Tissue Barriers
·
2024
·
IF 3.6
Qi Cao,Wei Zeng,Jingmin Nie,Yongjun Ye,Yanchao Chen
Impairment of the blood – brain barrier (BBB) and subsequent inflammatory responses contribute to the development of human immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND). Apelin-13, the most abundant member of the apelin family, acts as the ligand of the angiotensin receptor-like 1 (APJ). However, its pharmacological function in HAND and its underlying mechanism are unknown. In the current study, we report that the presence of HIV-1 Tat reduced the levels of Apelin-13 and APJ in the cortex tissue of mice. Importantly, Apelin-13 preserved BBB integrity against HIV-1 Tat in mice by increasing the expression of the tight junction protein zonula occludens-1 (ZO-1) and occludin. Interestingly, increased macrophage infiltration, indicated by elevated CD68-positive staining was observed in the cortex after stimulation with HIV-1, which was mitigated by the administration of Apelin-13. Correspondingly, Apelin-13 reduced the expression of monocyte chemoattractant protein-1; (MCP-1). An in vitro two-chamber and two-cell trans-well assay demonstrated that HIV-1 Tat challenge significantly promoted macrophage migration, which was notably attenuated by the introduction of Apelin-13. Accordingly, treatment with Apelin-13 restored the HIV-1 Tat-induced reduction of occludin and ZO-1, while preventing the upregulation of MCP-1 in human brain microvascular endothelial cells (HBMVECs). Our results suggest that Apelin-13 may reduce macrophage infiltration into brain tissues and mitigate BBB dysfunction in patients with HAND.
研究领域:
神经科学
·
免疫学
·
药理学
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DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2014
·
IF 3.552
Wenjing Zhang,Zhengwei Mao,Changyou Gao
Thermo-sensitive microgel particles may exert a swelling force inside cells and influence on cell viability due to their volume transition in response to external temperature change. In this study, cross-linked poly(N-isopropylacrylamide) (PNIPAM) microgel particles with a thermo-responsive volume expansion ability were prepared by precipitation polymerization of NIPAM, poly(ethylene glycol) diacrylate and acrylic acid. To endow the microgel particles with enhanced cellular uptake and visualization, cell penetrating peptide TAT and fluorescent probe were further covalently immobilized. The cellular uptake, intracellular distribution and thermo-responsive cytotoxicity of the microgel particles were studied by co-culture with lung adenocarcinoma (A549) cells. The PNIAPM microgel particles were largely ingested by A549 cells and mainly located in lysosomes. TAT modification enhanced the cellular internalization of particles but did not alter their intracellular distribution. While the PNIPAM microgel particles did not show significant impact on cell viability at 37 °C, they caused cytotoxicity to some extent when being cultured at 25 °C for 4 h. Doxorubicin loaded PNIPAM microgel particles showed the strongest cytotoxicity when being cultured at 25 °C for 4 h, suggesting the combinational effect of intracellular volume expansion and drug release on cells.
研究领域:
材料科学
·
生物医学工程
·
药学
·
细胞生物学
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DOI
PubMed
高影响因子
Pharmaceutics
·
2025
·Vol. 17
·期 6
·743
·
IF 5.5
Kaixin Liu,Xin Lu,Xudong Guo,Yi Yang,Wanying Liu,Hongbin Song,Rongtao Zhao
Background:Intracellular bacteria frequently result in chronic and recurrent infections. MRSA is one of the most prevalent facultative intracellular bacteria in clinical infections. The drug resistance of MRSA and the difficulty of most antibiotics in entering cells result in a suboptimal clinical efficacy of antibiotics in the treatment of intracellular MRSA. Bacteriophages represent a promising alternative therapy in the context of the current antimicrobial resistance crisis. Nevertheless, the low efficiency of phage entry into cells and their rapid inactivation remain challenges in the treatment of intracellular MRSA using phages. The utilization of functionalized carriers for the delivery of phages into cells and their protection represents a feasible strategy.Methods:In this study, a new MRSA bacteriophage (vB_SauS_PHM) was isolated from hospital sewage, exhibiting the characteristics of short incubation period, large lytic amount, and good environmental tolerance. Subsequently, vB_SauS_PHM was encapsulated by TAT peptide-functionalized liposomes through microfluidic technology and size-exclusion chromatography (SEC), forming a phage delivery system, designated TAT-Lip@PHM.Results:The encapsulation rate of the phage by TAT-Lip@PHM was 20.3%, and the cell entry efficiency was ≥90% after 8 h. The 24 h eradication rate of 300 μg/mL TAT-Lip@PHM against intracellular MRSA was 94.05% (superior to the 21.24% and 44.90% of vB_SauS_PHM and Lip@PHM, respectively), while the mammalian cell activity was >85% after 24 h incubation.Conclusions:The TAT-Lip@PHM effectively delivered the phage into the cell and showed an excellent killing effect on intracellular MRSA with low cytotoxicity. This work provides a technical reference for the application of phages in the treatment of intracellular bacterial infection.
