The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer
Serving as targeting ligands, aptamers have shown promise in precision medicine. However, the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’ clinical translation. To bridge this gap, here we report the first-in-human pharmacokinetics study of p...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Association for the Advancement of Science (AAAS)
2023-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0126 |
| _version_ | 1797283809967734784 |
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| author | Ding Ding Haitao Zhao Dali Wei Qinglai Yang Cai Yang Ruowen Wang Yumei Chen Lianghua Li Shuxian An Qian Xia Gang Huang Jianjun Liu Zeyu Xiao Weihong Tan |
| author_facet | Ding Ding Haitao Zhao Dali Wei Qinglai Yang Cai Yang Ruowen Wang Yumei Chen Lianghua Li Shuxian An Qian Xia Gang Huang Jianjun Liu Zeyu Xiao Weihong Tan |
| author_sort | Ding Ding |
| collection | DOAJ |
| description | Serving as targeting ligands, aptamers have shown promise in precision medicine. However, the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’ clinical translation. To bridge this gap, here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68 (68Ga) radiolabeled aptamers. The specificity and binding affinity of a radiolabeled aptamer, named 68Ga[Ga]-NOTA-SGC8, were maintained as proven in vitro. Further preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity, potential mutation risks, or genotoxicity at high dosage (40 mg/kg). Based on this result, a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles, as well as biosafety, of the radiolabeled SGC8 aptamer in the human body. Taking advantage of the cutting-edge total-body PET, the aptamers’ distribution pattern in the human body was acquired in a dynamic fashion. This study revealed that radiolabeled aptamers are harmless to normal organs and most of them are accumulated in the kidney and cleared from the bladder via urine, which agrees with preclinical studies. Meanwhile, a physiologically based pharmacokinetic model of aptamer was developed, which could potentially predict therapeutic responses and plan personalized treatment strategies. This research studied the biosafety and dynamic pharmacokinetics of aptamers in the human body for the first time, as well as demonstrated the capability of novel molecular imaging fashion in drug development. |
| first_indexed | 2024-03-07T17:37:13Z |
| format | Article |
| id | doaj.art-9bd3bbece46d487bbd0eefd35644efa8 |
| institution | Directory Open Access Journal |
| issn | 2639-5274 |
| language | English |
| last_indexed | 2024-03-07T17:37:13Z |
| publishDate | 2023-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Research |
| spelling | doaj.art-9bd3bbece46d487bbd0eefd35644efa82024-03-02T16:41:56ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742023-01-01610.34133/research.0126The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of AptamerDing Ding0Haitao Zhao1Dali Wei2Qinglai Yang3Cai Yang4Ruowen Wang5Yumei Chen6Lianghua Li7Shuxian An8Qian Xia9Gang Huang10Jianjun Liu11Zeyu Xiao12Weihong Tan13Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.Institute of Molecular Medicine (IMM), Renji Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.Serving as targeting ligands, aptamers have shown promise in precision medicine. However, the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’ clinical translation. To bridge this gap, here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68 (68Ga) radiolabeled aptamers. The specificity and binding affinity of a radiolabeled aptamer, named 68Ga[Ga]-NOTA-SGC8, were maintained as proven in vitro. Further preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity, potential mutation risks, or genotoxicity at high dosage (40 mg/kg). Based on this result, a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles, as well as biosafety, of the radiolabeled SGC8 aptamer in the human body. Taking advantage of the cutting-edge total-body PET, the aptamers’ distribution pattern in the human body was acquired in a dynamic fashion. This study revealed that radiolabeled aptamers are harmless to normal organs and most of them are accumulated in the kidney and cleared from the bladder via urine, which agrees with preclinical studies. Meanwhile, a physiologically based pharmacokinetic model of aptamer was developed, which could potentially predict therapeutic responses and plan personalized treatment strategies. This research studied the biosafety and dynamic pharmacokinetics of aptamers in the human body for the first time, as well as demonstrated the capability of novel molecular imaging fashion in drug development.https://spj.science.org/doi/10.34133/research.0126 |
| spellingShingle | Ding Ding Haitao Zhao Dali Wei Qinglai Yang Cai Yang Ruowen Wang Yumei Chen Lianghua Li Shuxian An Qian Xia Gang Huang Jianjun Liu Zeyu Xiao Weihong Tan The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer Research |
| title | The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer |
| title_full | The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer |
| title_fullStr | The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer |
| title_full_unstemmed | The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer |
| title_short | The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer |
| title_sort | first in human whole body dynamic pharmacokinetics study of aptamer |
| url | https://spj.science.org/doi/10.34133/research.0126 |
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