Materials Research Express
·
2019
·Vol. 6
·期 10
·105413
·
IF 1.449
Ke Song,Xin Wang,Xiao Liang,Mingxia Liu,Yang Zhou,Guolin Zhang,Lijiang Chen
The present study aims to develop a novel intelligent polymer-drug conjugate for the delivery of gambogic acid (GA). Specifically, the conjugate was composed of polyacrylic acid, GA and cystamine. GA-loaded nanoparticles (polyacrylic acid-cystamine-gambogic acid-nanoparticles, PAA-SS-GA-NPs) were simply and rapidly prepared using an ultrasonic-assisted direct dissolution method. Subsequently, we characterized the formulation by different methods, including dynamic light scattering (DLS), differential scanning calorimetry (DSC), transmission electron microscopy (TEM) and ultraviolet spectrophotometry (UV). Moreover, the in vitro release, cytotoxicity and cellular uptake were equally determined. The results showed that PAA-SS-GA-NPs had a small particle size (91.5 ± 9.19 nm), had a high drug loading efficiency ((32.5 ± 2.3) %) and greatly improved the water solubility of GA (over 9700-fold). Most importantly, they showed good response performance. The nanoparticles maintained the antitumor activity of GA but were less cytotoxic to normal cells than free GA. These results demonstrated that the nanoparticles may be a promising drug carrier.
研究领域:
药剂学
·
生物材料
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Keying Liang,Shengsheng Mei,Xiangzheng Gao,Shanshan Peng,Jinbiao Zhan
Purpose T-DM1 is an antibody–drug conjugate (ADC) consisting of trastuzumab and DM1 linked together. T-DM1 binds to human epidermal growth factor receptor-2 (HER2) in tumors and then triggers the endocytosis of T-DM1 and release of payload. Therefore, endocytosis efficacy is considered as a critical step for the initiation of T-DM1 therapy; however, the endocytosis mechanism of T-DM1 remains poorly understood. Meanwhile, HER2 is regarded as an internalization-resistant receptor, which hinders the endocytosis and effectiveness of T-DM1. The present study is to explore the T-DM1 endocytosis pathway, which may provide insights into the internalization mechanism of ADCs and help to improve efficacy.Methods Confocal microscopy and flow cytometry were used to analyse T-DM1 intracellular trafficking and endocytosis efficiency, while Western blot assay was performed to detect T-DM1 degradation.Results We found that intracellular T-DM1 was increased to 50% within 12 h. T-DM1 was colocalized with cholera toxin B (CTxB), a lipid raft marker, within 2 h and then degraded in lysosome. Upon overexpression of caveolin-1 (CAV-1) and utilization of caveolae/lipid-raft disruptors, we found that temporal CAV-1 upregulation significantly facilitated T-DM1 endocytosis and degradation, whereas nystatin and lovastatin disrupted caveolae/lipid-raft structure and inhibited T-DM1 degradation. We demonstrate that T-DM1 internalizes through the lipid raft-mediated endocytosis in a CAV-1 dependent manner, rather than through the clathrin-mediated endocytosis in HER2-positive cancer cells.Conclusion Our findings suggest that modulation of the caveolae/lipid-raft mediated endocytosis may be a possible option for improving the clinical therapeutic effect of T-DM1 because it plays a key role in regulating T-DM1 internalization.
研究领域:
肿瘤学
·
细胞生物学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2018
·
IF 3.466
Wen-Bin Zhao,Chi-Xiao Qiu,Ying Shen,Wen-Hui Liu,Jie Zhou,Ying-Chun Xu,Zhan Zhou,Shu-Qing Chen
Antibody-drug conjugates (ADCs) consist of cytotoxic agents covalently conjugated to monoclonal antibodies that substantially improve antitumour activity and reduce systemic toxicity. With the growing number of ADCs in clinical applications, more accurate bioanalysis data are urgently needed to facilitate the development and rational use of ADCs. Herein, we used antigen-positive cells as antigen carriers and ofatumumab (OFA-HL) and ofatumumab-based ADC (OFA-HL-MMAE) as examples to establish a new ligand-binding assay (LBA) method based on flow cytometry. We proved that the new method met the required analytical performance criteria and the lower limit of quantitation (LOQ) was 0.2 μg/mL. In addition, the LOQ of the quantitative OFA-HL flow cytometry method was reduced to 0.025 μg/mL by choosing an optimized fluorescent antibody, which indicated that the LOQ of the new method can be improved. What's more, the new method showed good stability and specificity when we used it to determine the concentrations of OFA-HL and OFA-HL-MMAE in mouse serum. During the bioanalysis of ADCs, various factors should be considered. Therefore, choosing optimal methods for ADC bioanalysis is necessary. This new method using in situ antigens not only extends the scope of application of the conventional LBA methods by avoiding the need for soluble antigens, but also improves the authenticity of ADC bioanalysis as a supplementary approach, which is valuable for developing accurate ADC assays.
