RSC Advances
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2019
·Vol. 9
·期 4
·1982-1989
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IF 3.049
Chao Zhang,HongLei Zhang,MengNan Han,XueLi Yang,ChaoHong Pei,ZhiDong Xu,Jie Du,Wei Li,Shengxi Chen
Cisplatin is the most widely used anticancer drug, but its side effects limit the maximum systemic dose. To circumvent the side effects, a DNA tetrahedron–affibody nanoparticle was prepared by combination of a DNA chain with cisplatin via interstrand crosslinks or adducts. Each nanocarrier can bind ∼68 molecules of cisplatin. This cisplatin nanoparticle exhibited high selectivity and inhibition for breast cancer HER2 overexpressing cells BT474 and lower toxicity in MCF-7 cells with low HER2 expression. The nano-drug inhibited the growth of BT474 cells by 94.57% at 512 nM (containing 33.3 μM cisplatin), which was higher than that of cisplatin (82.9%, 33.3 μM).
研究领域:
肿瘤学
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分子生物学
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纳米医学
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DOI
PubMed
高影响因子
American Journal of Cancer Research
·
2024
·Vol. 14
·期 12
·5752
·
IF 3.6
Xiaobo Cai,Min Cao,Qingliang Yang,Xiazhen Yu,Xin-Hua Feng,Robert Yongxin Zhao
Gastric cancer is a common malignant tumor with high incidence and mortality. The overexpression of Human epidermal growth factor receptor 2 (HER2) is associated with increased metastatic potential and poor clinical outcome in gastric cancer. Despite the proven clinical response rates of approved HER2-targeted therapies, including Trastuzumab combined with chemotherapy, their limited long-term clinical benefits and inevitable disease progression still pose significant challenges to the clinical treatment of gastric cancer. Hence, exploring novel strategies to enhance therapeutic outcomes for HER2-positive patients is extremely crucial and urgent. Here, we reported that DX126-262, a novel HER2-targeted antibody-drug conjugate, generated by conjugating a potent Tubulysin B analogue (Tub-114) to humanized anti-HER2 monoclonal antibody, exhibited a significant synergistic inhibitory effect with both Cisplatin and 5-FU in HER2-positive gastric cancer NCI-N87 cells. Moreover, the triple-drug combination strategy of DX126-262 combined with Cisplatin and 5-FU showed much better in vitro and in vivo therapeutic efficacy than monotherapy or double-drug combination (Cisplatin plus 5-FU) or first-line standard-of-care (SOC, Herceptin plus Cisplatin and 5-FU), and comparable or even superior in vivo efficacy than third-line SOC (DS-8201a) in NCI-N87 cells and xenograft models. Meanwhile, the triple-drug combination therapy did not exhibit superimposed toxicity. Taken together, our findings provide compelling evidence that DX126-262 in combination with Cisplatin and 5-FU exerts synergistic antitumor activity and is a promising strategy to improve the clinical efficacy of HER2-positive advanced or metastatic gastric cancer.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
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2017
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IF 4.44
Di Gao,Jinbiao Gao,Ming Xu,Zhong Cao,Luyao Zhou,Yingqin Li,Xiaoyan Xie,Qing Jiang,Wei Wang,Jie Liu
For successful gene therapy, it is imperative to accumulate therapeutic gene in tumor tissues followed by efficiently delivering gene into targeted cells. Ultrasound irradiation, as a noninvasive and cost-effective external stimulus, has been proved to be one of the most potential external-stimulating gene delivery strategies recently in further improving gene transfection. In this study, we developed tumor-targeting ultrasound-triggered phase-transition nanodroplets AHNP-PFP-TNDs comprising a perfluorinated poly(amino acid) C11F17–PAsp (DET) as a core for simultaneously loading perfluoropentane (PFP) and nucleic acids, and a polyanionic polymer PGA-g-PEG-AHNP as the shell for not only modifying the surface of nanodroplets but also introducing an anti-Her2/neu peptide (AHNP) aiming to targeted treatment of Her2-overexpressing breast cancer. The results showed the average diameter of AHNP-PFP-TNDs was below 400 nm, nearly spherical in shape. The modification of PGA-g-PEG-AHNP not only increased the serum stability of the nanodroplets but also improved the affinity between nanodroplets and Her2-overexpressing breast cells. Both intratumor and intravenous injection of AHNP-PFP-TNDs into nude mice bearing HGC-27 xenografts showed that the gene transfection efficiency and the ultrasound contrast effect were significantly enhanced after exposed to the ultrasound irradiation with optimized ultrasound parameters. Therefore, this targeting nanodroplets system could be served as a potential theranostic vector for tumor targeting ultrasound diagnosis and gene therapy.
