Bone tumor-targeted delivery of theranostic Pt-195m-bisphosphonate complexes promotes killing of metastatic tumor cells

Autor: J.J.J.P van den Beucken, Egbert Oosterwijk, Sandra Heskamp, N.W.M. Van Dijk, Gerben M. Franssen, Sander C.G. Leeuwenburgh, Nicola Margiotta, Michele Iafisco, M. De Weijert, K. Codee-van der Schilden, Robin A. Nadar
Rok vydání: 2021
Předmět:
DNA damage
medicine.medical_treatment
Biomedical Engineering
Bioengineering
Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9]
Metastatic tumor
Auger therapy
Biomaterials
All institutes and research themes of the Radboud University Medical Center
Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15]
medicine
lcsh:QH301-705.5
Molecular Biology
Cisplatin
lcsh:R5-920
Chemistry
Bone metastases
Cell Biology
Bisphosphonate
Theranostics
Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10]
lcsh:Biology (General)
Apoptosis
195m-platinum
Systemic administration
Cancer research
Biomarker (medicine)
Bone-targeting
lcsh:Medicine (General)
Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
Biotechnology
medicine.drug
Zdroj: Materials Today Bio, 9
Materials today bio 9 (2021). doi:10.1016/j.mtbio.2020.100088
info:cnr-pdr/source/autori:Nadar R.A.; Franssen G.M.; Van Dijk N.W.M.; Codee-van der Schilden K.; de Weijert M.; Oosterwijk E.; Iafisco M.; Margiotta N.; Heskamp S.; van den Beucken J.J.J.P.; Leeuwenburgh S.C.G./titolo:Bone tumor-targeted delivery of theranostic 195mPt-bisphosphonate complexes promotes killing of metastatic tumor cells/doi:10.1016%2Fj.mtbio.2020.100088/rivista:Materials today bio/anno:2021/pagina_da:/pagina_a:/intervallo_pagine:/volume:9
Materials Today Bio, Vol 9, Iss, Pp 100088-(2021)
ISSN: 2590-0064
DOI: 10.1016/j.mtbio.2020.100088
Popis: Platinum-based drugs such as cisplatin are very potent chemotherapeutics, whereas radioactive platinum (195mPt) 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, 195mPt-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 (195mPt-BP) complexes specifically accumulate in intratibial bone metastatic lesions in mice. The 195mPt-BP complexes accumulate 7.3-fold more effectively in bone 7 days after systemic delivery compared to 195mPt-cisplatin lacking bone-targeting bisphosphonate ligands. Therapeutically, 195mPt-BP treatment causes 4.5-fold more γ-H2AX formation, a biomarker for DNA damage in metastatic tumor cells compared to 195mPt-cisplatin. We show that systemically administered 195mPt-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 195mPt-BP vs. radioactive 195mPt-cisplatin or non-radioactive Pt-BP controls. These results provide the first preclinical evidence for specific accumulation and strong radiotherapeutic activity of 195mPt-BP in bone metastatic lesions, which offers new avenues of research on radiotherapeutic killing of tumor cells in bone metastases by Auger electrons.
Databáze: OpenAIRE
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