Bone tumor-targeted delivery of theranostic 195m Pt-bisphosphonate complexes promotes killing of metastatic tumor cells.
| Autor: | Nadar RA; Department of Dentistry - Regenerative Biomaterials, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Philips van Leydenlaan 25, 6525 EX, Nijmegen, the Netherlands., Franssen GM; Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands., Van Dijk NWM; Department of Dentistry - Regenerative Biomaterials, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Philips van Leydenlaan 25, 6525 EX, Nijmegen, the Netherlands., Codee-van der Schilden K; Nuclear Research & Consultancy Group, Westerduinweg 3, 1755 LE, Petten, the Netherlands., de Weijert M; Department of Urology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB, Nijmegen, the Netherlands., Oosterwijk E; Department of Urology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB, Nijmegen, the Netherlands., Iafisco M; Institute of Science and Technology for Ceramics (ISTEC), National Research Council (CNR), Via Granarolo 64, 48018, Faenza, Italy., Margiotta N; Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy., Heskamp S; Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands., van den Beucken JJJP; Department of Dentistry - Regenerative Biomaterials, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Philips van Leydenlaan 25, 6525 EX, Nijmegen, the Netherlands., Leeuwenburgh SCG; Department of Dentistry - Regenerative Biomaterials, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Philips van Leydenlaan 25, 6525 EX, Nijmegen, the Netherlands.; Institute of Science and Technology for Ceramics (ISTEC), National Research Council (CNR), Via Granarolo 64, 48018, Faenza, Italy. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Materials today. Bio [Mater Today Bio] 2020 Dec 07; Vol. 9, pp. 100088. Date of Electronic Publication: 2020 Dec 07 (Print Publication: 2021). |
| DOI: | 10.1016/j.mtbio.2020.100088 |
| Abstrakt: | Platinum-based drugs such as cisplatin are very potent chemotherapeutics, whereas radioactive platinum ( 195m Pt) is a rich source of low-energy Auger electrons, which kills tumor cells by damaging DNA. Auger electrons damage cells over a very short range. Consequently, 195m Pt-based radiopharmaceuticals should be targeted toward tumors to maximize radiotherapeutic efficacy and minimize Pt-based systemic toxicity. Herein, we show that systemically administered radioactive bisphosphonate-functionalized platinum ( 195m Pt-BP) complexes specifically accumulate in intratibial bone metastatic lesions in mice. The 195m Pt-BP complexes accumulate 7.3-fold more effectively in bone 7 days after systemic delivery compared to 195m Pt-cisplatin lacking bone-targeting bisphosphonate ligands. Therapeutically, 195m Pt-BP treatment causes 4.5-fold more γ-H2AX formation, a biomarker for DNA damage in metastatic tumor cells compared to 195m Pt-cisplatin. We show that systemically administered 195m Pt-BP is radiotherapeutically active, as evidenced by an 11-fold increased DNA damage in metastatic tumor cells compared to non-radioactive Pt-BP controls. Moreover, apoptosis in metastatic tumor cells is enhanced more than 3.4-fold upon systemic administration of 195m Pt-BP vs. radioactive 195m Pt-cisplatin or non-radioactive Pt-BP controls. These results provide the first preclinical evidence for specific accumulation and strong radiotherapeutic activity of 195m Pt-BP in bone metastatic lesions, which offers new avenues of research on radiotherapeutic killing of tumor cells in bone metastases by Auger electrons. Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.A.N. and S.C.G.L. are employees of Radboudumc. K.D.S. is employee of the Nuclear Research & Consultancy Group (NRG). N.M. is employee of the Università degli Studi di Bari Aldo Moro. A patent application has been submitted by the Nuclear Research & Consultancy Group (NRG), Radboudumc and N.M. based on these results. (© 2020 The Author(s).) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|