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PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Songlin Song,Lin Gui,Qiqi Feng,Ayijiang Taledaohan,Yuanming Li,Wei Wang,Yanming Wang,Yuji Wang
Purpose Histone citrullination by peptidylarginine deiminases 4 (PAD4) regulates the gene expression of tumor suppressor. In our previously study, YW3-56 (356) was developed as a potent PAD4 inhibitor for cancer therapy with novel function in the autophagy pathway. To enhance the antitumor activity, the PAD4 inhibitor 356 was modified by the well-established cationic penetrating peptide RKKRRQRRR (peptide TAT) and gold nanoparticles to obtain 356-TAT-AuNPs which could enhance the permeability of chemical drug in solid tumor.Methods 356-TAT-AuNPs were prepared, and their morphology were characterized. The antitumor activity of 356-TAT-AuNPs was evaluated in vitro and in vivo.Results 356-TAT-AuNPs exhibited higher anticancer activity against HCT-116, MCF-7 and A549 cells than 356 and 356-AuNPs. Compared with 356 and 356-AuNPs, 356-TAT-AuNPs entered the cytoplasm and nuclear, exhibited stronger anticancer activity by increasing apoptosis, inducing autophagy and inhibiting of histone H3 citrullination, and in HCT-116 xenograft mouse model, 356-TAT-AuNPs could improve the antitumor activity.Conclusion The modified AuNPs with peptide TAT as drug delivery system are potent in delaying tumor growth and could be a powerful vehicle for profitable anticancer drug development. We believe that peptide TAT modification strategy may provide a simple and valuable method for improving antitumor activity of PAD4 inhibitors for clinical use.
研究领域:
癌症研究
·
药学
·
纳米技术
·
分子生物学
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DOI
PubMed
高影响因子
ACS Applied Polymer Materials
·
2026
·Vol. 8
·期 15
·13238-13251
·
IF 5.2
Zou Jiaxin,Li Yanan,Kou Zhaojun,Wang Dayang,Lu Linlin,Cong Hailin,Yu Bing,Ma Xuezhen
Although nanodrug delivery systems
have advanced cancer therapy,
limited tumor penetration and inefficient intracellular transport
still restrict their therapeutic efficacy. Herein, we constructed
a matrix metalloproteinase (MMP)-responsive, TAT-containing polymeric
micelle, O@MTPP, for cascade delivery of oxaliplatin in gastric cancer.
O@MTPP integrates an MMP-2/9-cleavable peptide, MTP (GPLGIAG), with
the cell-penetrating and nuclear-localization-associated TAT peptide
(CYGRKKRRQRRR). In the tumor microenvironment, MMP-2/9-mediated cleavage
triggers charge conversion, enhancing tumor-cell internalization and
penetration-associated distribution. After cellular uptake, TAT further
promotes nuclear-associated accumulation of the nanocarrier-associated
payload, supporting improved intracellular delivery of oxaliplatin.
This cascade delivery strategy enhanced tumor accumulation, strengthened
antitumor activity, and induced immunogenic cell death (ICD)-associated
immune responses, including calreticulin exposure, high mobility group
box 1 (HMGB-1) expression, increased tumor necrosis factor-α
(TNF-α), interferon-γ (IFN-γ), and interleukin-12
(IL-12) levels, and decreased interleukin-6 (IL-6). Overall, O@MTPP
provides an enzyme-activated cascade delivery strategy for overcoming
tissue-level and intracellular barriers in oxaliplatin-based gastric
cancer therapy.