研究领域:
药理学
·
肿瘤学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2022
·
IF 5.307
Zheng Su,Fei Xie,Xin Xu,Lianqi Liu,Dian Xiao,Xinbo Zhou,Song Li
Antibody-drug conjugates are gradually revolutionizing anticancer therapy. Payload is one of the most crucial components of ADC for high antitumor activity. However, there is no direct and real-time monitoring method for the intracellular release mechanism of the payload. Herein, we developed a theranostic payload that possessed dual functions of therapy and imaging. This payload consisted of the classic payload MMAE and the novel nitro-coumarin probe reported for the first time, which has the dual characteristics of electron transfer ability and the on–off fluorescence property. In this paper, the theranostic property of the novel payload has been preliminarily demonstrated. The fluorescence intensity of the payload in target cells greatly increased approximately 9 times in 120 min through the high content analysis, and the intracellular distribution of the payload could be directly monitored by a confocal microscope. In in vitro cytotoxicity assays, the payload showed broad-spectrum and high antitumor activity (0.09 nM to 1.2 nM), which was equivalent to the MMAE (0.06 nM to 1.1 nM). Moreover, the ADC loaded with L-233 maintained the theranositc property. In conclusion, our work developed a theranostic payload for the first time and provides a new direct and real-time monitoring method for intracellular studies of ADC payloads.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2020
·
IF 4.845
Xican Zhang,Liangzhu Feng,Ziliang Dong,Xiaoqian Xin,Zhijuan Yang,Dashi Deng,Ernst Wagner,Zhuang Liu,Xiaowen Liu
Combining functional proteins with small molecular drugs into one entity may endow distinct synergistic advantages. However, on account of completely different physicochemical properties of such payloads, co-delivery through systemic administration for therapeutic purpose is challenging. Herein, we designed the protein-drug conjugate HSAP-DC-CAT (human serum albumin/Pt (IV)-dibenzocyclooctyne/chlorin e6-catalase) by modification of CAT and cisplatin pro-drug loaded HSA with pH-sensitive azide linker 3-(azidomethyl)-4-methyl-2,5-furandione (AzMMMan) followed by click chemistry assembly with DC. The dynamic covalent bonds between linker and proteins, on the one hand, can bridge proteins and small molecular drugs in the intermediate state for systemic delivery in the harsh in vivo environment; on the other hand, it can trigger traceless cleavage and release of drugs and proteins with full bioactivity in acidic microenvironment of tumor. The multifunctional HSAP-DC-CAT provides efficient cytosolic transduction in vitro, excellent blood half-lives after systemic administration, and significant antitumor outcome via integrated cisplatin-based chemotherapy and Ce6-based photodynamic therapy enhanced by catalase-induced manipulation of tumor hypoxia microenvironment. This study describes a universal formulation strategy for protein and small molecular drug by a bifunctional linker through amide reaction and click chemistry, with traceless in vivo release of therapeutic units.
研究领域:
药理学
·
肿瘤学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 5
·4646
·
IF 5.6
Longkun Wang,Chunqian Zhao,Lu Lu,Honglei Jiang,Fengshan Wang,Xinke Zhang
Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.Keywords:paclitaxel;peptide-drug conjugate;TAT peptide;A7R peptide;targeted delivery;anticancer therapy;transcytosis
研究领域:
药学
·
肿瘤学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2014
·
IF 4.787
Chaoyu Liu,Jiang Yuan,Xiaoming Luo,Maohua Chen,Zhoujiang Chen,Yuancong Zhao,Xiaohong Li
It is one of the challenges for a wide clinical application of polymer micelles to address the structure disintegration and premature drug release before reaching a pathological site. In the current study, folic acid (FA)-decorated polymer–drug conjugates (FSC) were synthesized with disulfide linkages between camptothecin (CPT) and amphiphilic poly(ethylene glycol)-b-poly(ε-caprolactone) (PECL) copolymers. FSC conjugates were proposed to assemble into micelles with a hydrophobic core of PCL segments and CPT and a hydrophilic corona of PEG segments. The addition of hexadecanol during micelle formation (FSC-16) was proposed to modulate the interactions of hydrophobic segments in micelles and enhance the reductive sensitivity. FSC-16 micelles were obtained with critical micelle concentration of around 2 μg/mL and an average size of around 200 nm, and the conjugated CPT was rapidly released out in response to glutathione. The reductive sensitivity was also demonstrated with respect to the changes of micelle size and morphologies as well as the fluorescent intensity of pyrene loaded in micelles. Benefiting from the FA receptor-mediated uptake and the reduction-sensitive release of CPT, significant cytotoxicity and cell apoptosis were identified for FSC-16 micelles against SKOV-3 cells with strong expressions of FA receptors. Flow cytometry and confocal laser scanning microscopy analyses demonstrated that CPT was distributed into nuclei after cellular uptake and intracellular release from FSC-16 micelles. Thus, the FA-decorated and reduction-sensitive micelles assembled from polymer–drug conjugates show advantages in inhibiting premature release during circulation, enhancing cellular uptake at the tumor tissues, and promoting intracellular release and nuclei location of the active moieties.
