Pharmaceutics
·
2023
·Vol. 15
·期 9
·2243
·
IF 5.4
Jiayi Zhang,Bing Gu,Shimiao Wu,Lin Liu,Ying Gao,Yucen Yao,Degong Yang,Juan Du,Chunrong Yang
Tumor hypoxia is considered one of the key causes of the ineffectiveness of various strategies for cancer treatment, and the non-specific effects of chemotherapy drugs on tumor treatment often lead to systemic toxicity. Thus, we designed M1 macrophage-biomimetic-targeted nanoparticles (DOX/CAT@PLGA-M1) which contain oxygen self-supplied enzyme (catalase, CAT) and chemo-therapeutic drug (doxorubicin, DOX). The particle size of DOX/CAT@PLGA-M1 was 202.32 ± 2.27 nm (PDI< 0.3). DOX/CAT@PLGA-M1 exhibited a characteristic core-shell bilayer membrane structure. The CAT activity of DOX/CAT@PLGA-M1 was 1000 (U/mL), which indicated that the formation of NPs did not significantly affect its enzymatic activity. And in vitro drug release showed that the cumulative release rate of DOX/CAT@PLGA-M1 was enhanced from 26.93% to 50.10% in the release medium of hydrogen peroxide, which was attributed to the reaction of CAT in the NPs. DOX/CAT@PLGA-M1 displayed a significantly higher uptake in 4T1 cells, because VCAM-1 in tumor cells interacted with specific integrin (α4 and β1), and thereby achieved tumor sites. And the tumor volume of the DOX/CAT@PLGA-M1 group was significantly reduced (0.22 cm3), which further proved the active targeting effect of the M1 macrophage membrane. Above all, a novel multifunctional nano-therapy was developed which improved tumor hypoxia and obtained tumor targeting activity.Keywords:tumor microenvironment;M1 macrophage;tumor hypoxia;catalase;cancer treatment
研究领域:
癌症生物学
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药学
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纳米技术
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 11
·期 12
·2102781
·
IF 11.092
Yutong Liu,Hui Li,Huajun Zhao,Yanyun Hao,Simon Van Herck,Zejun Xu,Guan Wang,Xiao Wang,Xinke Zhang,Xiaoyan Ge,Xia Li,Ailu Yang,Hongfei Chen,Jing Zou,Wentao Wang,Bruno G. De Geest,Zhiyue Zhang
In situ anti-tumor vaccination is an attractive type of cancer immunotherapy which relies on the effectiveness of dendritic cells (DCs) to engulf tumor antigens, become activated, and present antigens to T cells in lymphoid tissue. Here, a multifunctional nanocomplex based on calcium crosslinked polyaspartic acid conjugated to either a toll-like receptor (TLR)7/8 agonist or a photosensitizer is reported. Intratumoral administration of the nanocomplex followed by laser irradiation induces cell killing and hence generation of a pool of tumor-associated antigens, with concomitant promotion of DCs maturation and expansion of T cells in tumor-draining lymph nodes. Suppression of tumor growth is observed both at the primary site and at the distal site, thereby hinting at successful induction of an adaptive anti-tumor response. This strategy holds promise for therapeutic application in a pre-operative and post-operative setting to leverage to mutanome of the patient's own tumor to mount immunological memory to clear residual tumor cells and metastasis.
