学
·
生物医学工程
·
癌症研究
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Zhenqi Jiang,Yuchen Tian,Dingying Shan,Yinjie Wang,Ethan Gerhard,Jianbi Xia,Rong Huang,Yan He,Aiguo Li,Jianchao Tang,Huimin Ruan,Yong Li,Juan Li,Jian Yang,Aiguo Wu
Nanoparticle-based tumor therapies are extensively studied; however, few are capable of improving patient survival time due to premature drug leakage, off target effects, and poor tissue penetration. Previously, we successfully synthesized a novel family of Y 1 receptor (Y 1 R) ligand modified, photoluminescent BPLP nanobubbles and nanoparticles for targeted breast cancer ultrasound imaging ; however, increased accumulation could also be observed in the liver, kidney, and spleen, suggesting significant interaction of the particles with macrophages in vivo . Herein, for the first time, we imparted antiphagocytosis capability to Y 1 R ligand functionalized BPLP-WPU polymeric micelles through the incorporation of a CD47 human glycoprotein based self-peptide. Application of self-peptide modified, DOX loaded micelles in vivo resulted in a 100% survival rate and complete tumor necrosis over 100 days of treatment. In vivo imaging of SPION loaded, self-peptide modified micelles revealed effective targeting to the tumor site while analysis of iron content demonstrated reduced particle accumulation in the liver and kidney, demonstrating reduced macrophage interaction, as well as a 2-fold increase of particles in the tumor. As these results demonstrate, Y 1 R ligand, self-peptide modified BPLP-WPU micelles are capable of target specific cancer treatment and imaging, making them ideal candidates to improve survival rate and tumor reduction clinically.
研究领域:
癌症治疗
·
纳米医学
·
药理学
·
分子影像
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 6.514
Jiaqi Lu,Ru Li,Binsong Mu,Yao Peng,Yi Zhao,Yuesen Shi,Li Guo,Li Hai,Yong Wu
A type of pH-sensitive multi-targeted brain tumor site-specific liposomes (Lip-CTPP) co-modified with p -hydroxybenzoic acid (p-HA) and triphenylphosphonium (TPP) were designed and prepared to co-load doxorubicin (DOX) and lonidamine (LND). Lip-CTPP are promising potential carriers to exert the anti-glioma effect of DOX and LND collaboratively given the following features: 1) Lip-CTPP have a good pharmacokinetic behavior; 2) Lip-CTPP can cross the blood-brain barrier (BBB) and recognize tumor cells through the affinity of p-HA and dopamine/sigma receptors; 3) Lip-CTPP are highly positive charged once the acid-sensitive amide bonds are cleaved in endo/lysosomes to expose TPP and protonate amine groups; 4) the positive charged Lip-CTPP escape from endo/lysosomes and accumulate in mitochondria through electrostatic adsorption; 5) DOX and LND are released and synergistically increase anti-tumor efficacy. Our in vitro and in vivo results confirmed that Lip-CTPP could greatly elevate the inhibition rate of tumor cell proliferation , migration and invasion, promote apoptosis and necrosis, and interfere with mitochondrial function. In addition, Lip-CTPP could significantly prolong the survival time of glioma bearing mice, narrow the tumor region and inhibit the infiltration and metastasis capability of glioma cells. Collectively, Lip-CTPP are promising nano formulations to enhance the synergistic effect of DOX and LND in glioma treatment.
研究领域:
药学
·
神经科学
·
肿瘤学
·
药理学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2024
·
IF 5.3
Nuo Li,Ludan Zhang,Kaijun Sun,Junheng Liu,Zixuan Wang,Yujing Wang,Huinan Lu,Wenjun Xiang,Hailin Yang,Rupei Tang,Guoqing Yan
5-Fluorouracil (5FU) and its derivatives have been widely used for cancer treatment; however they fail to achieve selective chemotherapy. Herein, this work highlights a successful development of a pH-sensitive aliphatic 5-fluorouracil (5FU) derivative prodrug, which is synthesized via chemically linking 5FU and stearyl alcohol (SA) using ortho ester linkage. It can further self-assemble into a synergistic small molecule nanodrug through a noncovalent interaction with doxorubicin (DOX). The nanodrug displays precise structure and high drug loading (more than 15% of drug loading content (DLC) and 87% of drug loading efficiency (DLE)). SA and ortho ester linkages endow the nanodrug with high lipophilicity on tumor cell membrane and tumoral intracellular pH response, respectively. The nanodrug also exhibits a slightly negatively charged surface (−0.513 mV) at physiological pH (7.4) and a large-to-small size change from 176.2 to 128.9 nm at tumoral intracellular pH (5.0). These superior characteristics endow the nanodrugs with blood circulation stability, selective tumor accumulation, improved cellular uptake, efficient drug release, as well as synergistic effect on tumor cells, thereby significantly inhibiting tumor growth (smaller than initial tumor size), reducing side effects, and prolonging survival time. Thus, such a pH-sensitive small molecule nanodrug self-assembled from the aliphatic 5FU derivative and DOX has a great potential for selective synergistic cancer therapy, greatly advancing their clinical use.
