Synthesis of gem-bisphosphonic methotrexate conjugates and their biological response towards Walker's osteosarcoma

Sturtz, G.; Couthon, Hélène; Fabulet, O.; Mian, Mubashar Saeed; Rosini, S

doi:10.1016/0223-5234(93)90043-e

Cited by 42 publications

(9 citation statements)

References 10 publications

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“…Few reports indicated successful application of BP‐based delivery for other types of molecules. For example, BP—antineoplastic conjugates were prepared as bone‐seeking cancer drugs (42–45). For methotrexate—BP, bone targeting after intravenous injection (∼20% of dose) in mice was similar to that of BP alone (42), and the conjugate was 5–6 times more potent than the methotrexate alone (43).…”

Section: Discussionmentioning

confidence: 99%

“…Hip fractures are the single largest contributor to the overall cost of osteoporosis-related expenditures (63% of all osteoporosis-related fractures, according to a study (5)). The hip fracture incidence rate is estimated to be 1 fracture per 1000 individuals annually for individuals aged 45 and older (6). The direct cost of the medical expenditures related to fractures (in 1995) was approximately $14-17 billion in the U.S. (5,7).…”

Section: Introductionmentioning

confidence: 99%

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Bisphosphonate Conjugation to Proteins as a Means To Impart Bone Affinity

et al. 2000

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Growth factors are endogenous proteins capable of stimulating new bone formation, but their clinical benefit for systemic stimulation of bone mass has not been demonstrated. The critical challenge is to deliver a significant dose of the proteins to bone after intravenous injection. This challenge may be overcome by derivatizing proteins with ligands that exhibit a high bone affinity (e.g., bisphosphonates). To demonstrate the feasibility of this approach, 1-amino-1,1-diphosphonate methane (aminoBP) was conjugated to a model protein, albumin. The conjugation was performed by (1) converting the amino group of aminoBP to a thiol group using 2-iminothiolane, (2) derivatizing the albumin amino groups with a thiol-reactive sulfosuccinimidyl-4-(N-maleimidomethyl)-1-cyclohexane carboxylate, and (3) reacting the derivatized albumin with thiolated aminoBP. Typically, 1-4 aminoBP molecules per albumin were obtained. The conjugated albumin exhibited a high affinity to hydroxyapatite that was proportional to the extent of conjugation. The conjugates were shown to exhibit a high affinity to bone matrix in vitro in a serum-containing medium. Once bound to bone matrix, the conjugates were found to desorb more slowly than the unmodified albumin, especially from bone whose organic matrix was removed by ashing. In conclusion, conjugation of bisphosphonates to albumin was shown to impart a high bone affinity to the protein, and such conjugates can be potentially targeted to bone.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bisphosphonate Conjugation to Proteins as a Means To Impart Bone Affinity

et al. 2000

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“…Cytostatica like methotrexate [7], doxorubicin [8] or cisplatin [9] have been covalently attached via a chemical linkage to the terminal amino group of amino-BPs. The obtained conjugates should survive in the circulation, bind to the mineral matrix of the bone and subsequently release both, BPs as well as the linked cytostatica, by cleavage of the conjugates in the bone microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of the new antimetabolite-bisphosphonate (5-FdU-alendronate) in comparison to standard therapeutics on breast and ovarian cancer cell lines in the ATP tumor chemosensitivity assay

et al. 2011

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“…These ligands, normally known as ''bifunctional chelators'' (BFC), may also contain pharmacokinetic modifying linkers for modulation of the biological profile of the final complexes. 47,49 Technetium (Tc) and rhenium (Re)…”

Section: Radioactive Metal Complexesmentioning

confidence: 99%

Bisphosphonates as radionuclide carriers for imaging or systemic therapy

Palma¹,

Correia²,

Campello³

et al. 2011

Mol. BioSyst.

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Bisphosphonates (BP's), biologically stable analogs of naturally occurring pyrophosphates, became the treatment of choice for pathologic conditions characterized by increased osteoclast-mediated bone resorption, namely Paget's disease, osteoporosis and tumor bone disease. Moreover, the clinical success of BP's is also associated with their use in (99m)Tc-based radiopharmaceuticals for bone imaging. In addition to the successful delivery of (99m)Tc (γ-emitter) to bone, BP's have also been used to deliver β(-)-particle emitting radiometals (e.g.(153)Sm, (186/188)Re) for bone-pain palliation. The main goal of this Review is to update the most recent research efforts toward the synthesis, characterization and biological evaluation of novel BP-containing radiometal complexes and radiohalogenated compounds for diagnostic or therapeutic purposes. The structure and in vivo properties of those compounds will be discussed and compared to the clinically available ones, namely in terms of image quality and therapeutic effect. We will also mention briefly the use of BP's as carriers of multimodal nuclear and optical imaging probes.

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Synthesis of gem-bisphosphonic methotrexate conjugates and their biological response towards Walker's osteosarcoma

Cited by 42 publications

References 10 publications

Bisphosphonate Conjugation to Proteins as a Means To Impart Bone Affinity

Bisphosphonate Conjugation to Proteins as a Means To Impart Bone Affinity

Cytotoxicity of the new antimetabolite-bisphosphonate (5-FdU-alendronate) in comparison to standard therapeutics on breast and ovarian cancer cell lines in the ATP tumor chemosensitivity assay

Bisphosphonates as radionuclide carriers for imaging or systemic therapy

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