Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α<sub>v</sub>β<sub>3</sub>-Targeted Radionuclide Therapy
Peptide receptor radionuclide therapy (PRRT) is an emerging approach for patients with unresectable or metastatic tumors. Our previously optimized RGD peptide (3PRGD<sub>2</sub>) has excellent targeting specificity for a variety of integrin α<sub>v</sub>β<sub>3</sub&...
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MDPI AG
2022-06-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/7/1327 |
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| author | Guangjie Yang Hannan Gao Chuangwei Luo Xiaoyu Zhao Qi Luo Jiyun Shi Fan Wang |
| author_facet | Guangjie Yang Hannan Gao Chuangwei Luo Xiaoyu Zhao Qi Luo Jiyun Shi Fan Wang |
| author_sort | Guangjie Yang |
| collection | DOAJ |
| description | Peptide receptor radionuclide therapy (PRRT) is an emerging approach for patients with unresectable or metastatic tumors. Our previously optimized RGD peptide (3PRGD<sub>2</sub>) has excellent targeting specificity for a variety of integrin α<sub>v</sub>β<sub>3</sub>/α<sub>v</sub>β<sub>5</sub>-positive tumors and has been labeled with the therapeutic radionuclide [<sup>177</sup>Lu]LuCl<sub>3</sub> for targeted radiotherapy of tumors. However, the rapid clearance of [<sup>177</sup>Lu]Lu-DOTA-3PRGD<sub>2</sub> (<sup>177</sup>Lu-3PRGD<sub>2</sub>) in vivo requires two doses of 111 MBq/3 mCi to achieve effective tumor suppression, limiting its further clinical application. Albumin binders have been attached to drugs to facilitate binding to albumin in vivo to prolong the drug half-life in plasma and obtain long-term effects. In this study, we modified 3PRGD<sub>2</sub> with albumin-binding palmitic acid (Palm-3PRGD<sub>2</sub>) and then radiolabeled Palm-3PRGD<sub>2</sub> with <sup>177</sup>Lu. [<sup>177</sup>Lu]Lu-DOTA-Palm-3PRGD<sub>2</sub> (<sup>177</sup>Lu-Palm-3PRGD<sub>2</sub>) retained a specific binding affinity for integrin α<sub>v</sub>β<sub>3</sub>/α<sub>v</sub>β<sub>5</sub>, with an IC<sub>50</sub> value of 5.13 ± 1.16 nM. Compared with <sup>177</sup>Lu-3PRGD<sub>2</sub>, the <sup>177</sup>Lu-Palm-3PRGD<sub>2</sub> circulation time in blood was more than 6 times longer (slow half-life: 73.42 min versus 11.81 min), and the tumor uptake increased more than fivefold (21.34 ± 4.65 %IA/g and 4.11 ± 0.70 %IA/g at 12 h post-injection). Thus, the significant increase in tumor uptake and tumor retention resulted in enhanced efficacy of targeted radiotherapy, and tumor growth was completely inhibited by a single and relatively lowdose of 18.5 MBq/0.5 mCi. Thus, <sup>177</sup>Lu-Palm-3PRGD<sub>2</sub> shows great potential for clinical application. |
| first_indexed | 2024-03-09T10:13:34Z |
| format | Article |
| id | doaj.art-8d7d7d450a7444d988f86c19456b0536 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T10:13:34Z |
| publishDate | 2022-06-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-8d7d7d450a7444d988f86c19456b05362023-12-01T22:33:57ZengMDPI AGPharmaceutics1999-49232022-06-01147132710.3390/pharmaceutics14071327Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α<sub>v</sub>β<sub>3</sub>-Targeted Radionuclide TherapyGuangjie Yang0Hannan Gao1Chuangwei Luo2Xiaoyu Zhao3Qi Luo4Jiyun Shi5Fan Wang6Medical Isotopes Research Center and Department of Radiation Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University, Beijing 100191, ChinaKey Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, ChinaMedical Isotopes Research Center and Department of Radiation Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University, Beijing 100191, ChinaMedical Isotopes Research Center and Department of