Platinum–bisphosphonate complexes have proven to be inactive chemotherapeutics targeted for malignant mesothelioma because of inappropriate hydrolysis

Margiotta, Nicola; Ostuni, Rosa; Piccinonna, Sara; Natile, Giovanni; Zanellato, Ilaria; Boidi, Carla Doriana; Bonarrigo, Ilaria; Osella, Domenico

doi:10.1016/j.jinorgbio.2010.12.011

Cited by 19 publications

(10 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pt-BP underwent hydrolysis into a mononuclear Pt-n-BP derivative at both pH values, characterized by faster release of Pt at pH 5.25 than at pH 7.4. At physiological pH, Pt-BP forms new species with asymmetric bisphosphonate groups, which results most likely from displacement of one coordinated oxygen atom of the bridging bisphosphonate ligand by either a chloride (120 mM concentration) or bisphosphonate-bound amino group 43 . Besides, a signal belonging to an as yet unknown species appeared at 15.32 ppm at pH 5.25.…”

Section: Discussionmentioning

confidence: 99%

“…been chosen as lead compounds based on previous extensive investigation 43,50 . We modified our previously reported synthesis of dinuclear bis<ethylenediamineplatinum(II) > -2-amino-1-hydroxyethane-1,1-diyl-bisphosphonate complex (Pt-BP) by using Pt(NO 3 ) 2 (en) as Pt precursor instead of Pt(OSO 3 )(OH 2 )(en) 29,30,[50][51][52] .…”

Section: Synthesis and Characterization Of Pt-bp Complex Pt-bp Complmentioning

confidence: 99%

See 1 more Smart Citation

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

Nadar

Farbod

Schilden

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (195m Pt-BP) complexes to confirm preferential accumulation of these pt-based drugs in metabolically active bone. In vitro nMR studies revealed that release of pt from pt Bp complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. these pt-Bp complexes formed less pt-DnA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of pt from pt-Bp complexes proceeded relatively slow. Subsequently, radioactive 195m pt-Bp complexes were synthesized using 195m pt(no 3) 2 (en) as precursor and injected intravenously into mice. Specific accumulation of 195m pt-Bp was observed at skeletal sites with high metabolic activity using micro-Spect/ct imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195m pt Bp colocalized with calcium in the trabeculae of mice tibia. Most types of tumors, i.e. breast, prostate, lung, kidney, and thyroid, metastasize to bone since its physiological environment facilitates the formation and growth of cancer cells 1,2. These metastases affect healthy bone, which then become the primary cause of mortality 3. Distant metastases are the leading cause of death for both breast and prostate cancer patients, with 65-75% and 90% of these patients developing bone metastases in advanced stages, respectively 4,5. Bone metastases are often associated with accelerated bone resorption leading to complications such as skeletal-related events (SREs), bone pain or hypercalcemia 6,7. Unfortunately, current treatments for bone metastases are limited. Bisphosphonates (BP) and denosumab are most commonly used for palliative treatment to prevent or limit SREs 8. Although such treatments inhibit osteoclast activity and prevent the progression of metastases, they do not kill cancer cells effectively and do not improve the quality of life of patients substantially 9. Consequently, the development of effective therapies to treat bone metastases remains a major clinical challenge.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Synthesis and Characterization Of Pt-bp Complex Pt-bp Complmentioning

confidence: 99%

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

Nadar

Farbod

Schilden

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…54 Later on, several Pt(II)-BP conjugates have been investigated as bone or mesothelioma targeted antineoplastic drug candidates. [55][56][57][58][59] Natile et al reported the first Pt(IV)-BP complex 6 composed of two Pt units linked by an oxo bridge. 60 The reaction of 6 with glutathione, as a model of in vivo activation by reductive elimination, showed the Pt(IV) to Pt(II) reduction followed by the release of the BP ligands.…”

Section: Bifunctional Drugsmentioning

confidence: 99%

“…However, the occurrence of undesired chemical reactivity (already observed for other Pt(II)-BP complexes administered to MPM cells, where inadequate hydrolysis occurs and hence the split of two active components does not take place) is the likely cause of such a modest activity. 59…”

Section: Bifunctional Drugsmentioning

confidence: 99%

Pros and cons of bifunctional platinum(iv) antitumor prodrugs: two are (not always) better than one

2014

Self Cite

View full text Add to dashboard Cite

This article evaluates the efficacy and applicability of bifunctional prodrugs consisting of a six-coordinate Pt(iv) octahedral core and one or more bioactive molecules. The platinum(iv) complexes release upon reduction the corresponding cytotoxic Pt(ii) agents and the bioactive molecules, able to inhibit some biochemical mechanisms of cancer growth and/or prevent the deactivation of the Pt(ii) metabolites.

show abstract

“…Keppler and co‐workers reported novel platinum complexes with functional phosphonate groups, which showed prominent in vitro and in vivo biological activity against transplantable osteosarcoma. Natile and co‐workers have designed and prepared a series of platinum‐based complexes containing BP moiety and demonstrated a different mechanism of action from that of cisplatin. Bose et al .…”

Section: Introductionmentioning

confidence: 99%

Bifunctional Platinum(II) Complexes with Bisphosphonates Substituted Diamine Derivatives: Synthesis and In vitro Cytotoxicity

Sun

Zhao

2017

Chemistry & Biodiversity

View full text Add to dashboard Cite

A series of N,N'-dibisphosphonate-containing 1,3-propanediamine derivatives (L1 - L6) and their corresponding dichloridoplatinum(II) complexes (1 - 6) have been synthesized and characterized by elemental analysis, H-NMR, C-NMR, P-NMR and HR-MS spectra. The in vitro antitumor activities of compounds L1 - L6 and 1 - 6 were tested by WST-8 assay with Cell Counting Kit-8, indicating that platinum-based complexes 1 - 6 showed higher cytotoxicity than corresponding ligands L1 - L6 against A549 and MG-63, especially complex 2 which displayed comparable cytotoxicity to those of cisplatin and zoledronate after 48 h incubation. In addition, complexes 1 - 6 were more active in vitro on osteosarcoma cell line MG-63 than normal osteoblast cell line hFOB 1.19. The structure-activity relationship has been summarized based on the in vitro cytotoxicity of three series of platinum complexes from this and our previous studies. The in vitro bone affinity of platinum complexes was also tested by hydroxyapatite (HAP) chromatography in terms of capacity factor K'. Besides, in this paper, representative complex 2, which has been proved to be a promising antitumor agent with high cytotoxicity and bone HAP binding property, was investigated for its mechanism of action producing cell death against MG-63.

show abstract

Platinum–bisphosphonate complexes have proven to be inactive chemotherapeutics targeted for malignant mesothelioma because of inappropriate hydrolysis

Cited by 19 publications

References 37 publications

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

Pros and cons of bifunctional platinum(iv) antitumor prodrugs: two are (not always) better than one

Bifunctional Platinum(II) Complexes with Bisphosphonates Substituted Diamine Derivatives: Synthesis and In vitro Cytotoxicity

Contact Info

Product

Resources

About