Drug Design Development and Therapy
·
2022
·
IF 4.319
Na Yin,Hui Yu,Xiaodi Zhang,Xiaodan Lv
Purpose Pancreatic cancer (PCa) is projected to become the second leading cause of cancer-related deaths by 2030. Gemcitabine (GEM) combined with erlotinib (ERL) have been approved by the FDA for locally advanced, unresectable or metastatic pancreatic cancer therapy since 2005. Type-1 matrix metalloproteinase (MT1-MMP) has been recognized as a critical mediator of several steps in PCa progression including activating TGF-β or releasing latent TGF-β from LTBP-1, resulting in increased collagen production and cleavage collagen.Methods In the present research, GEM and ERL co-loaded nanoparticles (GEM/ERL NPs) were prepared. A non-substrate MT1-MMP binding peptide was decorated onto the GEM/ERL NPs surface.Results M-M GEM/ERL NPs exhibited the highest uptake ability (67.65 ± 2.87%), longest half-life period, largest area under the curve, and the best tumor inhibition efficiency (69.81 ± 4.13%). The body weight, blood urine nitrogen (BUN), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) of the system were steady when tested in mice model.Conclusion In conclusion, M-M GEM/ERL NPs protected the drugs in the plasma, improved cellular uptake capacity, exhibited the most remarkable tumor cell inhibition ability, and showed the most efficient tumor growth inhibition capacity in vivo. M-M GEM/ERL NPs could be applied as an efficient and safe system for the synergistic combination chemotherapy of PCa.
研究领域:
肿瘤学
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药剂学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
AAPS Journal
·
2017
·Vol. 19
·期 3
·814-826
·
IF 3.423
Li Fengqiao,Mei Hao,Xie Xiaodong,Zhang Huijuan,Liu Jian,Lv Tingting,Nie Huifang,Gao Yu,Jia Lee
Lung cancer is the leading cancer and has the highest death rate. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has had a promising response in lung cancer therapy. Unfortunately, individuals with TKI-resistant EGFR mutations often develop acquired resistance against erlotinib. To overcome this resistance, in the present study, we developed liposomes anchored with anti-EGFR aptamer (Apt)-conjugated chitosan (Apt-Cs) as stable carriers to deliver erlotinib to the target. We loaded erlotinib into Apt-Cs-anchored liposomal complexes (Apt-CL-E) and characterized the physicochemistry of Apt-CL-E. The nanoparticles showed good biostability and a binding specificity for EGFR-mutated cancer cells guided by the Apt. The specific binding facilitated the uptake of Apt-CL-E into EGFR-mutated cancer cells. A cytotoxicity study showed an advantage of Apt-CL-E over their nontargeted liposomal counterparts in delivering erlotinib to EGFR-mutated cancer cells, resulting in cell cycle arrest and apoptosis. These results provide a good platform for future in vivo animal studies with Apt-CL-E.
研究领域:
肿瘤学
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药剂学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Polymers
·
2022
·Vol. 14
·期 6
·1241
·
IF 4.967
Shuyu Jia,Shangqi Ning,Yuting Leng,Qiufang Jing,Zhongyu Xu,Fuzheng Ren
Microparticles (MPs) and amorphous solid dispersions (SDs) are effective methods to improve the dissolution of insoluble drugs. However, stability is a concern for these two high-energy systems, resulting from high surface area and amorphous polymorph, respectively. As an amphiphilic polymer, Soluplus (SOL) is usually used as a carrier in SDs. In this study, erlotinib microparticles (ERL MPs) and erlotinib solid dispersions (ERL SDs) were prepared with SOL by bottom-up technology and solvent evaporation. The solid-state properties of ERL MPs and ERL SDs were characterized by Differential Scanning Calorimetry (DSC), Powder X-Ray Diffraction (PXRD) and Scanning Electron Microscopy (SEM). The ERL MPs existed in a metastable crystal form A while the ERL SDs existed in an amorphous state. Fourier transform infrared spectroscopy (FT-IR) showed that there was a hydrogen bond interaction between the N-H group of ERL and the carbonyl group of SOL in ERL MPs and SDs. The dissolution profiles of ERL SDs and ERL MPs were improved significantly. ERL MPs showed better stability than ERL SDs in accelerated stability test. The discrepant stabilizing effects of polymer SOL in two systems may provide effective ideas for solubilization of insoluble drugs and the stability of drugs after recrystallization.Keywords:erlotinib;soluplus;microparticles;solid dispersions;stabilization
研究领域:
药剂学
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药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2023
·
IF 8.2
Chuan Xie,Qinqin Xiong,Yuanzhi Wei,Xin Li,Jiajun Hu,Min He,Shinan Wei,Jia Yu,Sha Cheng,Mashaal Ahmad,Yufei Liu,Sihai Luo,Xi Zeng,Jie Yu,Heng Luo
Sustained drug release has attracted increasing interest in targeted drug therapy. However, existing methods of drug therapy suffer drug action time, large fluctuations in the effective concentration of the drug, and the risk of side effects. Here, a biodegradable composite of polybutylene adipate co-terephthalate/polyvinylpyrrolidone (PBAT/PVP) consisting of electrospun hollow microspheres as sustained-released drug carriers is presented. The as-prepared PBAT/PVP composites show faster degradation rate and drug (Erlotinib) release than that of PBAT. Furthermore, PBAT/PVP composites loaded with Erlotinib provide sustained release effect, thus achieving a better efficacy than that after the direct injection of erlotinib due to the fact that the composites allow a high drug concentration in the tumor for a longer period. Hence, this work provides a potential effective solution for clinical drug therapy and tissue engineering using drug microspheres with a sustained release.
