Journal of Innovative Optical Health Sciences
·
2023
·
IF 2.5
Changqiang Xie,Yan Wang,Zhenzhen Cai,Jianghai Du,Zhengyu Chen,Junjie Wang,Xingzhou Peng
Monomethyl auristatin E (MMAE) is a derivative of the marine peptide Dolastatin 10, which has therapeutic effects against various cancers according to its antimitotic activity in multiple clinical trials. The antibody drug conjugate (ADC) of MMAE is currently used in clinical practice. However, the safety issues of MMAE-based ADC, such as high drug toxicity and poor bioavailability, still exist when using it for anticancer therapy. A sustained release of drug delivery approach should be used to reduce toxicity and achieve sufficient anticancer effects. Herein, PLGA-b-PEG 2 0 0 0 with excellent biocompatibility and slow degradation ability was adopted to construct MMAE-loaded nanoparticles for safe and effective chemotherapy. The sustained release effect and the immunogenic cell death (ICD) effect of PLGA-MMAE nanoparticles were assessed by in vitro experiments. The PLGA-MMAE nanoparticles effectively accumulated in the tumor through the enhanced permeability and retention (EPR) effect, inducing cell apoptosis and causing a certain degree of immune response. The sustained drug release of PLGA-MMAE improved the bioavailability and effectively reduced the toxicity and development of the tumor compared to the effect of free MMAE or ADC. Overall, this study provides a safe and effective chemotherapeutic approach, as well as a simple and effective synthetic process for MMAE-based nanoparticles, improving their therapeutic efficacy and safety.
研究领域:
药学
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肿瘤学
·
生物材料学
✓ 已验证
DOI
高影响因子
Journal of Pharmaceutical Analysis
·
2021
·
IF 4.769
Min Pei,Tingting Liu,Lu Ouyang,Jianhua Sun,Xiaojie Deng,Xiaomin Sun,Wei Wu,Peng Huang,Yi-Li Chen,Xiaorong Tan,Xiaoyue Liu,Peng Zhu,Yongzhen Liu,Deheng Wang,Junliang Wu,Qi Wang,Guifeng Wang,Likun Gong,Qiuping Qin,Chunhe Wang
Antibody-drug conjugates (ADCs) are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical studies. In this study, we report the generation of a monoclonal antibody against monomethyl auristatin E (MMAE) and the development, validation, and application of sensitive and high-throughput enzyme-linked immunosorbent assays (ELISA) to measure the concentrations of MMAE-conjugated ADCs and total antibodies (tAb, antibodies in ADC plus unconjugated antibodies) in cynomolgus monkey sera. These assays were successfully applied to in vitro plasma stability and pharmacokinetic (PK) studies of SMADC001, an MMAE-conjugated ADC against trophoblast cell surface antigen 2 (TROP-2). The plasma stability of SMADC001 was better than that of similar ADCs coupled with PEG4-Val-Cit, Lys (m-dPEG24)-Cit, and Val-Cit linkers. The developed ELISA methods for the calibration standards of ADC and tAb revealed a correlation between serum concentrations and the OD 450 values, with R 2 at 1.000, and the dynamic range was 0.3–35.0 ng/mL and 0.2–22.0 ng/mL, respectively; the intra- and inter-assay accuracy bias% ranged from −12.2% to −5.2%, precision ranged from −12.4% to −1.4%, and the relative standard deviation (RSD) was less than 6.6% and 8.7%, respectively. The total error was less than 20.4%. The development and validation steps of these two assays met the acceptance criteria for all addressed validation parameters, which suggested that these can be applied to quantify MMAE-conjugated ADCs, as well as in PK studies. Furthermore, these assays can be easily adopted for development of other similar immunoassays.