研究领域:
医学影像学
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肿瘤学
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基因治疗
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2025
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IF 5.4
Aimei Li,Xue Tian,Feihu Hu,Chuntao Li,Ziru Liu,Chunbo Lu,Xizhen Wang,Yingshuai Wang,Lingling Dai,Baolong Zhou,Jingkun Bai
High expression of human epidermal growth factor receptor 2 (HER2) accelerates the proliferation of breast cancer cells and the progression and malignancy of breast cancer. HER2-positive breast cancer cells often overexpress antiapoptotic proteins, enabling them to resist apoptosis despite the presence of proapoptotic signals. Additionally, traditional chemotherapeutic drugs are easily eliminated from tumor cells, preventing them from reaching concentrations adequate for effectively destroying tumors or inhibiting tumor growth. In this research, these obstacles were addressed by developing a drug delivery system based on the amphipathic peptide Pep1. The model chemotherapeutic drugs doxorubicin (DOX) and curcumin (CUR) are encapsulated by Pep1 (DC/Pep1) to form spherical nanoparticles, which are ultimately converted to nanofibers by alkaline phosphatase (ALP) to increase drug accumulation in SKBR3 cells. Compared with DC/Pep2, which cannot undergo a morphological transformation, DC/Pep1 increases the expression of E-cadherin and pro-Caspase-3 and inhibits the migration and accelerates the apoptosis of HER2-positive breast cancer cells. Morphologically transformable amphipathic peptides, as drug carriers that target HER2-positive breast cancer cells, represent a facile and promising strategy for breast cancer therapy.
研究领域:
肿瘤学
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药学
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生物材料学
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DOI
高影响因子
JOURNAL OF BIOMATERIALS APPLICATIONS
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2020
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IF 2.22
Qi Dong,Caifeng Wan,Hong Yang,Dongdong Zheng,Li Xu,Zhiguo Zhou,Shaowei Xie,Jing Du,Fenghua Li
A multifunctional targeted nanoplatform combining photothermal therapy and chemotherapy has emerged as a promising strategy for comprehensive therapies of breast cancer. In this study, we constructed human epidermal growth factor receptor 2 (Her2)-targeted gold nanoshelled poly(lactic-co-glycolic acid) hybrid nanocapsules encapsulating perfluorooctyl bromide, superparamagnetic iron oxide nanoparticles, and doxorubicin (Her2-GPDH nanocapsules) as theranostic agent for bimodal ultrasound/magnetic resonance imaging and synergistic photothermal-chemotherapy of Her2-postive breast cancer cells. Her2–GPDH nanocomposites possessed well-defined spherical morphology, and the average diameter was about 296 nm with good dispersion. Targeting assays demonstrated that Her2–GPDH nanocapsules exhibited higher targeting binding to Her2-positive SKBR3 cells than Her2-negative MDA-MB-231cells. The encapsulation efficiency and the loading content of doxorubicin in Her2–GPDH nanocapsules were 39 ± 1.45% and 3.8 ± 0.52%, respectively, and the agent exhibited pH-responsive and near-infrared light-triggered stepwise release behavior of doxorubicin. In vitro, the agent had potential to serve as feasible candidate for ultrasound imaging and T2-weighted magnetic resonance imaging with a relatively high relaxivity. Cell experiments confirmed that the agent had significant photothermal cytotoxicity on SKBR3 cells, and the combined photothermal–chemotherapy could significantly enhance the anti-tumor effect. In summary, the present Her2–GPDH nanocapsules, a novel multifunctional nanoplatform, will offer a new way for early bimodal molecular-level diagnosis and synergistic treatment of Her2-positve breast cancer.