研究领域:
癌症免疫疗法
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纳米技术
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免疫学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
STAR Protocols
·
2022
·
IF 0
Mei-Mei Li,Fan-En Kong,Guang-Meng Li,Yi-Ti He,Xiao-Feng Zhang,Cheng-Yang Zhang,Jie-Kai Liang,Xin-Yuan Guan,Ning-Fang Ma,Mao-Bin Xie,Ming Liu
Summary Here, we present a detailed protocol for the identification of potential oncofetal targets for hepatocellular carcinoma (HCC) patients through a hepatocyte differentiation model and a sorafenib refractory cell-line-derived xenograft model. We describe the procedures of tumor sphere formation, organoid generation, and subcutaneous tumor formation for functional studies. We then detail the procedures of immunohistochemistry and immunofluorescence for examination of changes in lineage-specific markers. Finally, we describe the development of antibody-based therapeutics targeting tumor lineage plasticity in HCC. For complete details on the use and execution of this protocol, please refer to Kong et al. (2021). 1
研究领域:
肿瘤学
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分子生物学
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癌症研究
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细胞生物学
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DOI
PubMed
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Weixia Xu,Shengmin Yang,Linwei Lu,Qianzhu Xu,Sunyi Wu,Jianfen Zhou,Jiashen Lu,Xingyan Fan,Nana Meng,Yuan Ding,Xudong Zheng,Weiyue Lu
Evidence is mounting that there is a significant gap between the antitumor efficacy of nanodrugs in preclinical mouse tumor models and in clinical human tumors, and that differences in tumor models are likely to be responsible for this gap. Herein, we investigated the enhanced permeability and retention (EPR) effect in mouse lung cancer models with different tumor growth rates, volumes and locations, and analyzed the nanodrug tumor targeting behaviors limited by tumor vascular pathophysiological characteristics in various tumor models. The results showed that the fast-growing tumors were characterized by lower vascular tight junctions, leading to higher vascular paracellular transport activity and nanodrug tumor accumulation. The paracellular transport activity increased with the growth of tumor, but the vascular density and transcellular transport activity decreased, and as a result, the average tumor accumulation of passive targeting nanodrugs decreased. Orthotopic tumors were rich in blood vessels, but had low vascular transcellular and paracellular transport activities, making it difficult for nanodrug accumulation in orthotopic tumors via passive targeting strategies. The antitumor efficacy of passive targeting nanodrugs in various lung cancer-bearing mice validated the aforementioned nanodrug accumulation behavior, and nanodrugs based on the angiogenesis-tumor sequential targeting strategy achieved obviously improved efficacy in orthotopic lung cancer-bearing mice. These results suggest that the EPR effect varies in different tumor models and should not be used as a universal targeting strategy for antitumor nanodrugs. Besides, attention should be paid to the animal tumor models in the evaluation of nanodrugs so as to avoid exaggerating the antitumor efficacy.
研究领域:
肿瘤学
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药学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Drug Delivery and Translational Research
·
2023
·
IF 5.4
Wang Yanzhi,Wang Linchao,Chang Hanyue,Shen Qing,Zhang Sai,Sun Shanshan,Liu Ying,Zheng Jiaxin,Liu Hongmin
In this study, we synthesized a novel compound, agmatine-cholesterol conjugate (AG-Chol), to enhance the anti-tumor activity of drug-loaded liposomes. We replaced cholesterol with AG-Chol in preparing doxorubicin hydrochloride (DOX) liposomes by using an active loading method for DOX. We assessed the physical and chemical properties of the resulting AG-Liposomes and evaluated their efficacy in vitro and in vivo. The results showed that AG-Liposomes were stable with high encapsulation efficiency. Compared with the control liposomes, AG-Liposomes exhibited a slower drug release rate in the release medium at pH 6.8. The in vitro cell experiments demonstrated that AG-Liposomes had higher tumor cell uptake rate, stronger migration inhibition rate, higher apoptosis rate, better anti-clonogenic ability, and higher lysosome escape ability than the control liposomes. In vivo distribution results demonstrate that liposomes prepared with AG-Chol instead of cholesterol can significantly enhance their tumor targeting abilities and reduce their distribution to non-targeted sites. In vivo tumor suppression experiments showed that AG-Liposomes had a higher tumor suppression rate than the control liposomes without causing apparent toxicity to normal tissues, as evidenced by histological staining. Therefore, substituting cholesterol with AG-Chol in the preparation of liposomes can result in enhanced lysosome escape, improved tumor targeting, and increased efficacy of anti-tumor drugs. Graphical Abstract
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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生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Shuaiqi Feng,Yan Chen,Zhifang Liu,Shilei Ji,Qingpeng Wang
Dysregulated cholesterol accumulation promotes tumor growth and metastasis. Herein, a series of ciprofibrate platinum(IV) conjugates with cholesterol-inhibiting effects was developed, and the transferrin-modified nanodrug Tf-PEG-COFs@Pt(IV) was prepared using COFs as the carrier. The nanodrug exhibited potent antiproliferative and antimetastatic activities both in vitro and in vivo. The transferrin moiety significantly enhanced the tumor-targeting ability of the nanodrug. The platinum core induced serious DNA damage, leading to an increased expression of γ-H2AX and p53. Mitochondria-mediated apoptosis occurred via the Bcl-2/Bax/caspase-3 cascade. Notably, cholesterol accumulation was inhibited by the ciprofibrate ligand through promoting PPAR-α expression and further regulating the LDLR/ACAT1/ABCA1 signaling. The nanodrug effectively reversed the epithelial-mesenchymal transition by inhibiting the PI3K/AKT/mTOR pathway and reversing the hypoxic microenvironment. Furthermore, antitumor immunity was enhanced by elevating the density of CD3+ and CD8+ T cells and triggering macrophage polarization from the M2 to M1 phenotype in tumors.
