Y-DOTA-Nimotuzumab: Synthesis of a Promising β- Radiopharmaceutical.

Background: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, nowadays used for tumour immunochemotherapy. This study aimed to label the conjugate DOTA-nimotuzumab with yttrium-90, in order to provide a β- emitting radioimmunoconjugate (Y-DOTA-nimotuzumab) potentially useful to assess the feasibility of a new radio-guided surgery approach.

Methods: The synthesis of 90Y-DOTA-nimotuzumab was performed in two days.

Author Correction: A new microdispersed albumin derivative potentially useful for radio-guided surgery of occult breast cancer lesions.

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

A new microdispersed albumin derivative potentially useful for radio-guided surgery of occult breast cancer lesions.

This paper describes a new nuclear imaging agent, 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid of human albumin (HAC), potentially suitable for application in the Radio-guided Occult Lesion Localization (ROLL) of non-palpable mammalian cancerous lesions, as a tool to overtake the short radio-signal half-life of the technetium-99m based radiopharmaceutical currently used. This conjugate is a microsized powder aggregate, water-insoluble between pH 3 and 8.5, obtained by conjugating the protein with the macrocyclic chelating agent DOTA through a one-pot reaction in aqueous medium.

State of the Art and Recent Developments of Radiopharmaceuticals for Pancreatic Neuroendocrine Tumors Imaging.

Background: Neuroendocrine Tumors (NETs) are relatively rare tumors, mainly originating from the digestive system, that tend to grow slowly and are often diagnosed when metastasised. Surgery is the sole curative option but is feasible only in a minority of patients. Among them, pancreatic neuroendocrine tumors (pancreatic NETs or pNETs) account for less than 5% of all pancreatic tumors.

Lutetium-177 Labeled Peptides: The European Institute of Oncology Experience.

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogues has shown encouraging results in various somatostatin receptor positive tumors. Partial remission rates up to 30% have been documented as well as significant improvements in quality of life and survival. This treatment takes advantage of the high specific binding of the radiolabeled peptide to somatostatin receptors overexpressed by the tumors thus being more effective on the tumor cells with less systemic side-effects.

Design and solid phase synthesis of new DOTA conjugated (+)-biotin dimers planned to develop molecular weight-tuned avidin oligomers.

Chemical modifications of the biotin carrier in pretargeted avidin–biotin radionuclide therapy may be of paramount importance for tuning the amount of the radioactivity delivered to cancer cells by labelled biotins. We report here the synthesis of a collection of new synthetic DOTA-constructs bearing two (+)-biotin molecules (bis-biotins), designed for the creation of multimeric Av units (tetramers) bonded to the antibody. All the syntheses were carried out following the solid phase strategy and growing the molecules on a Rink Amide resin.

Production and quality control of [(90)Y]DOTATOC for treatment of metastatic neuroendocrine tumors: results of 85 syntheses.

The aim of this paper was to describe the optimized labeling protocol and quality control measures used in the production of [(90)Y]DOTATOC, starting from three different radioactivity levels to treat one, two, or three patients per therapeutic session. We investigated three different starting radioactivity levels. For the low radioactivity preparation we used 5138±280 MBq of [Y] isotope, for the medium radioactivity preparation we used 8893±900 MBq, and for the high radioactivity preparation we used 11250±715 MBq.

Yttrium-labelled peptides for therapy of NET.

Peptide receptor radionuclide therapy (PRRT) consists in the systemic administration of a synthetic peptide, labelled with a suitable beta-emitting radionuclide, able to irradiate tumours and their metastases via the internalization through a specific receptor, overexpressed on the cell membrane. After 15 years of experience, we can state that PRRT with (90)Y-labelled peptides is generally well tolerated. Acute side effects are usually mild, some of which are related to the co-administration of amino acids, such as nausea.

Peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE: the IEO phase I-II study.