研究领域:
药剂学
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材料科学
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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
BIOMATERIALS
·
2017
·
IF 8.402
Fengqiao Li,Hao Mei,Yu Gao,Xiaodong Xie,Huifang Nie,Tao Li,Huijuan Zhang,Lee Jia
Tumor hypoxia is a common feature of the tumor microenvironment and has been regarded as one of the key factors in driving the emergence of drug resistance in solid tumors. To surmount the hypoxia-associated drug resistance, we fabricated the novel multifunctional liposomal complexes (ACLEP) that could co-deliver oxygen and molecular targeted drug to overcome the hypoxia-induced drug resistance in lung cancer. The ACLEP were fabricated with liposomes anchored with anti -EGFR aptamer-conjugated chitosan to co-administrate erlotinib and PFOB to EGFR-overexpressing non-small-cell lung cancer. Our results showed that the ACLEP possessed desired physicochemistry, good biostability and controlled drug release . The entrapped PFOB in nanoparticle facilitated the uptake of ACLEP in either normoxia or hypoxic condition. Comparing to those nanoparticles loading erlotinib alone, our innovative oxygen/therapeutic co-delivery system showed a promising outcome in fighting against hypoxia-evoked erotinib resistance both in vitro and in vivo . Hence, this work presents a potent drug delivery platform to overcome hypoxia-induced chemotherapy resistance.
研究领域:
肿瘤学
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药剂学
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生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2018
·Vol. 46
·期 4
·442-450
·
IF 3.64
Huimin Zhao,Siyuan Li,Zixin Yang,Ying Peng,Xiaohui Chen,Jiang Zheng
Erlotinib (ELT), a tyrosine kinase inhibitor, is widely used for the treatment of nonsmall cell lung cancer in clinic. Unfortunately, severe drug-induced liver injury and other adverse effects occurred during the treatment. Meanwhile, ELT has been reported to be a mechanism-based inactivator of cytochrome P450(CYPs) 3A4 and 3A5. The objectives of this study were to identify ketene intermediate of ELT and investigate the association of the acetylenic bioactivation with the enzyme inactivation caused by ELT. A ketene intermediate was detected in human microsomal incubations of ELT, using 4-bromobenzylamine as a trapping agent. CYPs 3A4 and 3A5 mainly contributed to the bioactivation of ELT. Microsomal incubation study showed that the ketene intermediate covalently modified the enzyme protein at lysine residues and destroyed the structure of heme. The vinyl and ethyl analogs of ELT showed minor enzyme inhibitory effect (less than 20%), whereas ELT inactivated more than 60% of the enzyme. The present study provided a novel bioactivation pathway of ELT and facilitated the understanding of the mechanisms of ELT-induced mechanism-based enzyme inactivation and liver injury.
