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Bone tumor-targeted delivery of theranostic ^195mPt-bisphosphonate complexes promotes killing of metastatic tumor cells.

ABSTRACT: 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 ?-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.

SUBMITTER: Nadar RA

PROVIDER: S-EPMC7809194 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Bone tumor-targeted delivery of theranostic 195mPt-bisphosphonate complexes promotes killing of metastatic tumor cells.

Nadar R A RA Franssen G M GM Van Dijk N W M NWM Codee-van der Schilden K K de Weijert M M Oosterwijk E E Iafisco M M Margiotta N N Heskamp S S van den Beucken J J J P JJJP Leeuwenburgh S C G SCG

Materials today. Bio 20201207

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 bis ...[more]

PMID: 33490949

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Project description:The major obstacles in intraperitoneal (i.p.) chemotherapy of peritoneal tumors are fast absorption of drugs into the blood circulation, local and systemic toxicities, inadequate drug penetration into large tumors, and drug resistance. Targeted theranostic nanoparticles offer an opportunity to enhance the efficacy of i.p. therapy by increasing intratumoral drug delivery to overcome resistance, mediating image-guided drug delivery, and reducing systemic toxicity. Herein we report that i.p. delivery of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (IONPs) led to intratumoral accumulation of 17% of total injected nanoparticles in an orthotopic mouse pancreatic cancer model, which was three-fold higher compared with intravenous delivery. Targeted delivery of near infrared dye labeled IONPs into orthotopic tumors could be detected by non-invasive optical and magnetic resonance imaging. Histological analysis revealed that a high level of uPAR targeted, PEGylated IONPs efficiently penetrated into both the peripheral and central tumor areas in the primary tumor as well as peritoneal metastatic tumor. Improved theranostic IONP delivery into the tumor center was not mediated by nonspecific macrophage uptake and was independent from tumor blood vessel locations. Importantly, i.p. delivery of uPAR targeted theranostic IONPs carrying chemotherapeutics, cisplatin or doxorubicin, significantly inhibited the growth of pancreatic tumors without apparent systemic toxicity. The levels of proliferating tumor cells and tumor vessels in tumors treated with the above theranostic IONPs were also markedly decreased. The detection of strong optical signals in residual tumors following i.p. therapy suggested the feasibility of image-guided surgery to remove drug-resistant tumors. Therefore, our results support the translational development of i.p. delivery of uPAR-targeted theranostic IONPs for image-guided treatment of peritoneal tumors.

Dataset Information

Bone tumor-targeted delivery of theranostic ^195mPt-bisphosphonate complexes promotes killing of metastatic tumor cells.

Publications

Bone tumor-targeted delivery of theranostic <sup>195m</sup>Pt-bisphosphonate complexes promotes killing of metastatic tumor cells.

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