In vitro and in vivo toxicity of 5-FdU-alendronate, a novel cytotoxic bone-seeking duplex drug against bone metastasis

Schott, Sarah; Vallet, Sonia; Tower, Robert J.; Noor, Seema; Tiwari, Sanjay; Schem, Christian; Busch, Christian

doi:10.1007/s10637-015-0253-3

Cited by 10 publications

(10 citation statements)

References 24 publications

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“…47,48 Furthermore, researchers are beginning to develop bone-targeting systems for drug delivery and bone tissue engineering. 49–53 Most of these studies employ bisphosphonates as the bone-targeting ligands. 54,55 While bisphosphonates have very high bone affinity, they also have potent pharmaceutical activities that can potentially disturb the physiological processes they are supposed to target.…”

Section: Resultsmentioning

confidence: 99%

Pre-Assembly of Near-Infrared Fluorescent Multivalent Molecular Probes for Biological Imaging

et al. 2016

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A programmable pre-assembly method is described and shown to produce near-infrared fluorescent molecular probes with tunable multivalent binding properties. The modular assembly process threads one or two copies of a tetralactam macrocycle onto a fluorescent PEGylated squaraine scaffold containing a complementary number of docking stations. Appended to the macrocycle periphery are multiple copies of a ligand that is known to target a biomarker. The structure and high purity of each threaded complex was determined by independent spectrometric methods and also by gel electrophoresis. Especially helpful were diagnostic red-shift and energy transfer features in the absorption and fluorescence spectra. The threaded complexes were found to be effective multivalent molecular probes for fluorescence microscopy and in vivo fluorescence imaging of living subjects. Two multivalent probes were prepared and tested for targeting of bone in mice. A pre-assembled probe with twelve bone-targeting iminodiacetate ligands produced more bone accumulation than an analogous pre-assembled probe with six iminodiacetate ligands. Notably, there was no loss in probe fluorescence at the bone target site after 24 hours in the living animal, indicating that the pre-assembled fluorescent probe maintained very high mechanical and chemical stability on the skeletal surface. The study shows how this versatile pre-assembly method can be used in a parallel combinatorial manner to produce libraries of near-infrared fluorescent multivalent molecular probes for different types of imaging and diagnostic applications, with incremental structural changes in the number of targeting groups, linker lengths, linker flexibility, and degree of PEGylation.

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Section: Resultsmentioning

confidence: 99%

Pre-Assembly of Near-Infrared Fluorescent Multivalent Molecular Probes for Biological Imaging

et al. 2016

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“…For example, the coupling of bisphosphonates to osteoprotegerin, a natural RANKL antagonist, should improve selective delivery to bone (58). Covalent conjugation of bisphosphonates with chemotherapies such as 5-fluoro-2’-deoxyuridine (5FdU) may also improve targeting and efficacy (59). …”

Section: Discussionmentioning

confidence: 99%

Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth

Tauro

Shay

Sansil

et al. 2017

Molecular Cancer Therapeutics

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Bone metastasis is common during breast cancer progression. Matrix metalloproteinase-2 (MMP-2) is significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor or host derived MMP-2 contributes to breast cancer growth and does so by processing substrates including type I collagen and transforming growth factorβ (TGFβ) latency proteins. These data provide strong rationale for the application of MMP-2 inhibitors to treat the disease. However, in vivo, MMP-2 is systemically expressed. Therefore, to overcome potential toxicities noted with previous broad-spectrum MMP inhibitors (MMPIs), we used highly selective bisphosphonic based MMP-2 inhibitors (BMMPIs) that allowed for specific bone targeting. In vitro, BMMPIs impacted the viability of breast cancer cell lines and osteoclast precursors but not osteoblasts. In vivo, we demonstrated using two bone metastatic models (PyMT-R221A and 4T1) that BMMPI treatment significantly reduced tumor growth and tumor associated bone destruction. Additionally, BMMPIs are superior in promoting tumor apoptosis compared to the standard of care bisphosphonate, zoledronate. We demonstrated MMP-2 selective inhibition in the bone microenvironment using specific and broad spectrum MMP probes. Further, compared to zoledronate, BMMPI treated mice had significantly lower levels of TGFβ signaling and MMP generated type I collagen carboxy-terminal (ICTP) fragments. Taken together, our data show the feasibility of selective inhibition of MMPs in the bone metastatic breast cancer microenvironment. We posit that BMMPIs could be easily translated to the clinical setting for the treatment of bone metastases given the well-tolerated nature of bisphosphonates.

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“…The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro 2′-deoxyuridine (5-FdU) is a new and effective drug to fight bone cancer. N 4 -(butyl-(4-hydroxy-4-phosphono) phosphate)-5-fluoro-2′deoxyuridine (5-FdU-alendronate, 5-FdU-ale) 34 has less toxicity than its two constituents in vitro and in vivo and is a promising candidate for the treatment of bone metastasis ( Supplementary Scheme S12 in SI) ( Schott et al, 2015 ).…”

Section: Biological Activation Of Hydroxy- and Amino-phosphonates And...mentioning

confidence: 99%

Hydroxy- and Amino-Phosphonates and -Bisphosphonates: Synthetic Methods and Their Biological Applications

et al. 2022

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Phosphonates and bisphosphonates are stable analogs of phosphates and pyrophosphates that are characterized by one and two carbon–phosphorus bonds, respectively. Among the various phosphonates and bisphosphonates, hydroxy and amino substitutes are of interest as effective in medicinal and industrial chemistry. For example, hydroxy bisphosphonates have proven to be effective for the prevention of bone loss, especially in osteoporotic disease. On the other hand, different substitutions on the carbon atom connected to phosphorus have led to the synthesis of many different hydroxy- and amino-phosphonates and -bisphosphonates, each with its distinct physical, chemical, biological, therapeutic, and toxicological characteristics. Dialkyl or aryl esters of phosphonate and bisphosphonate compounds undergo the hydrolysis process readily and gave valuable materials with wide applications in pharmaceutical and agriculture. This review aims to demonstrate the ongoing preparation of various classes of hydroxy- and amino-phosphonates and -bisphosphonates. Furthermore, the current review summarizes and comprehensively describes articles on the biological applications of hydroxyl- and amino-phosphonates and -bisphosphonates from 2015 until today.

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In vitro and in vivo toxicity of 5-FdU-alendronate, a novel cytotoxic bone-seeking duplex drug against bone metastasis

Cited by 10 publications

References 24 publications

Pre-Assembly of Near-Infrared Fluorescent Multivalent Molecular Probes for Biological Imaging

Pre-Assembly of Near-Infrared Fluorescent Multivalent Molecular Probes for Biological Imaging

Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth

Hydroxy- and Amino-Phosphonates and -Bisphosphonates: Synthetic Methods and Their Biological Applications

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