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高影响因子
Journal of Biomedical Nanotechnology
·
2018
·Vol. 14
·期 6
·1039-1051
·
IF 5.068
Guo Songyan,Zhou Qing,Yang Tiehong,Qiao Youbei,Fan Li,Wang Chaoli,Wu Hong
To overcome the strong negative charge and improve the endocytosis of poly-β-malic acid (PMLA) as a drug carrier, a pH-sensitive nanoconjugate of PMLA/hyd-PEG5000/PEG2000-TAT/DOX (PHPTD) was developed. The trans activator of transcription (TAT) modified
with polyethylene glycol2000(PEG2000) was conjugated with the PMLA backbone which improved the endocytosis of PMLA. PEG5000 was utilized to shield TAT by a pH-sensitive hydrazone (Hyd) bond. In order to decrease the potential risk of accelerated blood clearance
(ABC) phenomenon by anti-PEG IgM, the minimal content of TAT for penetrating tumor cells and the optimal protecting layer density of PEG5000 were screened. The result showed that 0.3 mol% TAT was enough to efficiently improve cellular uptake of PMLA (30 kda). The cytotoxicity and
the 1H-NMR results indicated that 3.6 mol% PEG5000-modified nanoconjugates could shield 0.3 mol% TAT. The antitumor effect in breast cancer cells (MDA-MB-231) in tumor-bearing BALB/C mice demonstrated that this nanoconjugates exhibits high therapeutic efficiency in artificial
solid tumors and low toxicity to normal tissues. It is indicated that TAT could be hidden in the long chain of PEG5000 at a neutral pH, when arrival to the tumor extracellular microenvironment, PEG5000 was cleaved from the nanoconjugates through the hydrazone bond due
to the acidic tumor environment. Then, TAT was exposed, allowing the nanoconjugates to be transported into tumor cells. Our findings provide important and detailed information regarding the optimal content of TAT and the shielded density of PEG5000 and reveal their abilities of
tumor penetration and potential for the efficient drug carrier.
研究领域:
药学
·
肿瘤学
·
生物医学工程
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2019
·
IF 3.973
Yukun Song,Xintong Li,Shuang Cong,Haidong Zhao,Mingqian Tan
Carbon dots (CDs) with both one- and two-photon fluorescence have attracted much attention in the field of bioimaging. In this study, we reported a strategy for the design of peptide-conjugated CDs for cellular nuclear-targeted imaging. The CDs were prepared from amino acid and formic acid via an one-step hydrothermal synthesis method, and then modified with trans-activator of transcription (TAT) peptide for both one- and two- photon nuclear-targeted fluorescence imaging. The CDs derived from tryptophan (Trp) and formic acid showed the highest fluorescence quantum yield of 58.4% with an average size about 1.7 nm in diameter. The maximum excitation and emission wavelengths of the Trp/formic acid CDs were 360 and 442 nm, respectively. The Trp/formic acid CDs were successfully conjugated with TAT peptide through the reaction between the amino group of the peptide and carboxylic group of the CDs. Upon grafting with TAT peptide, the resulted TAT-Trp/formic acid CDs could be used as nuclear-targeted fluorescent probes for both one- and two-photon live cell fluorescence imaging.
