Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution

Metaiodobenzylguanidine (MIBG) is an enzymatically stable synthetic analog of norepinephrine that when radiolabled with diagnostic ((123)I) or therapeutic ((131)I) isotopes has been shown to concentrate highly in sympathetically innervated tissues such as the heart and neuroendocrine tumors that possesses high levels of norepinephrine transporter (NET). As the transport of MIBG by NET is a saturable event, the specific activity of the preparation may have dramatic effects on both the efficacy and safety of the radiodiagnostic/radiotherapeutic. Using a solid labeling approach (Ultratrace), noncarrier-added radiolabeled MIBG can be efficiently produced. In this study, specific activities of >1200 mCi/micromol for (123)I and >1600 mCi/micromol for (131)I have been achieved. A series of studies were performed to assess the impact of cold carrier MIBG on the tissue distribution of (123/131)I-MIBG in the conscious rat and on cardiovascular parameters in the conscious instrumented dog. The present series of studies demonstrated that the carrier-free Ultratrace MIBG radiolabeled with either (123)I or (131)I exhibited similar tissue distribution to the carrier-added radiolabeled MIBG in all nontarget tissues. In tissues that express NETs, the higher the specific activity of the preparation the greater will be the radiopharmaceutical uptake. This was reflected by greater efficacy in the mouse neuroblastoma SK-N-BE(2c) xenograft model and less appreciable cardiovascular side-effects in dogs when the high-specific-activity radiopharmaceutical was used. The increased uptake and retention of Ultratrace (123/131)I-MIBG may translate into a superior diagnostic and therapeutic potential. Lastly, care must be taken when administering therapeutic doses of the current carrier-added (131)I-MIBG because of its potential to cause adverse cardiovascular side-effects, nausea, and vomiting

Phosphorylation of calmodulin by plasma-membrane-associated protein kinase(s)

Now known as FEBS Journal: Open Access content older than 1 year.Plasma-membrane-associated protein kinase(s) from normal rat liver phosphorylates exogenous bovine brain calmodulin in the absence of Ca2+ and in the presence of histone or poly(L-lysine). Maximum levels of calmodulin phosphorylation are obtained at a poly(L-lysine)/calmodulin molar ratio of 0.4. Phosphoamino acid analysis revealed that calmodulin is phosphorylated on serine, threonine and tyrosine residues. Endogenous plasma-membrane-associated calmodulin was also phosphorylated by plasma-membrane-associated protein kinase(s) in the absence of added cationic protein or polypeptide. The identity of endogenous phosphocalmodulin was confirmed by immunoprecipitation with a specific anti-calmodulin monoclonal antibody. Ehrlich ascites tumor cell plasma membranes do not contain endogenous calmodulin. However, membrane-associated protein kinase(s) from these tumor cells phosphorylates bovine brain calmodulin in the presence of poly(L-lysine). These data demonstrate that phosphocalmodulin is present in liver plasma membranes and suggest that this post-translational modification could have a physiological role in this location.This work was supported by Grants to A. V. from the Comisión lnterministerial de Ciencia y Tecnología (SAF392/93), from the Conejería de Educucición de la Comunidad de Madrid (AE16/94), and from the Direccición General de Investigaciones Científicas y Técnicas (PR94-343) (Spain), and Grant to D. B. S. from the National Institutes of Health (DK43682) (USA). A. B. is the recipient of a predoctoral fellowship from the Departamento de Educación, Universidades e Investigación del Gobierno Vasco (Spain). M. S. is the recipient of a postdoctoral fellowship from the Consejo Superior de Investigaciones Científicas (Spain). J. L. J. is the recipient of a postdoctoral fellowship (DK09062) from the National Institutes of Health (USA).Peer Reviewe

Triazole Appending Agent (TAAG): A New Synthon for Preparing Iodine-Based Molecular Imaging and Radiotherapy Agents

