BIOMATERIALS
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2022
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IF 15.304
Qin Zeng,Xipeng Li,Si Xie,Da Xing,Tao Zhang
Developing single molecule-assembled nanoprodrugs that can reverse the glutathione (GSH)–mediated drug resistance of tumors provides promising potentials for precision and effective cancer theranostics. Herein, we developed a novel single molecule-assembled nanoprodrug for effective photodynamic/chemotherapeutic eradication of drug-resistant tumors via the multistage GSH-depletion. The nanoprodrug MSSP-NP could be fancily fabricated by self-assembly of an amphiphilic activatable molecular MSSP, which is synthesized by covalently conjugating the photosensitizer methylene blue (MB) with a GSH-sensitive cisplatin prodrug via a tumor targeting thiolated polypeptide . Upon the nanoprodrug MSSP-NP systematic administrated, its photoactivities and pharmacological effects can be thoroughly switched on by intracellular GSH to produce the photosensitizer MB and chemotherapeutic drug cisplatin, along with the multi-step consumption of GSH, which could remarkably boost oxidative stress and reverse the drug resistance. As a result, the nanoprodrug could effectively disrupt the tumor GSH-defense system to afford high-efficiency photodynamic/chemotherapeutic inhibition of drug resistance tumors (96.4%) with minimum side effects.
研究领域:
癌症治疗
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纳米医学
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药学
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产品关联
DOI
PubMed
高影响因子
CHEMISTRY-A EUROPEAN JOURNAL
·
2025
·
IF 3.7
Fa Wang,Zhiyang Wang,Shuqi Huang,Jinrong Yang,Yu Chen,Hui Chao
Graphical A convenient strategy by synergistic delivering DNA and DNA photocleavage agents to tumor cells was developed for effective photodynamic immunotherapy under hypoxia. Plasmid DNAs intercalated with Ru(II) complexes were encapsulated in liposomes to create nano-photosensitizers. Upon light exposure, the ruthenium complex photo-cleavages DNA. The DNA fragments specifically stimulate the cGAS-STING pathway and induce immunogenic death. This study presents a convenient strategy for photodynamic immunotherapy against cisplatin-resistant tumor cells under hypoxia.
研究领域:
生物化学
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肿瘤学
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免疫学
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DOI
PubMed
高影响因子
Small
·
2021
·Vol. 17
·期 47
·2102269
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IF 13.281
Xuan Wang,Yuanyuan Zhao,Yan Hu,Yang Fei,Youbo Zhao,Chencheng Xue,Kaiyong Cai,Menghuan Li,Zhong Luo
Ferroptosis is a new form of regulated cell death with significant therapeutic prospect, but its application against drug-resistant tumor cells is challenging due to their ability to effuse antitumor agents via p-glycoprotein (P-gp) and anti-lipid peroxidation alkaline intracellular environment. Herein, an amorphous calcium phosphate (ACP)-based nanoplatform is reported for the targeted combinational ferroptosis/apoptosis therapy of drug resistant tumor cells by blocking the MCT4-mediated efflux of lactic acid (LA). The nanoplatform is fabricated through the biomineralization of doxorubicin-Fe 2+ (DOX-Fe 2+ ) complex and MCT4-inhibiting siRNAs (siMCT4) and can release them to the tumor cytoplasm after the hydrolysis of ACP and dissociation of DOX-Fe 2+ in the acidic lysosomes. siMCT4 can inhibit MCT4 expression and force the glycolysis-generated lactic acid (LA) to remain in cytoplasm for rapid acidification. The nanoplatform-induced remodeling of the tumor intracellular environment can not only interrupt the ATP supply required for P-gp-dependent DOX effusion to enhance H 2 O 2 production, but also increase the overall catalytic efficiency of Fe 2+ for the initiation and propagation of lipid peroxidation. These features could act in concert to enhance the efficacy of the combinational ferroptosis/chemotherapy and prolong the survival of tumor-bearing mice. This study may provide new avenues for the treatment of multidrug-resistant tumors.