Purpose: Peptide receptor radionuclide therapy (PRRT) is used in tumours expressing type 2 somatostatin receptors (sst(2)), mainly neuroendocrine. The aim of this prospective phase I-II study was to evaluate the toxicity and efficacy of (177)Lu-DOTATATE in multiple cycles.

Methods: Fifty-one consecutive patients with unresectable/metastatic sst(2)-positive tumours, divided into two groups, received escalating activities (3.

Preclinical evaluation of (177)lu-nimotuzumab: a potential tool for radioimmunotherapy of epidermal growth factor receptor-overexpressing tumors.

Background: The humanized monoclonal antibody Nimotuzumab (h-R3) has demonstrated an exceptional and better clinical profile than other monoclonal antibodies for immunotherapy of epidermal growth factor receptor-overexpressing tumors. This work deals with the preparation and radiolabeling optimization of (177)Lu-Nimotuzumab and their preclinical evaluation.

Methods: Nimotuzumab was conjugated with S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), testing different molar ratios.

AvidinOX for highly efficient tissue-pretargeted radionuclide therapy.

Avidin is widely used in vitro for its capacity to bind biotin. However, avidin's in vivo use is limited by its short residence in blood and tissues. An avidin variant, named AvidinOX, has been recently described.

Radiolabeling optimization and reduced staff radiation exposure for high-dose 90Y-ibritumomab tiuxetan (HD-Zevalin).

Introduction: (90)Y-Zevalin labeling may cause severe finger radiation exposure, especially in high-dose protocols (HD-Zevalin), where up to 7.4 GBq could be injected. In this work, we optimized the labeling of HD-Zevalin with special regard to simplicity, speed, safety and radiation protection.

Biotin derivatives carrying two chelating DOTA units. Synthesis, in vitro evaluation of biotinidases resistance, avidin binding, and radiolabeling tests.

The synthesis of four biotin derivatives carrying two DOTA moieties for each ligand (BisDOTA set) is reported, for increasing radiation/dose ratio and improving efficiency in the pretargeted avidin-biotin radioimmunotherapy. The biotin-containing scaffold of two BisDOTA was similar to the mono-DOTA derivative previously described. Then the scaffold was elongated by trifunctionalized spacers of different length and conjugated with one of the COOH groups of two DOTA.

Rapid determination of (90)Sr impurities in freshly "generator eluted"(90)Y for radiopharmaceutical preparation.

(90)Y is one of the most useful radionuclides for radioimmunotherapeutic applications and has a half-life (t(1/2)=64.14h) suitable for most therapeutic applications, beta particles of high energy and decays to a stable daughter. It is significant that (90)Y is available conveniently and inexpensively from a radionuclide "generator" by decay of its parent, (90)Sr.

High activity 90Y-ibritumomab tiuxetan (Zevalin) with peripheral blood progenitor cells support in patients with refractory/resistant B-cell non-Hodgkin lymphomas.

Radioimmunotherapy (RIT) is an alternative approach in the treatment of resistant/refractory B-cell non-Hodgkin lymphoma (NHL). We performed a feasibility and toxicity pilot study of escalating activity of 90Y-ibritumomab tiuxetan followed by autologous stem cell transplantation (ASCT). Three activity levels were fixed--30 MBq/kg (0.

Intraoperative avidination for radionuclide therapy: a prospective new development to accelerate radiotherapy in breast cancer.

Purpose: In a continuous effort to seek for anticancer treatments with minimal side effects, we aim at proving the feasibility of the Intraoperative Avidination for Radionuclide Therapy, a new procedure for partial breast irradiation.

Experimental Design: To assess doses of 90Y-DOTA-biotin to target (i.e.

Radiation protection in radionuclide therapies with (90)Y-conjugates: risks and safety.

Purpose: The widespread interest in (90)Y internal radionuclide treatments has drawn attention to the issue of radiation protection for staff. Our aim in this study was to identify personnel at risk and to validate the protection devices used.

Methods: (90)Y-MoAb (Zevalin, 15 cases, 1.