研究领域:
肿瘤学
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纳米医学
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生物医学工程
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DOI
PubMed
高影响因子
ACS Applied Nano Materials
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2024
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IF 5.3
Jiaqun Du,Junpeng Sun,Xiaobang Liu,Huan Shi,Chao Wu,Ying Liu,Yang Qiu,Yu Gao
This study aimed to develop trastuzumab (HCT)-functionalized albumin (BSA)-coated, pyrotinib (Ptb)-loaded hollow mesoporous selenium (HSE) nanoparticles (HBHSEP) for the targeted delivery of HER2-positive breast cancer. Characterization of the pharmaceutical properties in vitro revealed that HBHSEP was well dispersed, and the particle size was 172 ± 3.4 nm. In vitro release experiments revealed that HBHSEP effectively controlled the release of Ptb in the tumor microenvironment (high glutathione concentration), with a cumulative release rate of 86.5 ± 4.2% over 48 h. Cell uptake experiments and in vivo imaging confirmed that HBHSEP have good tumor-targeting ability. The results of in vitro cell experiments, such as MTT, flow cytometry, immunofluorescence staining, and in vivo antitumor experiments, confirmed that HBHSEP can significantly promote the apoptosis of SK-BR-3 cells and inhibit their proliferation. These findings strongly show that HBHSEP may be an effective targeted treatment for HER2-positive breast cancer.
研究领域:
药学
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肿瘤学
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纳米医学
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产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
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2021
·
IF 9.229
Lihong Sun,Jinxia Zhang,Menghong Xu,Lulu Zhang,Qingshuang Tang,Jing Chen,Ming Gong,Suhui Sun,Huiyu Ge,Shumin Wang,Xiaolong Liang,Ligang Cui
Trastuzumab combined with chemotherapy is the first-line treatment for advanced HER2-positive gastric cancer, but it still suffers from limited therapeutic efficiency and serious side effects, which are usually due to the poor delivery efficiency and the drug resistance of tumor cells to the chemotherapeutic drugs. Herein, a type of ultrasound microbubble for simultaneous delivery of sonosensitizers and therapeutic antibodies to achieve targeting combination of sonodynamic therapy and antibody therapy of HER2-positive gastric cancer was constructed from pyropheophorbide-lipid followed by trastuzumab conjugation (TP MBs). In vitro and in vivo studies showed that TP MBs had good biological safety, and their in vivo delivery can be monitored by ultrasound/fluorescence bimodal imaging. With ultrasound (US) located at the tumor area, TP MBs can be converted into nanoparticles (TP NPs) in situ by US-targeted microbubble destruction; plus the enhanced permeability and retention effects and the targeting effects of trastuzumab, the enrichment of sonosensitizers and antibodies in the tumor tissue can be greatly enhanced (∼2.1 times). When combined with ultrasound, TP MBs can not only increase the uptake of sonosensitizers in HER2-positive gastric cancer NCI-N87 cells but also efficiently generate singlet oxygen to greatly increase the killing effect on cells, obviously inhibiting the tumor growth in HER2-positive gastric cancer NCI-N87 cell models with a tumor inhibition rate up to 79.3%. Overall, TP MBs combined with US provided an efficient way for co-delivery of sonosensitizers and antibodies, greatly enhancing the synergistic therapeutic effect on HER2-positive gastric cancer while effectively reducing the side effects.