研究领域:
生物医学工程
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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
CHEMICAL ENGINEERING JOURNAL
·
2023
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IF 15.1
Xiao Zhang,Yachao Li,Yuying Yang,Kefurong Deng,Rongyan Liu,Ruigang Hou,Xianghui Xu
Discovering bioactive and efficient new agents for broad-spectrum multidrug resistance reversal is a worldwide challenge in the biomedical field. Herein, bioactive nanomaterials assembled from specially-designed lipopeptides are developed as a novel type of hole-punching nanotoxins to trigger multimodal tumor death for multidrug resistance reversal in vitro and in vivo . The dendritic arginine-rich peptides as hydrophilic parts could incorporate with multivalent scaffolds and multiple-interaction residues to boost membrane-binding intensity, and cholesterol as hydrophobic blocks are hopeful to improve and ameliorate membrane-targeting/inserting ability against drug-resistant tumor membranes. The amphiphilic lipopeptides are designed to drive supramolecular self-assembly into nanostructures for improving hole-punching potential and stability. As envisaged, these lipopeptide-based nanotoxins could maintain high stability, obtain strong hole-punching activity and trigger multimodal tumor death with 80.3% TUNEL-positive apoptotic cells, 97.8% PARP-positive necrotic cells and 71.0% LC3-positive autophagic cells for multidrug resistance reversal in vivo . This work opens a new opportunity to develop new-style toxins for antitumor treatment, and the lipopeptide-based nanotoxins are expected to be a candidate agent for dealing with multidrug resistance.
研究领域:
生物医学工程
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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
高影响因子
MOLECULAR PHARMACEUTICS
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2023
·
IF 4.9
Rui Chang,Rongrong Fu,Yujiao Huang,Jibing Zhang,Changshun Feng,Rui Wang,Hui Yan,Guangyong Li,Xiaohong Chu,Fengjiao Yuan,Dianlong Jia,Jun Li
Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) constitutes a promising antitumor drug, tumor resistance to TRAIL has become a major obstacle in its clinical application. Mitomycin C (MMC) is an effective TRAIL-resistant tumor sensitizer, which indicates a potential utility of combination therapy. However, the efficacy of this combination therapy is limited owing to its short half-life and the cumulative toxicity of MMC. To address these issues, we successfully developed a multifunctional liposome (MTLPs) with human TRAIL protein on the surface and MMC encapsulated in the internal aqueous phase to codeliver TRAIL and MMC. MTLPs are uniform spherical particles that exhibit efficient cellular uptake by HT-29 TRAIL-resistant tumor cells, thereby inducing a stronger killing effect compared with control groups. In vivo assays revealed that MTLPs efficiently accumulated in tumors and safely achieved 97.8% tumor suppression via the synergistic effect of TRAIL and MMC in an HT-29 tumor xenograft model while ensuring biosafety. These results suggest that the liposomal codelivery of TRAIL and MMC provides a novel approach to overcome TRAIL-resistant tumors.
研究领域:
药理学
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肿瘤学
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药物递送系统
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生物技术
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2023
·
IF 10.8
Shi-Jie Hao,Ya-Xuan Zhu,Fu-Gen Wu
Although nanocarriers have been widely applied in the delivery of anticancer drugs , many commercialized anticancer nanodrug systems still suffer from the problem of being easily trapped by lysosomes, which severely limits the drug delivery efficiency of a nanodrug system. Meanwhile, in drug-resistant tumors, the efflux of anticancer therapeutic drugs via the drug efflux transporters on the plasma membrane of cancer cells can significantly decrease the intracellular drug concentration and lead to the failure of the drug treatment. Here, we developed a small-molecule tyrosine kinase inhibitor (TKI)- and doxorubicin (Dox, a common anticancer drug)-loaded membrane fusion liposome (MFL) (termed [email protected] ) to achieve tumor cell membrane fusion-mediated drug delivery and enhanced chemotherapy of drug-resistant tumor. MFL could deliver drugs in a membrane fusion manner, circumventing the capture by lysosomes. Lapatinib, as the TKI doped in the MFL, could inhibit the efflux of Dox by ATP-binding cassette transporters (ABC transporters), further promoting the intracellular Dox accumulation. As a result, Dox achieved effective killing of drug-resistant tumors under the dual effect of MFL and lapatinib. To the best of our knowledge, it is the first example that employs membrane fusion-mediated TKI delivery for achieving tumor chemosensitization with good biosafety. This work presents an efficient and easily achievable strategy for treating drug-resistant tumors, which may hold promise for clinical applications.