研究领域:
药理学
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毒理学
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药物代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
·
IF 5.988
Hou Xi-xi,Gong Xiao-qing,Mao Long-fei,Sun Ge,Yang Jian-xue
Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor for the targeted therapy of non-small-cell lung cancer (NSCLC) However, the efficacy of erlotinib is limited because the development of drug resistance during chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1) is a rate-limiting tryptophan catabolic enzyme that is activated in many human cancers. In this study, we designed a series of erlotinib-based 1,2,3-triazole compounds by combining erlotinib with phenyl or benzyl azide. Attentive FP prediction model was used to predict the bioactivity of those compounds. We discovered that most of the erlotinib-based 1,2,3-triazole compounds are capable of suppressing IDO1 activities in vitro experiments. Among them, compound 14b (IC50 = 0.59 ± 0.05 μM) had the strongest inhibitory effect on IDO1. In addition, compound 14b significantly inhibited tumor growth comparable to the antitumor activity of erlotinib and the IDO1 inhibitor epacadostat in murine tumor models.
研究领域:
药理学
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肿瘤学
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生物化学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2016
·
IF 7.441
Yongju He,Zhigui Su,Lingjing Xue,Hui Xu,Can Zhang
Pretreatment of lung cancer cells with epidermal growth factor receptor (EGFR) inhibitor erlotinib has been recently reported that could dramatically synergize their apoptotic response to DNA damage agent doxorubicin (DOX). To translate this synergistic therapy into in vivo anticancer therapy and clinical practice, we designed a novel pH-sensitive charge conversion nanocarrier (M-HHG 2 C 18 -L) that contained erlotinib/DOX combination and produced a sequential staggered drug release for synergistic lung cancer therapy. In this study, a synthetic zwitterionic oligopeptide lipid (1,5-dioctadecyl- l -glutamyl2-histidyl-hexahydrobenzoic acid, HHG 2 C 18 ) was used to construct a pH-sensitive lipid bilayer (HHG 2 C 18 -L), which was subsequently applied to coat amino-functionalized mesoporous silica nanoparticles (MSN-NH 2 ). Erlotinib and DOX were separately incorporated into HHG 2 C 18 -L and MSN-NH 2 respectively to obtain pH-sensitive charge conversion erlotinib/DOX co-delivery nanoparticles (M-HHG 2 C 18 -L(E + D)). We confirmed that M-HHG 2 C 18 -L(E + D) were able to reverse surface zeta potential from negative to positive at tumor extracellular pH, thus facilitating the targeted cancer cell internalization. Furthermore, as erlotinib was sequestered in the exterior lipid bilayer and the controlled release ability of MSN-NH 2 , erlotinib released faster than DOX during the cellular transport. Additionally, HHG 2 C 18 -L became more positive at tumor intracellular pH and enhanced Coulombic repulsion with MSN-NH 2 , leading to increased sequential staggered release of erlotinib and DOX. Due to the pretreatment and time-staggered inhibition of EGFR with erlotinib and the enhanced intracellular release of DOX to the nucleus, the maximized synergistic cell killing effect was achieved. Compared to non-sensitive erlotinib/DOX co-delivery nanoparticles (M-SPC-L(E + D)) and simultaneous DRUG coadministration. M-HHG 2 C 18 -L(E + D) with sequential staggered drug release and pH-sensitive charge conversional properties showed great synergistic effects in antiproliferation and apoptosis of A549 human cancer cells in vitro. The in vivo study demonstrated that M-HHG 2 C 18 -L(E + D) exhibited considerable tumor accumulation and potent suppression of tumor growth in Lewis lung carcinoma tumor bearing mice. It was also demonstrated that M-HHG 2 C 18 -L(E + D) showed no systemic toxicity and possessed distinguished effect on extending survival period. These results suggested that M-HHG 2 C 18 -L(E + D) had great potential application in cancer treatment.
研究领域:
药学
·
肿瘤学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
DYES AND PIGMENTS
·
2019
·
IF 4.018
Lu Zhang,Jun Wang,Yingying Zhang,Linjie Ke,Xiaowen Lin,Ziying Li,Haijun Chen,Yu Gao
The outcome of application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small-cell lung cancer (NSCLC) always suffers from acquired drug resistance. Its combination with other therapies has been explored with promising synergistic results. Photodynamic therapy (PDT) is an established treatment modality for NSCLC, but the low tumor selectivity of currently available photosensitizers (PSs) hampered the wide clinical application of PDT. Here, we synthesized erlotinib modified chitosan (ECs) by click coupling and developed ECs/indocyanine green (ICG) self-assembled nanoparticles (GECs) for combined targeted chemo-photodynamic therapy. GECs showed oval-shaped particles with a diameter of 267.5 nm, a zeta potential of −15.2 mV, and considerable photostability. In vitro release experiment showed that erlotinib and ICG could be slowly released from GECs in acidic condition with lysozyme. GECs were capable of generating reactive oxygen species (ROS) for PDT under near-infrared laser irradiation . GECs showed synergistic molecular targeted and photodynamic therapeutic effects in inhibition of cellular growth and induction of apoptosis in NSCLC cells. This study demonstrated that the GECs could be a promising platform by combination of targeted chemo-photodynamic therapy for NSCLC treatment.