研究领域:
药剂学
·
生物医学工程
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
TALANTA
·
2024
·
IF 5.6
Xianjing Li,Minlu Cheng,Yiya Wang,Chang Shu,Bingjie Zou,Qinxin Song,Li Ding
Recently, peptide-drug conjugate (PDC) has become the most promising conjugated drug for tumor therapy after antibody-drug conjugate due to stronger tumor penetration capacity and lower immunogenicity . CBP-1018 was a PDC with dual-ligand conjugated to MMAE via a cleavable linker (MC-Val-Cit-PABC) that can be lysed by cathepsins B. In this study, two specific LC-MS/MS methods were developed and validated for the determination of CBP-1018 and its metabolite MMAE in human plasma. To prevent the cleavable MC-Val-Cit-PABC linker from degradation, a protease inhibitor (cOmplete solution) was added to the pre-cooled vacuum tubes and the separated plasma samples. The assays involved the pretreatment of CBP-1018 by protein precipitation with H 2 O-ACN (1:9, v / v ) and the extraction of MMAE by liquid-liquid extraction with ethyl acetate under alkaline condition to eliminate the interference of CBP-1018 on MMAE. The two analytes showed good linearities over the calibration ranges (R 2 ≥ 9980). Both accuracy and precision met the acceptance criteria. The validated methods were successfully applied to the phase I dose-escalation study of CBP-1018 injection in Chinese patients with solid tumors to evaluate the pharmacokinetic properties of CBP-1018 and MMAE. The results showed that CBP-1018 was eliminated immediately after injection and MMAE reached the maximum exposure at approximately 2 h after infusion. The maximum concentration of MMAE did not exceed 20.0 ng/mL, suggesting that the off-target toxicity of CBP-1018 injection was controllable.
研究领域:
药理学
·
肿瘤学
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Bio Materials
·
2021
·
IF 0
Ning Zhang,Daquan Wang,Xunan Jing,Tingting Yang,Hongbo Yang,Lingjie Meng
In the past decades, polymer–drug conjugates of anticancer agents have gained much attention due to their enhanced aqueous solubility, improved pharmacokinetics, and better drug utilization than their conventional insoluble counterparts. Several polymer–drug conjugates have entered the third phase of clinical trials yet suffer from inherent deficiencies, including uncontrolled drug release and unclear degradation mechanisms. In this study, a pH/reactive oxygen species (ROS) dual-responsive PEG-doxorubicin (DOX) conjugate (denoted as TPD) was synthesized through acyl alkynyl-amine click reaction by PEG dipropiolate (PEGB), amine-terminated thioketal (TKL), and doxorubicin (DOX). Due to the generated ene-amine and thioketal in the backbone, the prepared amphiphilic TPD not only has a high drug loading ratio for photosensitizer chlorin e6 (Ce6) but also has the sensitivity to the acidic tumor microenvironment (TME) and ROS. Considering the complex conditions of TME, the prepared TPD@Ce6 nanoparticles (NPs) might respond to the relatively low pH and release Ce6 initially, and upon laser radiation, Ce6 produces abundant singlet oxygen (1O2) to achieve a programmable accelerated release of DOX and more Ce6 at the tumor site. In addition, the NIR fluorescence of DOX could monitor drug delivery and controlled release. The developed TPD@Ce6 NPs can realize the targeted tumor in combination therapy with negligible cytotoxicity on normal tissues.