研究领域:
药学
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癌症研究
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纳米技术
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Nature Biomedical Engineering
·
2024
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IF 26.8
Liang Tingxizi,Dong Yuxiang,Cheng Irina,Wen Ping,Li Fengqin,Liu Feng,Wu Qing,Ren En,Liu Peifeng,Li Hongjun,Gu Zhen
Biomolecular condensates, which arise from liquid–liquid phase separation within cells, may provide a means of enriching and prolonging the retention of small-molecule drugs within cells. Here we report a method for the controlled in situ formation of biomolecular condensates as reservoirs for the enrichment and retention of chemotherapeutics in cancer cells, and show that the approach can be leveraged to enhance antitumour efficacies in mice with drug-resistant tumours. The method involves histones as positively charged proteins and doxorubicin-intercalated DNA strands bioorthogonally linked via a click-to-release reaction between trans -cyclooctene and tetrazine groups. The reaction temporarily impaired the phase separation of histones in vitro, favoured the initiation of liquid–liquid phase separation within cells and led to the formation of biomolecular condensates that were sufficiently large to be retained within tumour cells. The controlled formation of biomolecular condensates as drug reservoirs within cells may offer new options for boosting the efficacies of cancer therapies.
研究领域:
药理学
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癌症研究
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Xinlin Lin,Mengsi Zheng,Kai Xiong,Fa Wang,Yu Chen,Liangnian Ji,Hui Chao
Using photodynamic therapy (PDT) to trigger nonconventional cell death pathways has provided a new scheme for highly efficient and non-side effects to drug-resistant cancer therapies. Nonetheless, the unclear targets of available photosensitizers leave the manner of PDT-induced tumor cell death relatively unpredictable. Herein, we developed a novel Ru(II)-based photosensitizer, Ru-Poma. Possessing the E3 ubiquitin ligase CRBN-targeting moiety and high singlet oxygen yield of 0.96, Ru-Poma was demonstrated to specifically photodegrade endogenous CRBN, increase lipid peroxide, downregulate GPX4 and GAPDH expression, and consequently induce ferroptosis in cisplatin-resistant cancerous cells. Furthermore, with the deep penetration of two-photon excitation, Ru-Poma achieved drug-resistant circumvention in a 3D tumor cell model. Thus, we describe the first sample of the CRBN-targeting Ru(II) complex active in PDT.
研究领域:
癌症治疗
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光化学
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细胞生物学
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分子生物学
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药物化学
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DOI
高影响因子
MATERIALS TECHNOLOGY
·
2022
·
IF 3.297
Shichao Wu,Xiaobing Yang,Xiangrui Yang
Due to the complexity of cancer, combination therapy has been widely used in the clinic. The use of two kinds of anticancer agents with a synergistic effect may achieve excellent therapeutic effects, especially against drug-resistant tumours. In this paper, MTX and HCPT loaded pullulan nanoparticles (MHNPs) were prepared for tumour-targeted synergistic therapy. In the nanoparticles, MTX could serve as both a targeting ligand and a cytotoxic agent. The MHNPs possessed a size of 185.7 ± 16.7 nm and a sustained release profile of the dual drug over a period of 48 h. The cytotoxicity assays stated that the MHNPs exhibited an enhanced killing ability to HeLa cells than the individual drug loaded NPs. These results suggest that the MHNPs could be a potential carrier with an efficient antitumor effect for tumour-targeted drug delivery.
研究领域:
药学
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癌症研究
·
纳米技术
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药物递送系统
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产品关联
DOI
高影响因子
BIOORGANIC CHEMISTRY
·
2020
·
IF 4.831
Jiaguo Li,Dian Xiao,Fei Xie,Wei Li,Lei Zhao,Wei Sun,Xiaohong Yang,Xinbo Zhou
Antibody-drug conjugates (ADCs) are being developed worldwide with the potential to revolutionize current cancer treatment strategies. However, off-target toxicity caused by the instability of linkers remains one of the main issues to be resolved. Developing a novel photocontrol-ADC with good stability and photocontrolled release seemed to be an attractive and practical solution. In this study, we designed, for the first time, a novel ultraviolet (UV) light-controlled ADC by carefully integrating the UV-cleavable o -nitro-benzyl structure into the linker. Our preliminary work indicated that the ADC exhibited good stability and photocontrollability while maintaining a targeting effect similar to that of the naked antibody. Upon irradiation with UV light, the ADC rapidly released free cytotoxins and exerted significant cytotoxicity toward drug-resistant tumor cells. Compared to those of the unirradiated cells, the EC 50 values of ADCs increased by up to 50-fold. Furthermore, our research confirmed that the degradation products of unirradiated ADC, Cys- 1a, were relatively less toxic, thus potentially reducing the off-target toxicity caused by nonspecific uptake of ADCs. The novel design strategy of UV light-controlled ADCs may provide new perspectives for future research on ADCs and promote the development of photocontrol systems.
