PTD-Modified ATTEMPTS for Enhanced Toxin-based Cancer Therapy: An In Vivo Proof-of-Concept Study
文献类型：期刊论文
| 作者 | Shin, Meong Cheol1,6; Zhang, Jian4,5; Min, Kyoung Ah6; He, Huining1; David, Allan E.3; Huang, Yongzhuo2 ; Yang, Victor C.1,6,7,8
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| 刊名 | PHARMACEUTICAL RESEARCH
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| 出版日期 | 2015-08 |
| 卷号 | 32期号:8页码:2690-2703 |
| 关键词 | anti-CEA monoclonal antibody cancer heparin protein transduction domains toxin |
| ISSN号 | 0724-8741 |
| DOI | 10.1007/s11095-015-1653-y |
| 文献子类 | Article |
| 英文摘要 | Purpose To investigate the feasibility of applying PTD-modified ATTEMPTS (Antibody Targeted Triggered Electrically Modified Prodrug-Type Strategy) for enhanced toxin therapy for the treatment of cancer. Methods A heparin-functionalized murine anti-CEA monoclonal antibody (mAb), T84.66-heparin (T84.66-Hep), was chemically synthesized and characterized for specific binding to CEA overexpressed cells. The T84.66-Hep was then applied to the PTD-modified ATTEMPTS approach and the crucial features of the drug delivery system (DDS), 'antibody targeting' and 'heparin/protamine-based prodrug', were evaluated in vitro to examine whether it could selective delivery a PTD-modified toxin, recombinant TAT-gelonin chimera (TAT-Gel), to CEA high expression cancer cells (LS174T). Furthermore, the feasibility of the drug delivery system (DDS) was assessed in vivo by biodistribution and efficacy studies using LS174T s.c. xenograft tumor bearing mice. Results T84.66-Hep displayed specific binding, but limited internalization (35% after 48 h incubation) to CEA high expression LS174T cells over low expression HCT116 cells. When mixed together with TAT-Gel, the T84.66-Hep formed a strong yet reversible complex. This complex formation provided an effective means of active tumor targeting of TAT-Gel, by 1) directing the TAT-Gel to CEA overexpressed tumor cells and 2) preventing nonspecific cell transduction to non-targeted normal cells. The cell transduction of TAT-Gel could, however, be efficiently reversed by addition of protamine. Feasibility of in vivo tumor targeting and "protamine-induced release" of TAT-Gel from the T84.66-Hep counterpart was confirmed by biodistribution and preliminary efficacy studies. Conclusions This study successfully demonstrated in vitro and in vivo the applicability of PTD-modified ATTEMPTS for toxin-based cancer therapy. |
| WOS关键词 | CELL-PENETRATING PEPTIDES ; ANTI-CEA ANTIBODY ; CARCINOEMBRYONIC ANTIGEN ; DELIVERY ; PROTEIN ; GELONIN ; T84.66 ; SYSTEM ; TRANSDUCTION ; EXPRESSION |
| 资助项目 | NSFC[81361140344] ; National Key Basic Research Program of China[2013CB932502] ; National Institutes of Health[CA114612] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000357281500016 |
| 出版者 | SPRINGER/PLENUM PUBLISHERS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276461]  |
| 专题 | 药物制剂研究中心 |
| 通讯作者 | Yang, Victor C. |
| 作者单位 | 1.Tianjin Med Univ, Sch Pharm, Tianjin Key Lab Technol Enabling Dev Clin Therape, Tianjin 300070, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Auburn Univ, Dept Chem Engn, Auburn, AL 36849 USA; 4.Soochow Univ, Jiangsu Key Lab Adv Funct Polymer Design & Applic, Coll Chem Chem Engn & Mat Sci, Dept Polymer Sci & Engn, Suzhou 215123, Peoples R China; 5.Soochow Univ, Biomed Polymers Lab, Coll Chem Chem Engn & Mat Sci, Dept Polymer Sci & Engn, Suzhou 215123, Peoples R China; 6.Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA; 7.Seoul Natl Univ, Coll Pharm, Coll Med, Seoul 151742, South Korea 8.Seoul Natl Univ, Dept Mol Med & Biopharmaceut Sci, Grad Sch Convergence Sci & Technol, Seoul 151742, South Korea; |
| 推荐引用方式 GB/T 7714 | Shin, Meong Cheol,Zhang, Jian,Min, Kyoung Ah,et al. PTD-Modified ATTEMPTS for Enhanced Toxin-based Cancer Therapy: An In Vivo Proof-of-Concept Study[J]. PHARMACEUTICAL RESEARCH,2015,32(8):2690-2703. |
| APA | Shin, Meong Cheol.,Zhang, Jian.,Min, Kyoung Ah.,He, Huining.,David, Allan E..,...&Yang, Victor C..(2015).PTD-Modified ATTEMPTS for Enhanced Toxin-based Cancer Therapy: An In Vivo Proof-of-Concept Study.PHARMACEUTICAL RESEARCH,32(8),2690-2703. |
| MLA | Shin, Meong Cheol,et al."PTD-Modified ATTEMPTS for Enhanced Toxin-based Cancer Therapy: An In Vivo Proof-of-Concept Study".PHARMACEUTICAL RESEARCH 32.8(2015):2690-2703. |
入库方式： OAI收割
来源：上海药物研究所
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