CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Gongxi Qiao,Xuming Pan,Mengyun He,Ruixi Peng,Xiangrong Huang,Cunpeng Nie,Jianhui Jiang,Xia Chu
Tumor protein 53 (Tp53), a key regulator of suppressor genes, is commonly mutated in numerous malignant diseases. Consequently, elimination mutant protein 53 (mutp53) represents an appealing strategy for treating mutp53-related tumors. However, the treatment of these mutations remained challenging due to its formidable limitations. In this study, by loading glucose oxidase (GOX) into Zn-based layered double hydroxides (Zn-LDH) interlayer, a pH-responsive ultrathin nanotherapeutic platform (Zn-LDH@GOX) was created to suppress tumors growth by degrading mutp53. Upon exposure to the acidic environment of lysosomes, the lattice structure of Zn-LDH@GOX was partially disrupted, leading to the release of Zn 2+ ions and GOX into the cytoplasm. The increased intracellular concentration of Zn 2+ facilitated the restoration of wild-type protein 53 (wtp53) conformation, which in turn degraded mutp53 through activated autophagic pathways. Meanwhile, GOX-induced Heat Shock Protein 90 (HSP90) disruption resulted in the liberation of mutp53 from the HSP90/mutp53 complex and reactivated its degradation via the ubiquitination-mediated proteasomal pathway. In vitro and in vivo experiments confirmed the significant suppression of mutp53 expression and inhibition of tumor growth by Zn-LDH@GOX. Our work offers a novel pH-responsive nanotherapeutic platform with immense potential for mutp53 tumor-specific therapy.
研究领域:
肿瘤学
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分子生物学
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纳米技术
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癌症治疗
✓ 已验证
产品关联
DOI
高影响因子
DRUG DELIVERY
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2019
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IF 3.829
Xiaorong Zhou,Chuanpei Cao,Nan Li,Shaofei Yuan
The aim of this study is to construct a SYL3C aptamer-anchored microemulsion based on β-elemene and PTX (SYL3C/EP-MEs) for enhancement on colorectal cancer therapy. Such microemulsion is consist of encapsulated drugs (β-elemene and PTX), tumor targeting ligand (3’-end thiolated SYL3C aptamer), thiol conjugated site (maleimide-modified PEGylated 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, mal-DOPE-PEG), pH-sensitive component (DOPE) and other necessary excipients. SYL3C/EP-MEs showed a spherical particle with an average particle size around 30 nm and a high encapsulation efficiency (>80%) for both drugs. β-elemene and PTX could be released controllably from SYL3C/EP-MEs as pH values changed. SYL3C/EP-MEs displayed a selective affinity to HT-29 cells, leading to an obvious increase in cellular uptake, cell apoptosis and cytotoxicity. In the HT-29 tumor xenograft-bearing nude mice model studies, SYL3C/EP-MEs showed an overwhelming tumor growth inhibition, the longest survival time and the lowest systemic toxicity among all the treatments. The potential mechanism of enhanced anti-cancer ability was probably associated with the induction of M1 macrophage polarization, the downregulation of mutant p53 protein and the reduction of bcl-2 protein expression. Collectively, the microemulsion codelivery of β-elemene and PTX using functionalization with SYL3C aptamer provides a novel approach for combinational colorectal cancer-targeted treatment.
研究领域:
药学
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肿瘤学
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药物递送系统
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2019
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IF 8.355
Fan Wu,Ming Zhang,Xiaohong Chu,Qicheng Zhang,Yutian Su,Baohong Sun,Tingyu Lu,Ninglin Zhou,Jun Zhang,Jianxiu Wang,Xinyao Yi
Chemotherapy resistance hinders the successful clinical cancer therapy, because of the low sensitivity of drugs to resistant cancer cells. In resistant cancer cells, the mutant p53 possesses anti-apoptosis capability to tolerate chemotherapeutic drugs such as doxorubicin (DOX). Phenethyl isothiocyanate (PEITC) derived from cruciferous vegetables can deplete intracellular mutant p53. In this work, the black phosphorus nanosheets-based (BPNs-based) drug delivery system integrated with PEITC can effectively decrease mutant p53 level in resistant cancer cells and realize multiple drug resistance (MDR) reversal. The intrinsic properties of BPNs could achieve synergistic photothermal/photodynamic/chemo-therapy of resistant cancer. Magnetic resonance imaging (MRI) is used to investigate the biodistribution of nanoparticles which confirmed the efficient accumulations of nanoparticles at tumor sites. In vitro and in vivo anticancer experiments demonstrate the drug resistance tumor is effectively inhibited with minimal side effects by BPNs-based drug delivery system.
研究领域:
纳米技术
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肿瘤学
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药学
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生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
Bioactive Materials
·
2023
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IF 18.9
Yong Mei,Xiaohua Qin,Zhenyu Yang,Shiyao Song,Xiaoting Liu,Chong Wu,Jieying Qian,Xiaowan Huang,Yunjiao Zhang,Weiling He
KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers. Therefore, a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53 . Herein, we present a novel self-assembled nanoparticle (HA-TPP/A) that are functionalized nano-carrier hyaluronic acid (HA)-TPP conjugate (HA-TPP) to degrade mutant p53 proteins (mutp53) and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways. The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria. Furthermore, these nanoparticles abrogated the gain-of-function (GOF) phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing, thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation. The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model, particularly in KRAS-TP53 double mutant expressing cancer cells, compared with single drug and combined free drug groups. Notably, HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53 , providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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