研究领域:
药理学
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免疫学
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生物化学
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药物开发
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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
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肿瘤学
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分析化学
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2023
·
IF 6
Ce Yi,Fei Xie,Xin Xu,Dian Xiao,Xinbo Zhou,Maosheng Cheng
Aiming to address the insufficient endocytosis ability of traditional albumin drug conjugates, this paper reports elegant guanidine modification to improve efficacy for the first time. A series of modified albumin drug conjugates were designed and synthesized with different structures, including guanidine (GA), biguanides (BGA) and phenyl (BA), and different quantities of modifications. Then, the endocytosis ability and in vitro/vivo potency of albumin drug conjugates were systematically studied. Finally, a preferred conjugate A4 was screened, which contained 15 BGA modifications. Conjugate A4 maintains spatial stability similar to that of the unmodified conjugate AVM and could significantly enhance endocytosis ability (p*** = 0.0009) compared with the unmodified conjugate AVM. Additionally, the in vitro potency of conjugate A4 (EC50 = 71.78 nmol in SKOV3 cells) was greatly enhanced (approximately 4 times) compared with that of the unmodified conjugate AVM (EC50 = 286.00 nmol in SKOV3 cells). The in vivo efficacy of conjugate A4 completely eliminated 50% of tumors at 33 mg/kg, which was significantly better than the efficacy of conjugate AVM at the same dose (P** = 0.0026). In addition, theranostic albumin drug conjugate A8 was designed to intuitively realize drug release and maintain antitumor activity similar to conjugate A4. In summary, the guanidine modification strategy could provide new ideas for the development of new generational albumin drug conjugates.
研究领域:
药学
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生物医学工程
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癌症研究
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
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IF 6.8
Jingsheng Jiang,Sigang Jian,Feifei Lin,Zhuo Zhang,Qianqian Shen,Guozhang Long,Biyu Yang,Junzhen Lin,Yanfen Fang,Jian Ding,Jia Liu,Yi Chen,Youhong Hu
The ASGR-mediated endocytosis has been successfully applied to the hepatocyte-targeted delivery of therapeutic oligonucleotides via glycoconjugates. However, few studies have explored the conjugated small molecules due to the challenge of cleaving suitable linkers for the release of active small molecules, which is especially different from GalNAc-ONs cleaved by the deoxyribonuclease II in the lysosome. In this study, GalNAc-MMAE conjugates linked by CTSB-cleavable linkers were designed and synthesized. A comprehensive approach revealed that the conjugates were endocytosed by ASGR and subsequently hydrolyzed by CTSB, releasing MMAE. The optimized conjugate with a succinic acid monoamide as the fragment of the linker demonstrated favorable plasma stability, excellent biodistribution, and significant antitumor activities in vivo with weight gain at the effective dose in an orthotopic hepatocellular carcinoma mouse model. This research provides a strategy for developing anti-HCC therapeutic agents using GalNAc drug conjugates with CTSB-cleavable linkers to release active small molecules.
研究领域:
药物化学
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肿瘤学
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肝脏病学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2024
·Vol. 14
·期 14
·9602-9608
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IF 3.9
Tiantian Wu,Yanqiang Shi,Tao Yang,Pengxuan Zhao,Zhu Yang,Bin Yang
Dolastatin derivatives possess excellent anticancer activity and have been translated into clinical trials for cancer therapy. Drug delivery systems enable dolastatin derivatives to break the limitation of instability during blood circulation and ineffective cell internalization in the application. Nevertheless, their potential has not been thoroughly established because of the limited loading efficacy and complicated chemical modification. Herein, we rationally propose a rolling circle amplification-based polymer–DNA assembled nanoflower for targeted and efficient delivery of dolastatin-derived drugs to achieve efficient anticancer therapy. The polymer–DNA assembled nanoflower with targeted aptamer conjugate is widely applicable for loading dolastatin-derived drugs with high encapsulation efficiency. The developed monomethyl auristatin E (MMAE) loaded PN@M exhibited increased cellular uptake and enhanced inhibitory effect, especially in multidrug-resistant tumor cells. The results of in vivo anticancer effects indicate that nanoflower as a dolastatin derivatives delivery system holds considerable potential for the treatment of malignant cancer.
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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生物医学工程
✓ 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）