Harnessing the bone-seeking ability of Ca(ii)-like metal ions in the treatment of metastatic cancer and resorption disorders

Abstract

Metal ions are naturally retained by skeletal tissues in living systems because of their high affinity for the hydroxyapatite-like mineral matrix that makes up cortical bone. This is particularly true for metal ions that bear a close resemblance to calcium(ii) (such as the lanthanides or alkaline earth metals), and in a few key cases this targeting ability has been exploited in order to develop medicinal agents that are intended to treat bones which have become diseased. In this review, we focus on two areas where this has been particularly effective: first is in the diagnosis and therapy of metastatic bone cancer, in which radioactive metal ions including (99m)Tc, (153)Sm, and (223)Ra are used to image, alleviate, and ablate harmful cancerous legions with good specificity versus healthy tissues; second is the use of trivalent lanthanides to treat osteoporosis, an emerging concept which has gathered significance over the last 15 years, and is now entering preclinical trials with carefully designed systems.

Phosphonate Chelators for Medicinal Metal Ions

“…In these cases, chelators chauffeur (radio)­metal ions to regions with an abnormally high bone growth rate or rapid bone turnover. Upon release, the (radio)metal ions may become adsorbed onto bone or even incorporated into hydroxyapatite (HA, the mineral matrix that makes up cortical bone), where they can evoke a localized response . Moreover, chelators may be used to decrease unusually high levels of free metal ions in vivo, as is commonly achieved during chelation therapy.…”

“…Another interesting feature of (bis)­phosphonates is their natural tendency to interact with bone. Phosphonates are a fundamental component of HA (along with Ca 2+ and OH – ), and so naturally their interactions have been studied to investigate any medicinal properties that can be harnessed to treat bone disorders . While the long-term efficacy remains unclear, bisphosphonates such as alendronate (trade name: Fosamax) have long been established as agents capable of increasing the bone density in patients suffering from osteoporosis. , Taken together, the hard and labile coordination properties of phosphonates, along with their affinity toward HA, has led to their elegant application as metal-based bone-targeting agents.…”

“…Upon release, the (radio)metal ions may become adsorbed onto bone or even incorporated into hydroxyapatite (HA, the mineral matrix that makes up cortical bone), where they can evoke a localized response. 4 Moreover, chelators may be used to decrease unusually high levels of free metal ions in vivo, as is commonly achieved during chelation therapy. In this case, toxic concentrations of endogenous (e.g., Fe 3+ , Cu 2+ ) or exogenous (e.g., Pb 2+ , Hg 2+ ) metal ions can be diminished through an administration of chelators to sequester free metal ions and more rapidly excrete them, mitigating deleterious effects such as an excessive formation of reactive oxygen species (ROS).…”

Die faszinierende bioanorganische Chemie der Selten‐Erd‐Elemente

“…Es hat sich jedoch gezeigt, dass Knochenmetastasen fünfmal mehr 153 Sm anreichern – vermutlich durch ihre erhöhte Zellwachstumsrate – als gesundes Knochengewebe und so einer höheren β‐Strahlungsdosis ausgesetzt werden. Weitere Vorteile des 153 Sm‐Isotops sind neben einer schnellen und gezielten Aufnahme im Zielgewebe seine kurze Halbwertszeit von 47 Stunden sowie seine einfache Generierung durch Bestrahlung von angereichertem 152 Sm 2 O 3 .…”

Rapid Thermodynamically Stable Complex Formation of [nat/111In]In3+, [nat/90Y]Y3+, and [nat/177Lu]Lu3+ with H6dappa

“…The biological role of phosphonates on BFCs is also quite multifaceted. Naturally, the high affinity of (bis)­phosphonates toward hydroxyapatite (HAthe mineral matrix that makes up cortical bone) has led to extensive use as bone targeting agents, most notably in [ 153 Sm]­[Sm­(EDTMP)] 5– (Quadramet) and [ 177 Lu]­[Lu­(EDTMP)] 5– for bone pain palliation. , Nontargeting (purely coordinating) phosphonate-containing BFCs with in vivo behavior dictated by bioconjugates also exist in the literature, ,, albeit to a much lesser extent. This is likely due to difficulties controlling the inherent affinity of (bis)­phosphonates toward bone; this issue appears to be mitigated through the use of phosphinates, which are similarly “hard” and present a low kinetic barrier for coordination but scantily adsorb to HA .…”