研究领域:
肿瘤学
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生物医学工程
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诊疗学
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DOI
PubMed
高影响因子
ChemistryOpen
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2019
·Vol. 8
·期 4
·451-456
·
IF 2.205
Joo Hee Jang,Sang Jin Han,Jung Young Kim,Kwang Il Kim,Kyo Chul Lee,Chi Soo Kang
Graphical Conjugate for double duty : A new antibody-drug conjugate composed of paclitaxel (PTX), deferoxamine (DFO) and trastuzumab (DFO-trastuzumab-PTX) was prepared using simple conjugation chemistry. The new conjugate displayed instant complexation kinetics with 89 Zr and showed feasible cytotoxic effect and binding property on HER2-positive MDA-MB-231 breast cancer cell showing promising potential as a theranostic agent utilizing chemo-drug and positron emission tomography (PET). The preparation and in vitro evaluation of a theranostic conjugate composed of trastuzumab, paclitaxel (PTX), and deferoxamine (DFO)-chelated 89 Zr have been reported. These comounds have potential applications against HER2 receptor positive breast cancers. We conjugated DFO and PTX to trastuzumab by exploiting simple conjugation chemistry. The conjugate (DFO-trastuzumab-PTX) showed excellent radiolabeling efficiency with 89 Zr and the labeled conjugate had high in vitro stability in human serum. Furthermore, DFO-trastuzumab-PTX displayed comparable cytotoxicity with PTX and 89 Zr-DFO-trastuzumab-PTX exhibited HER2 receptor-mediated binding on HER2-positive MDA-MB-231 breast cancer cells. The results of our in vitro study indicate high potential of 89 Zr-DFO-trastuzumab-PTX to be utilized in the theranostic application against HER2-postive breast cancers.
研究领域:
肿瘤学
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药理学
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核医学
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
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2018
·
IF 3.095
Yiwen You,Zhiyuan Xu,Yun Chen
HER2-positive breast cancer correlates with more aggressive tumor growth, a poorer prognosis and reduced overall survival. Currently, trastuzumab (Herceptin), which is an anti-HER2 antibody, is one of the key drugs. There is evidence indicating that conjugation of trastuzumab with chemotherapy drugs, such as doxorubicin (DOX), for multiple targets could be more effective. However, incomplete penetration into tumors has been noted for those conjugates. Compared to an antibody, peptides may represent an attractive alternative. For HER2, a similar potency has been observed for a 12-amino-acid anti-HER2 peptide mimetic YCDGFYACYMDV-NH2 (AHNP, disulfide-bridged) and full-length trastuzumab. Thus, a peptide, GPLGLAGDDYCDGFYACYMDV-NH2, which consists of AHNP and an MMP-2 cleavable linker GPLGLAGDD, was first designed, followed by conjugation with DOX via a glycine residue at the N-terminus to form a novel DOX-peptide conjugate MAHNP-DOX. Using HER2-positive human breast cancer cells BT474 and SKBR3 as in vitro model systems and nude mice with BT474 xenografts as an in vivo model, this conjugate was comprehensively characterized, and its efficacy was evaluated and compared with that of free DOX. As a result, MAHNP-DOX demonstrated a much lower in vitro IC50, and its in vivo extent of inhibition in mice was more evident. During this process, enzymatic cleavage of MAHNP-DOX is critical for its activation and cellular uptake. In addition, a synergistic response was observed after the combination of DOX and AHNP. This effect was probably due to the involvement of AHNP in the PI3K–AKT signaling pathway, which can be largely activated by DOX and leads to anti-apoptotic signals.