研究领域:
肿瘤学
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药理学
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纳米医学
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分子生物学
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转化医学
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肿瘤代谢
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免疫肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Fan Gao,Jian-Hui Dong,Chun Xue,Xin-Xin Lu,Yu Cai,Zi-Yang Tang,Chang-Jin Ou
Interfering with intratumoral metabolic processes is proven to effectively sensitize different antitumor treatments. Here, a tumor-targeting catalytic nanoplatform (CQ@MIL-GOX@PB) loading with autophagy inhibitor (chloroquine, CQ) and glucose oxidase (GOX) is fabricated to interfere with the metabolisms of tumor cells and tumor-associated macrophages (TAMs), then realizing effective antitumor chemodynamic therapy (CDT). Once accumulating in the tumor site with the navigation of external biotin, CQ@MIL-GOX@PB will release Fe ions and CQ in the acid lysosomes of tumor cells, the latter can sensitize Fe ions-involved antitumor CDT by blocking the autophagy-dependent cell repair. Meanwhile, the GOX component will consume glucose, which not only generates many H 2 O 2 for CDT but also once again decelerates the tumor repair process by reducing energy metabolism. What is more, the release of CQ can also drive the NO anabolism of TAMs to further sensitize CDT. This strategy of multiple metabolic regulations is evidenced to significantly improve the antitumor effect of traditional CDT nanoagents and might provide a new sight to overcome the bottlenecks of different antitumor treatments.
研究领域:
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
PubMed
高影响因子
Bioactive Materials
·
2021
·
IF 14.593
Haoran Wang,Honghui Liu,Yunfei Guo,Wenjing Zai,Xianghui Li,Wei Xiong,Xiaozhi Zhao,Yingfang Yao,Yiqiao Hu,Zhigang Zou,Jinhui Wu
The ideal photodynamic therapy (PDT) should effectively remove the primary tumor, and produce a stronger immune memory effect to inhibit the tumor recurrence and tumor metastasis. However, limited by the hypoxic and immunosuppressive microenvironment, the PDT efficiency is apparently low. Here, Chlorella (Chl.) is exploited to enhance local effect by producing oxygen to reverse hypoxia, and release adjuvants to reverse immunosuppressive microenvironment to enhance abscopal effect afterwards. Results from different animal models indicated that Chl. could enhance local effect and PDT related immune response. Ultimately, Chl. coupled PDT elicited anti-tumor effects toward established primary tumors (inhibition rate: 90%) and abscopal tumors (75%), controlled the challenged tumors (100%) and alleviated metastatic tumors (90%). This Chl. coupled PDT strategy can also produce a stronger anti-tumor immune memory effect. Overall, this Chl. coupled PDT strategy generates enhanced local tumor killing, boosts PDT-induced immune responses and promotes anti-tumor immune memory effect, which may be a great progress for realizing systemic effect of PDT.
研究领域:
肿瘤学
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免疫疗法
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生物技术
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微生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Rengui Xu,Honglian Guo,Xiuli Chen,Jiarong Xu,Yusheng Gong,Peng Cao,Chunyu Wei,Fei Xiao,Di Wu,Wei Chen,Lin Wang,Zheng Wang
Locoregional therapy has attracted increasing attention for subcutaneous tumors owing to its merits of minimally invasive operation and negligible systematic toxicity. However, to accelerate clinical translation, further promotions in deep-seated penetration, temporal-spatial controllability, personalized adaptability, as well as easy operation are still urgently needed. This work proposed a self-heating-cooking-package-inspired hydrothermally responsive multi-round acturable microneedle (HRMAM) system, which loaded docetaxel (DTX) in the polycaprolactone (PCL), to serve as deeply penetrable, hydrothermal-chemotherapy synergetic, on-demand and self-service anti-tumor treatment. The optimized hydrothermally responsive formulation served as base components for water-based self-heating responsive drug release with synergistic anti-tumor thermal therapy, and simultaneously in combination with well-designed grooved-structure needle tips for directional deep delivery and enhanced transfer efficiency. To satisfy spatial precision and flexible controllability, this engineering-based detachable HRMAM system was divided into three relatively independent segments, which were fitted perfectly with an original-designed applicator for ensuring easy operation in a smart self-service manner. Impressively, the HRMAM system achieved encouraging tumor growth inhibition of 75.11% and 72.29% in animal model of melanomas and breast carcinoma , respectively, much higher than those of other groups receiving traditional treatment, without obvious side effects. It was anticipated that the HRMAM system would manifest great promise to combat unreachable and deep-seated subcutaneous tumors, bellowing clinical values upon locoregional therapy products with high efficiency, low toxicity, flexible controllability, temporal-spatial precision, easy operation, as well as patient's painless, comfort and compliance.