研究领域:
生物成像
·
材料科学
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
Current Drug Delivery
·
2026
·Vol. 23
·期 6
·681-697
·
IF 3.1
Lin Jing,Simei Luo,Ye Gan,Lili Li,Haotian Wu,Jiajia Zhang,Xu Liu,Mingqing Yuan
Introduction The toxicity of nontargeted chemotherapy hinders liver cancer treatment. This study developed dual-peptide (SP94/TAT) co-modified liposomes (SP94/TAT-DOX/DTX-LPs) for enhanced targeting and efficacy. Methods Liposomes encapsulating docetaxel (DTX) and doxorubicin (DOX) were prepared via film dispersion/ammonium sulfate gradient using DSPE-PEG, lecithin, and cholesterol. SP94 (targeting) and TAT (penetrating) peptides were conjugated via organic phase reaction/insertion. Their physicochemical properties, encapsulation efficiency, stability, drug release, and in vitro antitumor activity were evaluated. Results Optimized SP94/TAT-DOX/DTX-LPs were spherical (119.6 ± 4.1 nm; PDI 0.161 ± 0.006; zeta -9.84 ± 1.54 mV), and their encapsulation efficiency was high (DOX: 92.97 ± 1.73%; DTX: 80.33 ± 0.96%). Stability was confirmed at 4 °C for 30 days (PDI < 0.2, size change < 10%) and in 50% fetal bovine serum (FBS) for 24 hours (transmittance > 90%). Sustained release showed 68.2 ± 3.5% (DTX) and 74.8 ± 2.9% (DOX) cumulative release at 48h (PBS pH 7.4). In vitro, SP94/TAT-DOX-LPs showed 2.3-fold higher HepG2 cellular uptake versus single-modified liposomes (p<0.001), with minimal LO2 uptake. Cytotoxicity assays revealed a 3.11-fold lower IC50 (0.096 ± 0.026 μg/mL) versus unmodified liposomes (0.299 ± 0.103 μg/mL). Apoptosis was significantly higher (39.5% in HepG2) than in single-modified formulations (20.55–26.74%). Discussion SP94/TAT-LPs enable dual-stage targeting: SP94 targets liver cancer cells, and TAT enhances penetration, significantly improving in vitro antitumor activity. Study limitations include sole in vitro validation (HepG2/LO2), small sample size (n=3), parameter variability, and lack of in vivo data on targeting, pharmacokinetics, and toxicity. Conclusion SP94/TAT-DOX/DTX-LPs achieved effective dual-stage targeting and synergistic cytotoxicity. High encapsulation, stability, and sustained release support their potential as a targeted platform for liver cancer therapy, reducing off-target toxicity.
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DOI
高影响因子
BIOMATERIALS
·
2014
·
IF 8.312
Qi-Ming Wang,Zhonggao Gao,Shan Liu,Bo Fan,Lin Kang,Wei Huang,Mingji Jin
The bioactive polymer poly( l -glutamic acid) n - b -poly( d , l -lactic acid) m was synthesized and used to form doxorubicin-loaded hybrid polymeric micelles to treat melanoma. These polymers exhibited pH-responsive changes in conformation, which controlled the diverse functionalities of the micelles. During circulation, poly( l -glutamic acid) n - b -poly( d , l -lactic acid) m protected Tat peptides on the micelles from proteolysis . Under tumor-acidic conditions, polymers with shorter poly( l -glutamic acid) blocks underwent a conformational change to form channels that accelerated the release of doxorubicin . The conformational change also exposed the Tat peptides to tumor cells, thereby promoting cellular internalization of the micelles. Enhanced cellular uptake of the micelles induced significant apoptosis of A375 melanoma cells in tumor-acidic conditions. In vivo studies demonstrated that the micelles with shorter poly( l -glutamic acid) blocks could effectively accumulate in tumor tissues, suppress tumor growth and help maintain the body weight of tumor-bearing mice. However, micelles with longer poly( l -glutamic acid) blocks did not undergo a conformational change under acidic conditions and performed poorly in both in vitro and in vivo evaluations. Our work provides a strategy for applying bioactive polymers to the rational construction of pH-responsive delivery systems for solid tumors and lends insight into possible conformational effects on the bioactivity of drug carriers.
研究领域:
药剂学
·
肿瘤学
·
生物材料学
✓ 已验证
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2018
·
IF 5.08
Guan-Hai Wang,Hua Chen,Yin-Yu Cai,Li Li,Hui-Kang Yang,Qin Li,Zhi-Jiang He,Jian-Tao Lin
The nucleus is one of the most important cellular organelles, where gene encode and transcribe at that location. However, nucleus-targeting gene delivery are rare been reported. It is important to develop a high-efficiency nucleus-targeting gene vector that can deliver targeted gene into nucleus directly for destroy of cancer cells. Here, special nucleus-targeting and size changeable deliver system based on TAT-SS-PAMAM-D3 with TAT functional on the surface and disulfide linked between D2 and D3 is designed to perform highly efficient nucleus-targeting gene delivery for effective cancer cell killing in vitro. CLSM observations reveal that more TAT-SS-PAMAM-D3 are enter into the nucleus when compare to SS-PAMAM-D3. The TAT modified vector can also act as gene deliver to reach high gene transfection efficiencies, high apoptosis and low viability in HeLa cells. This TAT functionalized and disulfide linking in the carrier may become a prospective vector for cancer gene treatment and also offered a different strategy for designing a better gene delivery system.
