BIOMACROMOLECULES
·
2024
·
IF 5.5
Panpan Zhang,Leitao Zhang,Zhihao Wang,Qiuli Cheng,Wenlan Wu,Junbo Li,Gaofeng Liang,Ravin Narain
Bioorthogonal reactions present a promising strategy for minimizing off-target toxicity in cancer chemotherapy, yet a dependable nanoplatform is urgently required. Here, we have fabricated an acid-responsive polymer micelle for the specific delivery and activation of the prodrug within tumor cells through Ru catalyst-mediated bioorthogonal reactions. The decomposition of micelles, triggered by the cleavage of the hydrazone bond in the acidic lysosomal environment, facilitated the concurrent release of Alloc-DOX and the Ru catalyst within the cells. Subsequently, the uncaging process of Alloc-DOX was demonstrated to be induced by the high levels of glutathione within tumor cells. Notably, the limited glutathione inside normal cells prevented the conversion of Alloc-DOX into active DOX, thereby minimizing the toxicity toward normal cells. In tumor-bearing mice, this nanoplatform exhibited enhanced efficacy in tumor suppression while minimizing off-target toxicity. Our study provides an innovative approach for in situ drug activation that combines safety and effectiveness in cancer chemotherapy.
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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药物递送系统
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生物化学
✓ 已验证
产品关联
DOI
PubMed
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
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药学
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分子生物学
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化学工程
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2022
·Vol. 32
·期 17
·2111344
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IF 19.924
Kaicheng Tang,Xiaoyou Wang,Miaomiao Niu,Xinyu Wang,Guanghua Zhou,Jinjin Shi,Yang Yu,Zhangbao Chen,Chong Li
Antimicrobial peptides (AMPs) have aroused extensive attention due to their low incidences of resistance, yet their clinical transformation is thwarted by inferior selectivity and metabolic stability concerns, manifesting as rapid degradation, off-target, and non-selective toxicity. Here, a captivating affinity-filtering strategy is proposed as a feasible solution for such challenges. Specifically, based on the selective affinity of AMPs toward distinct phospholipids, the membrane of host cells (e.g., erythrocytes) is pre-bound to AMPs as the “filter,” which could screen out off-target substances with non-specific affinity while maintaining effective interaction with high-affinity pathogens through competitive binding, realizing precise targeting, and enhanced stability. The practicability of the affinity-filtering strategy has been demonstrated both in vitro and in vivo, through systematic studies on various AMPs and AMPs-modified delivery systems with multiple fungal infection models ( Candida albicans and Cryptococcus neoformans ), which pose severe threats to human health worldwide yet are often neglected. AMP-modified nanoparticles with affinity filtering exhibit reduced off-target toxicity, sufficient binding with target pathogen, as well as a substantially elevated 21-day survival rate from 30% (conventional drug-loaded nanoparticles) to 70%. In summary, this strategy may provide inspiration for overcoming off-target effects in drug targeting and further promote the clinical application of AMPs.
研究领域:
药学
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微生物学
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药物递送系统
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传染病学
✓ 已验证
DOI
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2022
·
IF 5.999
Yu Zhou,Chengyu Zhang,Yuefei Wang,Jiaxing Zhang,Xiaohui Yan,Shengping You,Wei Qi,Rongxin Su,Zhimin He
Nanotechnology has been widely used in cancer treatment but only a small fraction (0.7 %) of the administered nanoparticle was delivered into a solid tumor, while the remaining fraction causes off-target toxicity in healthy tissues. The activation of prodrugs by exogenous enzymes can be used as an effective anticancer strategy to reduce systemic toxicity. In this study, the [email protected] imidazolate framework-8 ( [email protected] ) enzyme-activated prodrug system was created based on the high catalytic activity of LA in an acidic environment and the pH response (pH∼5.5) of ZIF-8. Quercetin (QU) was selected as the prodrug, which is non-toxic and even beneficial without being activated by LA. LA could be precisely released in the acidic tumor microenvironment for activating nontoxic QU successfully to produce toxic oxidized quercetin (OQU), and the LA was steady loaded on the [email protected] under physiological conditions (pH∼7.4). Especially, the high concentrations of glutathione (GSH) in tumors could accelerate the oxidation of QU by LA. Meanwhile, GSH could be consumed continuously by the reduction of OQU for regenerating QU, thus a LA-QU-GSH redox was formed ingeniously. Therefore, the synergistic effect of OQU toxicity and GSH depletion induced reactive oxygen species (ROS) accumulation and tumor cell apoptosis. Overall, the [email protected] prodrug system provides ideas for safe and effective cancer treatment with low off-target toxicity.