研究领域:
药学
·
纳米技术
·
癌症研究
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
Biomaterials Science
·
2019
·Vol. 8
·期 5
·1418-1430
·
IF 5.251
Tiankuan Li,Zhongqian Hu,Chao Wang,Jian Yang,Chuhui Zeng,Rui Fan,Jinhe Guo
Immunotherapy is gradually becoming as important as traditional therapy in the treatment of cancer, but adverse drug reactions limit patient benefits from PD1/PD-L1 checkpoint inhibitor drugs in the treatment of non-small cell lung cancer (NSCLC). As a chemotherapeutic drug for NSCLC, docetaxel (DTX) can synergize with PD1/PD-L1 checkpoint inhibitors but increase haematoxicity and neurotoxicity. Herein, anti-PD-L1 monoclonal antibody (mAb)-conjugated and docetaxel-loaded multifunctional lipid-shelled microbubbles (PDMs), which were designed with biologically safe phospholipids to produce synergistic antitumour effects, reduced the incidence of side effects and promoted therapeutic effects under ultrasound (US) irradiation. The PDMs were prepared by the acoustic-vibration method and then conjugated with an anti-PD-L1 mAb. The material features of the microbubbles and their cytotoxic effects, cellular apoptosis and cell cycle inhibition were studied. A subcutaneous tumour model was established to test the drug concentration-dependent and antitumour effects of the PDMs combined with US irradiation, and an orthotopic lung tumour model simultaneously confirmed the antitumour effect of this synergistic treatment. The PDMs achieved higher cellular uptake than free DTX, especially when combined with US irradiation. The PDMs combined with US irradiation also induced an increased rate of cellular apoptosis and an elevated G2-M arrest rate in cancer cells, which was positively correlated with PD-L1 expression. An in vivo study showed that synergistic treatment had relatively strong effects on tumour growth inhibition, increased survival time and decreased adverse effect rates. Our study possibly provides a well-controlled design for immunotherapy and chemotherapy and has promising potential for clinical application in NSCLC treatment.
研究领域:
肿瘤学
·
药学
·
生物医学工程
·
免疫学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2016
·
IF 4.342
Haijun Zhao,Qian Li,Zehui Hong
Although PEGylation allows a drug delivery vehicle to have prolonged blood circulation time, it faces the problem of reduced cellular uptake. Removal of the polyethylene glycol (PEG)-shell at the appropriate time through tumor-microenvironment triggers could be a feasible solution to this problem. Here, paclitaxel (PTX)-loaded mixed micelles (PTX-mM) self-assembled from stearate-modified hyaluronic acid (SHA), mPEG-b-poly(β-amino ester) (mPEG-b-PAE), and ethylene acetyl-b-poly(β-amino ester) (EA-b-PAE) were developed. In the preparation of PTX-mM, SHA micelles were coated with EA-b-PAE followed by coloading of PTX and mPEG-b-PAE. PTX-mM were capable of extracellular pH-triggered PEG-detachment and poly(β-amino ester) (PAE)-mediated endosomal escape. When the pH was changed from pH 7.4 to pH 6.8, the particle size of PTX-mM significantly decreased from 97.5 ± 4.4 to 71.5 ± 2.3 nm. It also resulted in rapid and complete release of mPEG-b-PAE from PTX-mM as monitored using quartz crystal microbalance (QCM) technology. PTX-mM capable of PEG detachment provided significant enhancement of PTX accumulation in SKOV-3 cells compared to PEG nondetachable PTX-mM. Interestingly, intracellular transport studies using confocal laser scanning microscopy (CLSM) showed that EA-b-PAE could promote the escape of micelles from endolysosomes. The half-maximal inhibitory concentration (IC50) of PTX-mM against SKOV-3 cells was 5.7 μg/mL, and PTX-mM containing 20 μg/mL of PTX induced apoptosis in 53.0% of the cell population. PTX-mM exhibited a highly prolonged elimination half-life (t1/2, 2.83 ± 0.37 h) and improved area under the curve (AUC, 7724.82 ± 1190.75 ng/mL/h) than the PTX-loaded SHA micelles (PTX-M). Furthermore, PTX-mM showed the highest tumor inhibition rate (64.9%) and the longest survival time (53 days) against the SKOV-3 ovarian cancer xenograft models among all formulations. Taken together, the results suggested that PTX-mM have potential as an efficient anticancer formulation in treatment of ovarian cancer.
研究领域:
药学
·
癌症研究
·
药物递送系统
·
纳米技术
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2013
·
IF 7.604
Jian-Qing Gao,Qing Lv,Li-Ming Li,Xin-Jiang Tang,Fan-Zhu Li,Yu-Lan Hu,Min Han
Effective chemotherapy for glioblastoma requires a carrier that can penetrate the blood–brain barrier (BBB) and subsequently target the glioma cells. Dual-targeting doxorubincin (Dox) liposomes were produced by conjugating liposomes with both folate (F) and transferrin (Tf), which were proven effective in penetrating the BBB and targeting tumors, respectively. The liposome was characterized by particle size, Dox entrapment efficiency, and in vitro release profile. Drug accumulation in cells, P-glycoprotein (P-gp) expression, and drug transport across the BBB in the dual-targeting liposome group were examined by using bEnd3 BBB models. In vivo studies demonstrated that the dual-targeting Dox liposomes could transport across the BBB and mainly distribute in the brain glioma. The anti-tumor effect of the dual-targeting liposome was also demonstrated by the increased survival time, decreased tumor volume, and results of both hematoxylin–eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis. The dual-targeting Dox liposome could improve the therapeutic efficacy of brain glioma and were less toxic than the Dox solution, showing a dual-targeting effect. These results indicate that this dual-targeting liposome can be used as a potential carrier for glioma chemotherapy.
研究领域:
药剂学
·
神经科学
·
肿瘤学
·
药物递送系统
✓ 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）