0000000000148748
AUTHOR
Marian Meckel
Synthesis and preliminary in vivo evaluation of well-dispersed biomimetic nanocrystalline apatites labeled with positron emission tomographic imaging agents.
In recent years, biomimetic synthetic apatite nanoparticles (AP-NPs), having chemical similarity with the mineral phase of bone, have attracted a great interest in nanomedicine as potential drug carriers. To evaluate the therapeutic perspectives of AP-NPs through the mechanisms of action and organs they interact with, the noninvasive monitoring of their in vivo behavior is of paramount importance. To this aim, here the feasibility to radiolabel AP-NPs ("naked" and surface-modified with citrate to reduce their aggregation) with two positron emission tomographic (PET) imaging agents ([F-18]NaF and Ga-68-NO(2)AP(BP)) was investigated. [F-18]NaF was used for the direct incorporation of the radi…
In vivo comparison of DOTA based 68Ga-labelled bisphosphonates for bone imaging in non-tumour models.
Bone metastases are a class of cancerous metastases that result from the invasion of a tumor into bone. The solid mass which forms inside the bone is often associated with a constant dull ache and severe spikes in pain, which greatly reduce the quality of life of the patient. Numerous (99m)Tc-labeled bisphosphonate functionalised complexes are well established tracers for bone metastases imaging. The objective of this research was to evaluate the pharmacokinetics and behaviour of three DOTA based bisphosphonate functionalised ligands (BPAMD, BPAPD and BPPED), using both (68)Ga μ-PET in vivo imaging and ex vivo biodistribution studies in healthy Wistar rats. The compounds were labelled with …
Bone targeting compounds for radiotherapy and imaging: *Me(III)-DOTA conjugates of bisphosphonic acid, pamidronic acid and zoledronic acid
Background Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing 68Ga-labelled analogues, endoradiotheraphy with 177Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases. Methods Based on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTAPAM and DOTAZOL(MM1.MZ) were successfully synthesized. The ligands were labe…
Evaluation of Safety and Dosimetry of 177Lu-DOTA-ZOL for Therapy of Bone Metastases
Palliative treatment of bone metastasis using radiolabeled bisphosphonates is a well-known concept proven to be safe and effective. A new therapeutic radiopharmaceutical for bone metastasis is 177Lu-DOTA-zoledronic acid (177Lu-DOTA-ZOL). In this study, the safety and dosimetry of a single therapeutic dose of 177Lu-DOTA-ZOL were evaluated on the basis of a series of SPECT/CT images and blood samples. Methods: Nine patients with exclusive bone metastases from metastatic castration-resistant prostate cancer (mCRPC) (70.8 ± 8.4 y) and progression under conventional therapies participated in this prospective study. After receiving 5,780 ± 329 MBq 177Lu-DOTA-ZOL, patients underwent 3-dimensional …
A DOTA based bisphosphonate with an albumin binding moiety for delayed body clearance for bone targeting
Radiolabeled bisphosphonates are commonly used in the diagnosis and therapy of bone metastases. Blood clearance of bisphosphonates is usually fast and only 30%-50% of the injected activity is retained in the skeleton, while most of the activity is excreted by the urinary tract. A longer blood circulation may enhance accumulation of bisphosphonate compounds in bone metastases. Therefore, a chemically modified macrocyclic bisphosphonate derivative with an additional human albumin binding entity was synthesized and pharmacokinetics of its complex was evaluated. The DOTA-bisphosphonate conjugate BPAMD was compared against the novel DOTAGA-derived albumin-binding bisphosphonate DOTAGA(428-d-Lys)…
Novel Radiolabeled Bisphosphonates for PET Diagnosis and Endoradiotherapy of Bone Metastases.
Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68Ge/68Ga generator, an analog to the established 99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are ofte…
Development of a [177Lu]BPAMD Labeling Kit and an Automated Synthesis Module for Routine Bone Targeted Endoradiotherapy
Painful bone lesions, both benign and metastatic, are often managed using conventional analgesics. However, the treatment response is not immediate and is often associated with side-effects. Radionuclide therapy is used for pain palliation in bone metastases as well as some benign neoplasms. Endoradiotherapy has direct impact on the pain-producing bone elements, and hence, response is significant, with minimal or no side-effects. A new potential compound for endoradiotherapy is [(177)Lu]BPAMD. It combines a highly affine bisphosphonate, covalently bridged with DOTA through an amide bond, with the low-energy β(-) emitting therapeutic radiolanthanide (177)Lu. For routine chemical application,…
68Ga- und 177Lu-markierte Bisphosphonate als Knochenmetastasen-Theranostika
Der erhohte Metabolismus der Knochenmatrix kann zum einen mit der SPECT- und zum anderen mit der PET-Technik visualisiert werden. Als SPECT-Nuklid wird uberwiegend 99 mTc in Form von [99mTc]Bisphosphonat-Komplexen verwendet. Die PET bietet im Gegensatz zur SPECT eine hohere lokale und temporale Auflosung. Mit dem 68Ge/68Ga-Generatorsystem existiert ein mittlerweile bewahrtes PET-Pendant zum etablierten 99mTc-Generator. Neuartige Bisphosphonate (BP) in Kombination mit makrozyklischen Chelatoren sind derzeit weltweit Gegenstand der Forschung. Zur Komplexierung von Ga(III) werden haufig DOTA und NOTA sowie deren Derivate verwendet. Speziell im Fall von DOTA-Derivaten bieten DOTA-BP die Moglich…