研究领域:
纳米技术
·
癌症治疗
·
药学
·
生物医学工程
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Zhan Huang,Xing Huang,Yanfei Zhang,Meng Chen,Shaoqiang Wen,Zhou Zhang,Zong Dai,Xiaoyong Zou,Si-Yang Liu
DNAzyme-based gene silencing is a promising cancer therapy technology, while its efficiency and safety issues still need to be addressed. In this study, we developed a chirality/microRNA dual-gating theranostic nanomachine for messenger RNA (mRNA) gene silencing therapy with enhanced targeting towards human cervical cancer (HeLa) cells. The chiral nanoparticle, an emerging material with unique chirality-induced properties, e.g. chirality-dependent cellular uptake, has been widely applied in biomedical fields. The L-type gold nanoparticles (L-AuNPs) are used as the nanocarrier with the first “chirality-gating”. L-AuNPs showed 2.4-fold uptake efficiency for HeLa cells comparing to normal cell, as well as 2.2-fold uptake efficiency in cancer cell comparing to D-type gold nanoparticles (D-AuNPs), which exhibited no cancer cell targeting effect. Moreover, an entropy-driven-DNAzyme (EDz) circuit that can release numerous DNAzyme and fluorescence probes with the trigger of single microRNA (miRNA) conducted the theranostic role of both miRNA imaging and gene silencing, constituting the second “miRNA gating”. Ascribing to the prominent targeting nanocarrier L-AuNPs, the miRNA imaging sensitivity and gene silencing therapy efficiency were improved by 2.6- and 5.0-fold, respectively, comparing to those by D-AuNPs. In general, this dual-gating nanomachine, designed with a powerful yet simple strategy, has showed great prospects in optimizing delivery specificity and avoiding off-target toxicities.
研究领域:
癌症治疗
·
纳米技术
·
分子生物学
·
生物医学工程
·
基因治疗
✓ 已验证
产品关联
DOI
高影响因子
Journal of the American Chemical Society
·
2019
·
IF 14.695
Xi Hu,Fangyuan Li,Fan Xia,Xia Guo,Nan Wang,Lili Liang,Bo Yang,Kelong Fan,Xiyun Yan,Daishun Ling
Recent advances in nanomedicine have facilitated the development of potent nanomaterials with intrinsic enzyme-like activities (nanozymes) for cancer therapy. However, it remains a great challenge to fabricate smart nanozymes that precisely perform enzymatic activity in tumor microenvironment without inducing off-target toxicity to surrounding normal tissues. Herein, we report on designed fabrication of biodegradation-medicated enzymatic activity-tunable molybdenum oxide nanourchins (MoO3–x NUs), which selectively perform therapeutic activity in tumor microenvironment via cascade catalytic reactions, while keeping normal tissues unharmed due to their responsive biodegradation in physiological environment. Specifically, the MoO3–x NUs first induce catalase (CAT)-like reactivity to decompose hydrogen peroxide (H2O2) in tumor microenvironment, producing a considerable amount of O2 for subsequent oxidase (OXD)-like reactivity of MoO3–x NUs; a substantial cytotoxic superoxide radical (·O2–) is thus generated for tumor cell apoptosis. Interestingly, once exposed to neutral blood or normal tissues, MoO3–x NUs rapidly lose the enzymatic activity via pH-responsive biodegradation and are excreted in urine, thus ultimately ensuring safety. The current study demonstrates a proof of concept of biodegradation-medicated in vivo catalytic activity-tunable nanozymes for tumor-specific cascade catalytic therapy with minimal off-target toxicity.
研究领域:
纳米医学
·
癌症治疗
·
材料科学
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生物医学工程
·
酶学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
·
2023
·
IF 7.4
Jianzhong Zhang,Xue Liu,Yutian Xia,Shuyu Xu,Xuan Liu,Haiqing Xiao,Xiaoyong Wang,Chao Liu,Gang Liu
Melittin, the principal constituent in bee venom, is an attractive candidate for cancer therapy. However, its clinical applications are limited by hemolysis, nonspecific cytotoxicity, and rapid metabolism. Herein, a novel genetically engineered vesicular antibody-melittin (VAM) drug delivery platform was proposed and validated for targeted cancer combination therapy. VAM generated from the cellular plasma membrane was bio-synthetically fabricated, with the recombinant protein (hGC33 scFv-melittin) being harbored and displayed on the cell membrane. The bioactive and targetable nanomelittin conjugated by hGC33 scFv could be released in an MMP14-responsive manner at tumor sites, which reduced off-target toxicity, especially the hemolytic activity of melittin. Importantly, VAM could be loaded with small-molecule drugs or nanoparticles for combination therapy. Nanomelittin formed pores in membranes and disturbed phospholipid bilayers, which allowed the anticancer agents (i.e., chemotherapeutic drug doxorubicin and sonosensitizer purpurin 18 nanoparticles) co-delivered by VAM to penetrate deeper tumor sites, leading to synergistic therapeutic effects. In particular, the punching effect generated by sonodynamic therapy further improved the immunomodulatory effect of nanomelittin to activate the immune response. Taken together, our findings indicate that clinically translatable VAM-based strategies represent a universal, promising approach to multimodal synergetic cancer therapy.
研究领域:
癌症治疗
·
药物递送系统
·
纳米技术
·
生物医学工程
·
药学
·
免疫疗法
✓ 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）