Radioimmunotherapy of brain tumor.

Despite years of intensive research, the prognosis of high-grade gliomas (HGG) remains poor, as these tumors are highly resistant to currently available therapies. Therefore, there is a need for the development of new therapeutic strategies, such as the use of monoclonal antibodies (MoAbs) in association with radioisotopes, in order to achieve better responses and prognosis. This article describes our experience in radioimmunotherapy (RIT) with MoAbs and tumor pre-targeting with the avidin-biotin system, either in systemic or locoregional administrations.

Evaluation of a new biotin-DOTA conjugate for pretargeted antibody-guided radioimmunotherapy (PAGRIT).

Purpose: A novel biotin-DOTA conjugate (r-BHD: reduced biotinamidohexylamine-DOTA) was investigated in order to provide an efficient pretargeted antibody-guided radioimmunotherapy (PAGRIT) application. Preclinical and clinical results are described.

Methods: (90)Y and (177)Lu were used to label r-BHD.

Low and high tenascin-expressing tumors are efficiently targeted by ST2146 monoclonal antibody.

ST2146biot is a biotinylated anti-tenascin monoclonal antibody (mAb) to be used for Pretargeted Antibody Guided Radioimmunotherapy (PAGRIT) of solid tumors. In vivo biodistribution studies of (125)I-labeled ST2146biot were done in nude mice transplanted with human HT-29 colon carcinoma and/or human U-118MG glioblastoma cells characterized for low and high tenascin expression, respectively. In vitro results show that ST2146 retains immunoreactivity upon biotinylation, in contrast to other anti-tenascin mAbs.

Dosimetric model for locoregional treatments of brain tumors with 90Y-conjugates: clinical application with 90Y-DOTATOC.

Unlabelled: Locoregional (LR) administration of (90)Y-conjugates after surgical debulking is a promising therapeutic option of gliomas. Dosimetry is highly recommended, as patient-specific parameters influence the absorbed dose to target and normal tissues. After tumor resection, the absorbed dose must be carefully evaluated in the rim of tissue surrounding the resected area.

Preparation and characterization of active site protected poly(ethylene glycol)-avidin bioconjugates.

Avidin was modified with poly(ethylene glycol) in the presence of a biotin binding site protective agent synthesised by imminobiotin conjugation to branched 20 kDa PEG. Avidin was incubated with imminobiotin-PEG and reacted with high amounts of 5, 10 or 20 kDa PEG to modify the protein amino groups. Circular dichroism demonstrated that the extensive PEGylation does not alter the protein conformational structure.

Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs.

A new treatment modality for inoperable or metastasized gastroenteropancreatic tumors is the use of radiolabeled somatostatin analogs. Initial studies with high doses of [(111)In-diethylenetriaminepentaacetic acid (DTPA)(0)]octreotide in patients with metastasized neuroendocrine tumors were encouraging, although partial remissions were uncommon. Another radiolabeled somatostatin analog that is used for peptide receptor radionuclide therapy (PRRT) is [(90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)(0),Tyr(3)]octreotide.

Radioimmunotherapy in advanced ovarian cancer: is there a role for pre-targeting with (90)Y-biotin?

Objectives: Despite recent advances in the management of ovarian cancer, this tumor remains the leading cause of death among gynecologic malignancies. Moreover, advanced ovarian carcinoma has a poor prognosis, thus requiring new therapeutic modalities. Previous studies have indicated a survival advantage for ovarian cancer patients (pts) treated with radioimmunotherapy (RIT).

Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours.

Somatostatin receptors are over-expressed in many tumours, mainly of neuroendocrine origin, thus enabling treatment with somatostatin analogues. Almost a decade of clinical experience of receptor radionuclide therapy with the analogue (90)Y-[DOTA](0)-Tyr(3)-octreotide [(90)Y-DOTATOC] has now been obtained at a few centres of excellence. This review reports on the present state of the art of receptor radionuclide therapy and discusses new perspectives.