研究领域:
药学
·
肿瘤学
·
生物材料学
✓ 已验证
产品关联
DOI
PubMed
Materials Science & Engineering C-Materials for Biological Applications
·
2020
·
IF 5.88
Jingjing Wang,Ying Qian,Liu Xu,Yurou Shao,Hu Zhang,Fanli Shi,Jiaxin Chen,Siqi Cui,Xiaoyan Chen,Dongwei Zhu,Rongfeng Hu,Zhipeng Chen
Peptide-drug conjugate (PDC) is a promising prodrug in drug delivery systems. To fabricate nanostructures with proper molecular design which can self-assemble to spherical morphologies is very important for PDC chemotherapy. In this study, a novel PDC (PDC-DOX 2 ), in which two doxorubicin (DOX) molecules are conjugated onto a short peptide (KIGLFRWR) with self-assembly function, was designed and synthesized. PDC-DOX 2 with self-assembly properties forms a spherical structure under hydrophobic interaction in water. Hyaluronic acid (HA) was then coated on PDC-DOX 2 micelles to form a HA-shelled, peptide-doxorubicin conjugate-cored nanomedicine (HA@PDC-DOX 2 ). The amount of HA can regulate the particle size and stabilization of HA@PDC-DOX 2 . In addition, HA can actively enhance the targeting effects of PDC-DOX 2 micelles since it can interact with overexpressed receptors in cancer cells. The core-shell structured HA@PDC-DOX 2 nanomedicine showed significantly enhanced potency against hepatocellular carcinoma compared to PDC-DOX 2 micelles as well as free DOX. In this work, a novel PDC which can self-assemble to spherical morphologies and a core-shell structure HA@PDC-DOX 2 nanomedicine are designed and prepared. It provides a convenient strategy for the size control of PDC assemblies and constructs effective PDC-based drug delivery systems for cancer treatment.
研究领域:
药学
·
纳米技术
·
肿瘤学
✓ 已验证
DOI
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-14
·
IF 16.6
Liu Di,Song Yanling,Chen Hui,You Yuchan,Zhu Luwen,Zhang Jucong,Xu Xinyi,Hu Jiahao,Huang Xiajie,Wu Xiaochuan,Xu Xiaoling,Jiang Saiping,Du Yongzhong
Poor renal distribution of antibody-based drugs is the key factor contributing to low treatment efficiency for renal diseases and side effects. Here, we prepare F(ab′) 2 fragmented vascular endothelial growth factor receptor 2 antibody (anti-VEGFR2 (F(ab′) 2 ) to block VEGFR2 overactivation in diabetic nephropathy (DN). We find that the anti-VEGFR2 F(ab′) 2 has a higher accumulation in DN male mice kidneys than the intact VEGFR2 antibody, and simultaneously preserves the binding ability to VEGFR2. Furthermore, we develop an antibody fragment drug conjugate, anti-VEGFR2 F(ab′) 2 -SS31, comprising the anti-VEGFR2 F(ab′) 2 fragment linked to the mitochondria-targeted antioxidant peptide SS31. We find that introduction of SS31 potentiates the efficacy of anti-VEGFR2 F(ab′) 2 . These findings provide proof of concept for the premise that antibody fragment drug conjugate improves renal distribution and merits drug validation in renal disease therapy.
研究领域:
药理学
·
肾病学
·
糖尿病
✓ 已验证
DOI
PubMed
高影响因子
mAbs
·
2018
·
IF 5.165
De-zhi Li,Bing-nan Han,Rui Wei,Gui-yang Yao,Zhizhen Chen,Jie Liu,Terence C.W. Poon,Wu Su,Zhongyu Zhu,Dimiter S. Dimitrov,Qi Zhao
Site-specific conjugation of small molecules to antibody molecules is a promising strategy for generation of antibody-drug conjugates. In this report, we describe the successful synthesis of a novel bifunctional molecule, 6-(azidomethyl)-2-pyridinecarboxyaldehyde (6-AM-2-PCA), which was used for conjugation of small molecules to peptides and antibodies. We demonstrated that 6-AM-2-PCA selectively reacted with N-terminal amino groups of peptides and antibodies. In addition, the azide group of 6-AM-2-PCA enabled copper-free click chemistry coupling with dibenzocyclooctyne-containing reagents. Bifunctional 6-AM-2-PCA mediated site-specific conjugation without requiring genetic engineering of peptides or antibodies. A key advantage of 6-AM-2-PCA as a conjugation reagent is its ability to modify proteins in a single step under physiological conditions that are sufficiently moderate to retain protein function. Therefore, this new click chemistry-based method could be a useful complement to other conjugation methods.
研究领域:
化学
·
生物化学
·
药学
✓ 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）