研究领域:
遗传学
·
肿瘤学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 13.2
Linlin Xie,Xingye Ma,Zheng Wang,Caifang Wang,Zhongxin Xiao,Ling-Dong Sun,Chun-Hua Yan,Chen-Jie Fang
Pyroptosis resulted from photodynamic therapy (PDT) plays a crucial role in triggering photoimmunotherapy (PIT). However, visible light-triggered PDT may rise phototoxicity, with low penetration into biological tissues. Crucially, the efficacy of PDT in eliciting pyroptosis remains suboptimal. To address these formidable challenges, we developed a O 2 -supplementing photosensitizer AuNCs@TAT that could efficiently induce pyroptosis upon irradiation with second near-infrared (NIR-II) light in hypoxic tumor microenvironment (TME). Replacing GSH with TAT resulted in a gold nanocluster AuNCs@TAT. The ratio of Au (I) to Au (0) shifted from 1: 0.26 in pristine AuNCs to 1: 1.21 in AuNCs@TAT, which contributed to enhanced catalytic activity of AuNCs@TAT. The superior catalase-like activity of AuNCs@TAT produced 1.9-fold higher O 2 than AuNCs. This O 2 self-supplying capability of AuNCs@TAT not only relieved hypoxic condition in TME but also significantly enhanced the efficiency of AuNCs@TAT to induce pyroptosis upon 1064 nm light irradiation. Western blotting indicated both remarkable upregulation of cleft Caspase-3 and GSDME-N, suggesting GSDME mediated pyroptosis. Further, release of pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs) triggered a strong systematic immune response and reprogrammed the immunosuppressive microenvironment into an immunostimulatory state, which led to a significant suppress of tumor metastasis in mice. Overall, this work sets the stage for future advancements in the design of NIR-II photosensitizer with O 2 -supplementing capability and therefore offers an innovative framework and solid foundation for tumor PIT.
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高影响因子
Journal of Materials Chemistry B
·
2024
·Vol. 12
·期 45
·11696-11707
·
IF 6.1
Songyan Guo,Youbei Qiao,Chaoli Wang,Yuming Zhang,Tiehong Yang,Hong Wu
Nanoparticles (NPs) derived from branched copolymers of poly (β-L-malic acid) (PMLA) have been extensively investigated for drug delivery due to their high density of pendant carboxyl groups. This abundant functional group availability enhances their potential as effective drug delivery systems; however, the strong negative charge of PMLA poses a challenge in its uptake by cancer cells due to electrostatic repulsion. In this study, we developed novel enzyme- and pH-sensitive nanoparticles (EP-NPs) based on PMLA, demonstrating tumor-specific behavior and selective activation within tumor tissues. To enhance the cellular internalization of the nanoparticles, we incorporated transactivator of transcription (TAT). In summary, long-chain polyethylene glycol (PEG) was conjugated to PMLA to confer specificity to the TAT peptide. This was achieved using a tetrapeptide linker: alanine–alanine–asparagine–leucine (AANL), which serves as a substrate for legumain. Legumain is a highly conserved cysteine protease primarily found in lysosomes and blood vessels, initially discovered in legumes. It is markedly overexpressed in numerous solid tumors, as well as in endothelial cells and tumor-associated macrophages. The release of doxorubicin in tumor cells was sustained due to the low pH (5.0–5.5) and degradation of PMLA. The PEG modification optimized the particle size and shielded the nanoparticles from plasma proteins and detection by the reticuloendothelial system, thereby prolonging their long circulation time. Once the nanoparticles reached the tumor microenvironment, the AANL was cleaved by legumain, exposing the TAT peptide on the surface, which enhances cellular internalization. Both in vitro and in vivo efficacy studies demonstrated that these EP-NPs significantly inhibited tumor growth while exhibiting negligible systemic toxicity, thereby suggesting that the developed enzyme/pH-sensitive PMLA-based nanoparticle holds great promise as an anti-tumor drug delivery system.
研究领域:
药学
·
生物医学工程
·
肿瘤学
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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）