研究领域:
癌症治疗
·
药学
·
分子生物学
·
化学工程
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2019
·
IF 10.273
Jia Liu,Zhilan Ye,Mengxi Xiang,Bingcheng Chang,Jinyuan Cui,Tiantian Ji,Lei Zhao,Qilin Li,Yan Deng,Luming Xu,Guobin Wang,Lin Wang,Zheng Wang
Multidrug resistance (MDR) is a key issue accounting for ineffectiveness of cancer chemotherapy. Numerous multifunctional nanocarriers have been developed to increase drug delivery efficacy and inhibit drug efflux for overcoming cancer drug resistance. However, limited success has been achieved in clinic because of nanocarriers' complicated multi-step fabrication procedures and their undesired side toxicity as well as potential immunogenicity . Here, hyaluronic acid (HA) functionalized extracellular vesicles (EVs) are generated as natural vehicles to efficiently deliver doxorubicin (DOX) and reverse MDR. The EVs isolated from noncancerous HEK293T cells (hEVs) reduce P-glycoprotein (P-gp) expression in drug resistant MCF7/ADR cells. To acquire tumor-targeting capability, hEVs are modified with lipidomimetic chains-grafted HA (lipHA) by a simple incubation. Owing to CD44-mediated cancer-specific targeting and P-gp suppressive capability, the HA-functionalized hEVs (lipHA-hEVs) remarkably promote the intracellular DOX accumulation in drug resistant breast cancer cells. In preclinical MDR tumor models, lipHA-hEVs deeply penetrate into tumor tissue and effectively transport DOX into tumor local, while eliminating DOX's systemic toxicity. Importantly, [email protected] inhibited MDR tumor growth by 89% and extend animal survival time by approximately 50%. Thus, our engineered tumor-targeting hEVs are promising natural carriers for overcoming cancer MDR.
研究领域:
药学
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癌症研究
·
纳米技术
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2019
·
IF 8.456
Ying Chen,Yongchao Yao,Xueying Zhou,Chunyan Liao,Xin Dai,Jie Liu,Yunlong Yu,Shiyong Zhang
We report a chemo/starvation/chemodynamic trimodal combination therapy to combat multidrug-resistant (MDR) tumors by developing a ferrocene-containing nanovesicle (FcNV), which encapsulates glucose oxidase (GOx) in the hydrophilic core and coordinates cisplatin (Pt) in the hydrophobic layer (GOx&Pt@FcNV). Contrasting with other reported multimodal combination therapies, the new nanodrug (GOx&Pt@FcNV) relies on cascade reactions to drastically increase the overall effectiveness against MDR tumors. Specifically, Pt blocks deoxyribonucleic acid replication and activates hydrogen peroxide (H2O2) generation for chemotherapy; GOx consumes glucose to produce H2O2 and gluconic acid for starvation therapy; and all H2O2 products are catalyzed by ferrous ions decomposed from ferrocene to generate the highly toxic hydroxyl radicals (•OH) for chemodynamic therapy. The in vitro studies reveal that GOx&Pt@FcNV exhibits a highly efficient killing effect against various MDR tumor cells. The in vivo studies of double-tumor-bearing nude mice demonstrate that the tumor inhibitory rates (TIRs) of GOx&Pt@FcNV against cisplatin-resistant A549/DDP are 8.1 times and 3.3 times higher than those of Pt and Pt@FcNV, respectively; they are also 8.6 times and 4.3 times higher than Pt and Pt@FcNV against adriamycin-resistant MCF-7/ADR, respectively. This nanodrug with endogenous stimuli-activated cascade reactions offers a reference for the design of effective trimodal combination therapies to combat MDR tumors.
研究领域:
纳米医学
·
癌症治疗
·
化学工程
·
药学科学
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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）