研究领域:
肿瘤学
·
药剂学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Furong Cheng,Qingqing Pan,Wenxia Gao,Yuji Pu,Kui Luo,Bin He
Mitochondrial drug delivery has attracted increasing attention in various mitochondrial dysfunction-associated disorders such as cancer owing to the important role of energy production. Herein, we report a lysosomal pH-activated mitochondrial-targeting polymer nanoparticle to overcome drug resistance by a synergy between mitochondrial delivery of doxorubicin (DOX, an anticancer drug) and erlotinib-mediated inhibition of drug efflux. The obtained nanoparticles, DE-NPs could maintain negative charge and have long blood circulation while undergoing charge reversal at lysosomal pH after internalization by cancer cells. Thereafter, the acidity-activated polycationic and hydrophobic polypeptide domains boost lysosomal escape and mitochondrial-targeting drug delivery, leading to mitochondrial dysfunction, ATP suppression, and cell apoptosis. Moreover, the suppressed ATP supply and erlotinib enabled dual inhibition of drug efflux by DOX-resistant MCF-7/ADR cells, leading to significantly augmented intracellular DOX accumulation and a synergistic anticancer effect with a 17-fold decrease of IC50 relative to DOX. In vivo antitumor study demonstrates that DE-NPs efficiently suppressed the tumor burden in MCF-7/ADR tumor-bearing mice and led to negligible toxicity. This work establishes that a combination of mitochondrial drug delivery and drug efflux inhibition could be a promising strategy for combating multidrug resistance.
研究领域:
肿瘤学
·
药理学
·
生物材料学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Cancer
·
2019
·
IF 3.182
Mingtong Ye,Nengzhi Pang,Ting Wan,Yuanling Huang,Tianyi Wei,Xuye Jiang,Yujia Zhou,Yufeng Huang,Hainan Yang,Zhenfeng Zhang,Lili Yang
Switching aerobic respiration to anaerobic glycolysis of cancer cells plays an important role in development and progression of acquired resistance. Since vitamin C enabled the inhibition of glycolysis of cancer cells, and erlotinib-resistant sub-line of HCC827 (ER6 cells) switched its metabolic features to higher glycolysis for survival, we hypothesize that vitamin C is able to inhibit glycolysis of ER6 cells. In this study, we found that both reduced vitamin C and oxidized vitamin C (DHA) could selectively suppress the viability of ER6 cells. DHA was efficient in inhibiting glycolysis and leading to energy crisis, which could be one mechanism for overcoming drug resistance to erlotinib of ER6 cells. Our data suggest that applying DHA could be a novel treatment strategy for NSCLC with acquired resistance to targeted therapy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2019
·
IF 10.273
Yanlin Feng,Yan Cheng,Yun Chang,Hui Jian,Runxiao Zheng,Xiaqing Wu,Keqiang Xu,Li Wang,Xiaomin Ma,Xi Li,Haiyuan Zhang
Photochemotherapy is currently an effective anticancer therapy. Recently, it has been reported that cancer cells pretreated with epidermal growth factor receptor (EGFR) inhibitor erlotinib (Erl) can significantly synergize its apoptosis against the DNA damaging agent doxorubicin (Dox). As a result, we designed two gold nanocages (Au NCs) microcontainers covered with different smart polymer shell-PAA (pH responsive) and p (NIPAM-co-AM) (temperature responsive) containing Erl and Dox respectively. The acidic tumor microenvironment and NIR light irradiation can selectively activate the release of Erl and Dox. Time staggered release of Erl and Dox and photothermal therapy enhance the apoptotic signaling pathways , resulting in improved tumor cell killing in both MCF-7 (low EGFR expression) and A431 (very high EGFR expression) tumor cells, but more efficient in the latter. The photochemotherapy strategy controls the order and duration of drug exposure precisely in spatial and temporal, and significantly improves the therapeutic efficacy against high EGFR expressed tumors.
研究领域:
肿瘤学
·
纳米医学
·
药理学
✓ 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）