研究领域:
生物医学工程
·
药学
·
癌症治疗
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2023
·
IF 13.3
Hong Wang,Junbin Gao,Cong Xu,Yuejun Jiang,Meihuan Liu,Hanfeng Qin,Yicheng Ye,Li Zhang,Wanxian Luo,Bin Chen,Lingli Du,Fei Peng,Yingjia Li,Yingfeng Tu
Nanotechnology-based strategy has recently drawn extensive attention for the therapy of malignant tumors due to its distinct strengths in cancer diagnosis and treatment. However, the limited intratumoral permeability of nanoparticles is a major hurdle to achieving the desired effect of cancer treatment. Due to their superior cargo towing and reliable penetrating property, micro-/nanomotors (MNMs) are considered as one of the most potential candidates for the coming generation of drug delivery platforms. Here, near-infrared (NIR)-actuated biomimetic nanomotors (4T1-JPGSs-IND) are fabricated successfully and we demonstrate that 4T1-JPGSs-IND selectively accumulate in homologous tumor regions due to the effective homing ability. Upon laser irradiation, hyperthermia generated by 4T1-JPGSs-IND leads to self-thermophoretic motion and photothermal therapy (PTT) to ablate tumors with a deep depth, thereby improving the photothermal therapeutic effect for cancer management. The developed nanomotor system with multifunctionalities exhibits promising potential in biomedical applications to fight against various diseases.
研究领域:
纳米技术
·
癌症治疗
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生物医学工程
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2023
·Vol. 59
·期 3
·193-203
·
IF 2.1
Li Zhe,Jiang Da,Liu Fengling,Li Ying
Palmitoylation is a post-translational modification occurring on cysteine residues, which process is catalyzed by a family of zinc finger Asp-His-His-Cys (DHHC) domain-containing (ZDHHC) protein acyltransferases. As a family member, ZDHHC9 plays a crucial role in varied malignancies by regulating protein stability via protein substrate palmitoylation. Based on the bioinformatic analysis of GEO gene microarray GSE75037 (|log 2 fold change|> 1, P < 0.05), ZDHHC9 was defined as a significantly upregulated gene in lung adenocarcinoma (LUAD), which was also confirmed in our collected clinical specimens. It is necessary to explore the biological function of ZDHHC9 in LUAD cells. The follow-up functional experiments revealed that ZDHHC9 deficiency inhibited proliferation, migration, and invasion, while stimulated apoptosis in HCC827 cells. Besides, these malignant phenotypes could be accelerated by ZDHHC9 overexpression in A549. Moreover, we revealed that ZDHHC9 knockdown could promote PD-L1 protein degradation by reducing its palmitoylation level. The reduction of PD-L1 protein level could enhance anti-tumor immunity and inhibit the growth of LUAD cells. Therefore, our study uncovers the tumor-promoting role of ZDHHC9 in LUAD via regulating PD-L1 stability through palmitoylation, highlighting ZDHHC9 as a novel therapeutic target for LUAD. Graphical abstract
研究领域:
肿瘤学
·
分子生物学
·
癌症免疫学
✓ 已验证
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2019
·
IF 4.511
Quan Wang,Dongqin Lei,Fan Chen,Yuanwei Chen,Xianglin Luo
Although smart polymer micelles able to respond to the tumor acid microenvironment are potential anticancer drug carriers, fruitful clinical application of these carriers is inadequate. For the purpose of finding the origin of the unsatisfactory therapeutic efficacy of pH-sensitive drug carriers with tertiary amine groups, we newly designed and synthesized poly{α-[4-(diethylamino)methyl-1,2,3-triazol]-caprolactone-co-caprolactone}-b-poly(2-methacryloyloxyethyl phosphorylcholine) (PDCL-PMPC), a biomimetic phosphorylcholine polymer with pH-ensitive groups. PDCL-PMPC self-assembles into small and uniform micelles as its counterpart poly(caprolactone)-b-poly(2-methacryloyloxyethyl phosphorylcholine) (PCL-PMPC) without pH-sensitive groups. The in vitro and in vivo properties of PDCL-PMPC and PCL-PMPC micelles are investigated in detail. PDCL-PMPC micelles display obvious pH sensitivity by micelle change and fast drug release at pH 5, but the insensitive micelles do not. The internalization of PDCL-PMPC micelles by tumor cells is stronger than that of PCL-PMPC micelles. However, in comparison with the insensitive micelles, the pH-sensitive micelles present much shorter blood circulation time in pharmacokinetics and demonstrate worse accumulation in the tumor site in vivo study. As a result, DOX loaded PCL-PMPC micelles demonstrate much better antitumor efficiency than pH-sensitive micelles. Furthermore, DOX loaded PCL-PMPC micelles show similar therapeutic efficacy to DOX·HCl but with considerably lower side effects.
研究领域:
药剂学
·
肿瘤学
·
生物材料学
✓ 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）