A new prosthetic group referred to as the triazole appending agent (TAAG) was developed as a means to prepare targeted radioiodine-based molecular imaging and therapy agents. Tributyltin-TAAG and the fluorous analogue were synthesized in high yield using simple click chemistry and the products labeled in greater than 95% RCY with ¹²³I. A TAAG derivative of an inhibitor of prostate-specific membrane antigen was prepared and radiolabeled with ¹²³I in 85% yield where biodistribution studies in LNCap prostate cancer tumor models showed rapid clearance of the agent from nontarget tissues and tumor accumulation of 20% injected dose g^–1 at 1 h. The results presented demonstrate that the TAAG group promotes minimal nonspecific binding and that labeled conjugates can achieve high tumor uptake and exquisite target-to-nontarget ratios

Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma

Radiolabeled benzamides are attractive candidates for targeted radiotherapy of metastatic melanoma as they bind melanin and exhibit high tumor uptake and retention. One such benzamide, N-(2-diethylamino-ethyl)-4-(4-fluoro-benzamido)-5-iodo-2-methoxy-benzamide (MIP-1145), was evaluated for its ability to distinguish melanin-expressing from amelanotic human melanoma cells, and to specifically localize to melanin-containing tumor xenografts. The binding of [(131)I]MIP-1145 to melanoma cells in vitro was melanin dependent, increased over time, and insensitive to mild acid treatment, indicating that it was retained within cells. Cold carrier MIP-1145 did not reduce the binding, consistent with the high capacity of melanin binding of benzamides. In human melanoma xenografts, [(131)I]MIP-1145 exhibited diffuse tissue distribution and washout from all tissues except melanin-expressing tumors. Tumor uptake of 8.82% injected dose per gram (ID/g) was seen at 4 hours postinjection and remained at 5.91% ID/g at 24 hours, with tumor/blood ratios of 25.2 and 197, respectively. Single photon emission computed tomography imaging was consistent with tissue distribution results. The administration of [(131)I]MIP-1145 at 25 MBq or 2.5 GBq/m(2) in single or multiple doses significantly reduced SK-MEL-3 tumor growth, with multiple doses resulting in tumor regression and a durable response for over 125 days. To estimate human dosimetry, gamma camera imaging and pharmacokinetic analysis was performed in cynomolgus monkeys. The melanin-specific binding of [(131)I]MIP-1145 combined with prolonged tumor retention, the ability to significantly inhibit tumor growth, and acceptable projected human dosimetry suggest that it may be effective as a radiotherapeutic pharmaceutical for treating patients with metastatic malignant melanoma

Economic Burden and Cost Determinants of Deep Venous Thrombosis During the Two Years Following Diagnosis a Prospective Evaluation

BACKGROUND: Few studies have evaluated the long-term economic consequences of deep vein thrombosis (DVT). None of them have incorporated prospectively collected clinical data to ensure accurate identification of incident cases of DVT and DVT-related health outcomes of interest, such as post-thrombotic syndrome (PTS). OBJECTIVES: To prospectively quantify medical and non-medical resource use and costs related to DVT during 2 years following diagnosis, and to identify clinical determinants of costs. METHODS: Three hundred and fifty-five consecutive patients with acute DVT were recruited at seven Canadian hospital centers. Resource use and cost information were retrieved from three sources: weekly patient-completed cost diaries, nurse-completed case report forms, and the Quebec provincial administrative healthcare database (RAMQ). RESULTS: The rate of DVT-related hospitalization was 3.5 per 100 patient-years (95% confidence interval [CI] 2.2-4.9). Patients reported a mean (standard deviation) of 15.0 (14.5) physician visits and 0.7 (1.2) other healthcare professional visits. The average cost of DVT was $5180 (95$4344-6017) in Canadian dollars, with 51.6% of costs being attributable to non-medical resource use. Multivariate analysis identified four independent predictors of costs: concomitant pulmonary embolism (relative increase in cost [RIC] 3.16; 95% CI 2.18-4.58), unprovoked DVT (RIC 1.65; 95% CI 1.28-2.13), development of PTS during follow-up (RIC 1.35; 95% CI 1.05-1.74), and management of DVT in the inpatient setting (RIC 1.79; 95% CI 1.33-2.40). CONCLUSIONS: The economic burden of DVT is substantial. The use of measures to prevent the occurrence of PTS and favoring outpatient care of DVT has the potential to diminish costs

Author Correction: Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA

An amendment to this paper has been published and can be accessed via a link at the top of the paper