Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity
Xiao-qian Dou,1 Hua Wang,2 Jing Zhang,3 Fang Wang,3 Gui-li Xu,1 Cheng-cheng Xu,1 Huan-hua Xu,1 Shen-si Xiang,1 Jie Fu,1 Hai-feng Song1 1Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China; 2Ophthalmology Department, Eye Hospi...
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| Autores principales: | , , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2018
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/d97216c704854400aacb4cc46a28b3e5 |
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| Sumario: | Xiao-qian Dou,1 Hua Wang,2 Jing Zhang,3 Fang Wang,3 Gui-li Xu,1 Cheng-cheng Xu,1 Huan-hua Xu,1 Shen-si Xiang,1 Jie Fu,1 Hai-feng Song1 1Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China; 2Ophthalmology Department, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing, China; 3Bioanalysis Department, United-Power Pharma Tech Co., Ltd., Beijing, China Introduction: The toxic side effects of doxorubicin (DOX) have limited its use in chemotherapy. Neither liposomal DOX nor pegylated liposomal DOX are able to completely resolve this issue. This is a proof-of-concept study testing aptamer-drug conjugate (ApDC) targeted delivery systems for chemotherapeutic drugs.Methods: Aptamer library targeting human epidermal growth factor receptor 3 (HER3) was screened and affinity was determined by enzyme-linked immunosorbent assay. Specificity was tested in MCF-7HER3-high, BT474HER3-high, and 293THER3-negative cells using flow cytometry and confocal microscopy. We further developed a HER3 aptamer-functionalized liposome encapsulating DOX and the efficiency of this ApDC was detected by cellular uptake analysis and cell viability assay. In MCF-7 tumor-bearing mice, tumor targeting evaluation, efficacy, toxicity and preliminary pharmocokinetic study was performed.Results: The candidate #13 aptamer had highest affinity (Kd =98±9.7 nM) and specificity. ApDC effectively reduces the half maximal inhibitory concentration of DOX compared with lipsome-DOX and free DOX. In vivo imaging and preliminary distribution studies showed that actively targeted nanoparticles, such as Apt-Lip-DOX molecules, could facilitate the delivery of DOX into tumors in MCF-7–bearing mice. This targeted chemotherapy caused greater tumor suppression than other groups and alleviated side effects such as weight loss, low survival rate, and organ (heart and liver) injury demonstrated by H&E staining.Conclusion: The results indicate that targeted chemotherapy using the aptamer–drug conjugate format could provide better tolerability and efficacy compared with non-targeted delivery in relatively low-dose toxic drugs. Keywords: breast cancer, human epidermal growth factor receptor 3, aptamer–drug conjugate, doxorubicin, cardiac toxicity, targeted therapy |
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