Peptide receptor radiotherapy (PRRT) with somatostatin analogs has been successfully utilized as a treatment for somatostatin overexpressing tumors for years. Treatment of neuroendocrine tumors (NETs) with the beta particle emitter 177 Lu-DOTATATE is currently considered the standard of care for subjects with gastroenteropancreatic NETs (GEP-NETs). Despite the success of 177 Lu-DOTATATE, there remains significant room for improvement in terms of both safety and efficacy. Targeted alpha-emitter therapy with isotopes such as lead-212 ( 212 Pb) has the potential to improve both. Herein, we present the preliminary results of the phase 1 first-in-human dose-escalation trial evaluating 212 Pb-DOTAMTATE in patients with somatostatin receptor positive NETs.Methods: A total of 20 subjects with histologically confirmed NETs, prior positive somatostatin analogue scans, and no prior history of 177 Lu/ 90 Y/ 111 In PRRT, with different primary sites of the disease, were enrolled. Treatment began with single ascending doses of 212 Pb-DOTAMTATE, with subsequent cohorts receiving an incremental 30% dose increase, which was continued until a tumor response or a dose-limiting toxicity was observed. This was followed by a multiple ascending dose regimen. The recommended phase 2 dose (RP2D) regimen consisted of 4 cycles of 2.50 MBq/kg (67.6 µCi/kg) of 212 Pb-DOTAMTATE administrated at 8-week intervals, intravenously.Results: Ten subjects received the highest dose of 2.50 MBq/kg/cycle (67.6 µCi/kg/cycle). Treatment was well tolerated, with the most common treatment-emergent adverse events (TEAEs) being nausea, fatigue, and alopecia.No serious TEAEs were related to the study drug, and no subjects required treatment delay or a dose reduction. An objective radiological response (ORR) of 80% was observed for the first 10 subjects treated at the RP2D. Conclusion:Targeted alpha therapy with 212 Pb-DOTAMTATE has been shown to be well-tolerated.Preliminary efficacy results are highly promising. If these results are confirmed in a larger, multicenter clinical trial, it would provide a substantial benefit over currently FDA approved therapies for patients with metastatic or inoperable SSTR-expressing NETs regardless of the grade and location of the primary tumor.
Somatostatin analogues have been examined as a treatment for somatostatin receptor overexpressing tumors for years; specifically, octreotate (TATE) and octreotide (TOC). Several versions of these analogues coupled to beta or gamma nuclides are currently used as imaging agents, as treatments with peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumors or are being explored in preclinical and clinical settings. Our study describes the use of 212 Pb-DOTAMTATE, the octreotate analogue, in combination with 212 Pb, the parent of an alpha emitter. Preclinical studies demonstrated tumor targeting of 212 Pb-DOTAMTATE of >20% ID/g up to 24 hours post drug injection. The addition of kidney protection agents, including L-lysine and L-arginine decreases drug accumulation in the kidneys and the addition of ascorbic acid to the chelation mixture reduces oxidation of the drug product. 212 Pb-DOTAMTATE displays a favorable toxicity profile with single-dose injections of 20 mCi showing 100% survival and with nontoxic cumulative doses up to 45 mCi, when fractionated into three smaller doses of 15 mCi. In an initial efficacy study, a single 10 mCi injection of 212 Pb-DOTAMTATE extended the mean survival 2.4-fold. Efficacy was enhanced by giving three treatment cycles of 212 Pb-DOTAMTATE and reducing the time between injections to two weeks. Efficacy was optimized further by the addition of a chemo-sensitizing agent, 5-fluorouracil, given in combination with three cycles of 10 mCi 212 Pb-DOTAMTATE. These conditions led to 79% of the animals being tumor free at the end of the 31-week study suggesting that 212 Pb-DOTAMTATE alone or in combination with a chemotherapeutic may have positive clinical implications.
Lu-octreotate peptide receptor radionuclide therapy has shown promising potential as a safe and effective targeted therapy in inoperable, well to moderately differentiated metastatic neuroendocrine cancers. The results of the multicenter randomized clinical trial conducted in United States and Europe are concordant with current study.
Nucleoside base modifications can alter the structures, dynamics, and metal ion binding properties of transfer RNA molecules and are important for accurate aminoacylation and for maintaining translational fidelity and efficiency. The unmodified anticodon stem-loop from Escherichia coli tRNA(Phe) forms a trinucleotide loop in solution, but Mg(2+) and dimethylallyl modification of A(37) N6 disrupt the loop conformation and increase the mobility of the loop and loop-proximal nucleotides. We have used NMR spectroscopy to investigate the binding and structural effects of multivalent cations on the unmodified and dimethylallyl-modified anticodon stem-loops from E. coli tRNA(Phe). The divalent cation binding sites were probed using Mn(2+) and Co(NH(3))(6)(3+). These ions bind along the major groove of the stem and associate with the anticodon loop on the major groove side in a nonspecific manner. Co(NH(3))(6)(3+) stabilizes the U-turn conformation of the loop in the dimethylallyl-modified molecule, and the chemical shift changes that accompany Co(NH(3))(6)(3+) binding are similar to those observed with the addition of Mg(2+). The base-phosphate and base-2'-OH hydrogen bonds that characterize the UNR U-turn motif lead to spectral signatures in the form of unusual (15)N and (1)H chemical shifts and reduced solvent exchange of the U(33) 2'-OH and N3H protons. The unmodified molecule also displays spectral features of the U-turn fold in the presence of Co(NH(3))(6)(3+), but the loop has additional conformations and is dynamic. The results indicate that charge neutralization by a polyvalent cation is sufficient to promote formation of the U-turn fold. However, base modification is necessary to destabilize competing alternative conformers even for a purine-rich loop sequence that is predicted to have strongly favorable base stacking energy.
Gallium-68 (68Ga) is a generator-produced radionuclide with a short half-life (t½ = 68 min) that is particularly well suited for molecular imaging by positron emission tomography (PET). Methods have been developed to synthesize 68Ga-labeled imaging agents possessing certain drawbacks, such as longer synthesis time because of a required final purification step, the use of organic solvents or concentrated hydrochloric acid (HCl). In our manuscript, we provide a detailed protocol for the use of an advantageous sodium chloride (NaCl)-based method for radiolabeling of chelator-modified peptides for molecular imaging. By working in a lead-shielded hot-cell system, 68Ga3+ of the generator eluate is trapped on a cation exchanger cartridge (100 mg, ∼8 mm long and 5 mm diameter) and then eluted with acidified 5 M NaCl solution directly into a sodium acetate-buffered solution containing a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or DOTA-like chelator-modified peptide. The main advantages of this procedure are the high efficiency and the absence of organic solvents. It can be applied to a variety of peptides, which are stable in 1 M NaCl solution at a pH value of 3–4 during reaction. After labeling, neutralization, sterile filtration and quality control (instant thin-layer chromatography (iTLC), HPLC and pH), the radiopharmaceutical can be directly administered to patients, without determination of organic solvents, which reduces the overall synthesis-to-release time. This procedure has been adapted easily to automated synthesis modules, which leads to a rapid preparation of 68Ga radiopharmaceuticals (12–16 min).
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