研究领域:
肿瘤学
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CELL CYCLE
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2018
·
IF 3.304
Xiaoyu Chen,Danrui Cui,Yanli Bi,Jianfeng Shu,Xiufang Xiong,Yongchao Zhao
Breast cancer is a common type of cancer among female cancer patients and the main cause of cancer-related deaths. During the last decades, targeted therapies for breast cancer have been rapidly developing. Among them, MLN4924, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, has performed antitumor activity by inactivating the cullin-RING ligases and causing the accumulation of their substrates to induce apoptosis in a number of studies. In this study, we found that MLN4924 activates the AKT pathway in both HER2-positive and triple-negative breast cancer (TNBC) cell lines. Given that AKT signaling is responsible for tumor progression and drug resistance in some types of cancers, we hypothesized that the AKT inhibitor may synergistically enhance the tumor suppression capability in breast cancer by MLN4924. To demonstrate the sensitizing effect, MK-2206 was chosen as the adjuvant treatment, and cell growth, migration and apoptosis were detected. The results showed that MLN4924 treatment inhibited cell growth and migration and induced apoptosis in both SK-BR3 and MDA-MB231 breast cancer cell lines. More importantly, the combined treatment of MLN4924 and MK-2206 indeed caused stronger cytotoxicity and inhibition of migration and a much higher induction of apoptosis compared with MLN4924 treatment alone. Our study provides the proof-of-concept evidence for strategic drug combination of MLN4924 with an AKT inhibitor for maximal killing of breast cancer cells via the enhancement of apoptosis.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
PeerJ
·
2023
·
IF 2.7
Junfeng Zhu,Gaoqi Xu,Dihong Yang,Yu Song,Yinghui Tong,Sisi Kong,Haiying Ding,Luo Fang
Background Lapatinib is an oral small-molecule tyrosine kinase inhibitor indicated for advanced or metastatic HER2-positive breast cancer. In order to reduce the treatment cost, a high-fat enteral nutrition emulsion TPF-T was selected as a dose-sparing agent for lapatinib-based therapies. This study aimed to investigate the effect of TPF-T on lapatinib pharmacokinetics. Methods First, a simple and rapid liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed to quantitatively evaluate lapatinib in rabbit plasma. The method was fully validated according to the China Pharmacopoeia 2020 guidance. Rabbits and rats were chosen as the animal models due to their low and high bile flows, respectively. The proposed LC–MS/MS method was applied to pharmacokinetic studies of lapatinib, with or without TPF-T, in rabbit and rat plasma. Results The LC–MS/MS method revealed high sensitivity and excellent efficiency. In the rabbit model, co-administration with TPF-T resulted in a 32.2% increase in lapatinib exposure. In the rat model, TPF-T had minimal influence on the lapatinib exposure. In both models, TPF-T was observed to significantly elevate lapatinib concentration in the absorption phase. Conclusion Co-administration with TPF-T had a moderate effect on increasing exposure to lapatinib. Dose sparing using a high-fat liquid diet is potentially feasible for lapatinib-based therapies.
研究领域:
药理学
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肿瘤学
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临床研究
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2015
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IF 6.025
Kaiyuan Wang,Hui Yao,Ying Meng,Yi Wang,Xueying Yan,Rongqin Huang
Tumor-specific therapeutic platforms designed for combined tumor therapy has recently received wide attention. In this work, a new HB5 aptamer-functionalized mesoporous silica–carbon based doxorubicin (DOX)-loaded system (MSCN-PEG-HB5/DOX) was successfully constructed and characterized for chemo-photothermal combined therapy of human epithelial growth factor receptor 2 (HER2)-positive breast cancer cells. The in vitro release result showed that MSCN-PEG-HB5/DOX exhibited pH-sensitive and NIR-triggered release manner. HB5-modified nanoparticles showed significant higher cellular uptake in HER2-positive breast cancer cells (SK-BR-3) but not in normal breast epithelial cells (MCF-10A), compared to unmodified counterparts. The intracellular uptake of functional nanoparticles was mainly based on the receptor-mediated mechanism which was energy-dependent. Cytotoxicity experiments demonstrated that combined therapy induced highest cell killing effect compared to chemotherapy and photothermal therapy alone. The combination index (CI) was 0.253 indicating the synergistic effect of chemotherapy and photothermal therapy. These findings suggested that MSCN-PEG-HB5/DOX was a potential chemo-photothermal therapeutic platform targeting to HER2-positive breast cancers.
研究领域:
肿瘤学
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纳米医学
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药剂学
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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）