Radiation Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University, Beijing 100191, ChinaGuangzhou Laboratory, Guangzhou 510005, ChinaKey Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, ChinaMedical Isotopes Research Center and Department of Radiation Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University, Beijing 100191, ChinaPeptide receptor radionuclide therapy (PRRT) is an emerging approach for patients with unresectable or metastatic tumors. Our previously optimized RGD peptide (3PRGD<sub>2</sub>) has excellent targeting specificity for a variety of integrin α<sub>v</sub>β<sub>3</sub>/α<sub>v</sub>β<sub>5</sub>-positive tumors and has been labeled with the therapeutic radionuclide [<sup>177</sup>Lu]LuCl<sub>3</sub> for targeted radiotherapy of tumors. However, the rapid clearance of [<sup>177</sup>Lu]Lu-DOTA-3PRGD<sub>2</sub> (<sup>177</sup>Lu-3PRGD<sub>2</sub>) in vivo requires two doses of 111 MBq/3 mCi to achieve effective tumor suppression, limiting its further clinical application. Albumin binders have been attached to drugs to facilitate binding to albumin in vivo to prolong the drug half-life in plasma and obtain long-term effects. In this study, we modified 3PRGD<sub>2</sub> with albumin-binding palmitic acid (Palm-3PRGD<sub>2</sub>) and then radiolabeled Palm-3PRGD<sub>2</sub> with <sup>177</sup>Lu. [<sup>177</sup>Lu]Lu-DOTA-Palm-3PRGD<sub>2</sub> (<sup>177</sup>Lu-Palm-3PRGD<sub>2</sub>) retained a specific binding affinity for integrin α<sub>v</sub>β<sub>3</sub>/α<sub>v</sub>β<sub>5</sub>, with an IC<sub>50</sub> value of 5.13 ± 1.16 nM. Compared with <sup>177</sup>Lu-3PRGD<sub>2</sub>, the <sup>177</sup>Lu-Palm-3PRGD<sub>2</sub> circulation time in blood was more than 6 times longer (slow half-life: 73.42 min versus 11.81 min), and the tumor uptake increased more than fivefold (21.34 ± 4.65 %IA/g and 4.11 ± 0.70 %IA/g at 12 h post-injection). Thus, the significant increase in tumor uptake and tumor retention resulted in enhanced efficacy of targeted radiotherapy, and tumor growth was completely inhibited by a single and relatively lowdose of 18.5 MBq/0.5 mCi. Thus, <sup>177</sup>Lu-Palm-3PRGD<sub>2</sub> shows great potential for clinical application.https://www.mdpi.com/1999-4923/14/7/1327<sup>177</sup>LuRGD (Arg-Gly-Asp)albumin binderpalmitic acidpeptide receptor radionuclide therapy (PRRT)tumor |
| spellingShingle | Guangjie Yang Hannan Gao Chuangwei Luo Xiaoyu Zhao Qi Luo Jiyun Shi Fan Wang Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α<sub>v</sub>β<sub>3</sub>-Targeted Radionuclide Therapy Pharmaceutics <sup>177</sup>Lu RGD (Arg-Gly-Asp) albumin binder palmitic acid peptide receptor radionuclide therapy (PRRT) tumor |
| title | Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α<sub>v</sub>β<sub>3</sub>-Targeted Radionuclide Therapy |
| title_full | Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α<sub>v</sub>β<sub>3</sub>-Targeted Radionuclide Therapy |
| title_fullStr | Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α<sub>v</sub>β<sub>3</sub>-Targeted Radionuclide Therapy |
| title_full_unstemmed | Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α<sub>v</sub>β<sub>3</sub>-Targeted Radionuclide Therapy |
| title_short | Palmitic Acid-Conjugated Radiopharmaceutical for Integrin α<sub>v</sub>β<sub>3</sub>-Targeted Radionuclide Therapy |
| title_sort | palmitic acid conjugated radiopharmaceutical for integrin α sub v sub β sub 3 sub targeted radionuclide therapy |
| topic | <sup>177</sup>Lu RGD (Arg-Gly-Asp) albumin binder palmitic acid peptide receptor radionuclide therapy (PRRT) tumor |
| url | https://www.mdpi.com/1999-4923/14/7/1327 |
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