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[^nat/44Sc(pypa)]^-: Thermodynamic Stability, Radiolabeling, and Biodistribution of a Prostate-Specific-Membrane-Antigen-Targeting Conjugate.

ABSTRACT: ⁴⁴Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc³⁺ ion with nonmacrocyclic chelator H₄pypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques (¹H, ¹³C, ¹H-¹³C HSQC, ¹H-¹³C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), [Sc(pypa)]^- presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence. [Sc(pypa)]^- was found to have superior thermodynamic stability (pM = 27.1) compared to [Sc(AAZTA)]^- (24.7) and [Sc(DOTA)]^- (23.9). In radiolabeling, [⁴⁴Sc][Sc(pypa)]^- formed efficiently at RT in 15 min over a range of pH (2-5.5), resulting in a complex that is highly stable (>99%) in mouse serum over at least six half-lives of scandium-44. Similar labeling efficiency was observed with the PSMA (prostate-specific membrane antigen)-targeting H₄pypa-C7-PSMA617 at pH = 5.5 (RT, 15 min), confirming negligible disturbance from the bifunctionalization on scandium-44 scavenging. Moreover, the kinetic inertness of the radiocomplex was proved in vivo. Surprisingly, the molar activity was found to have profound influence on the pharmacokinetics of the radiotracers where lower molar activity drastically reduced the background accumulations, particularly, kidney, and thus, yielded a much higher tumor-to-background contrast.

SUBMITTER: Li L

PROVIDER: S-EPMC7408314 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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[nat/44Sc(pypa)]-: Thermodynamic Stability, Radiolabeling, and Biodistribution of a Prostate-Specific-Membrane-Antigen-Targeting Conjugate.

Li Lily L Jaraquemada-Peláez María de Guadalupe MG Aluicio-Sarduy Eduardo E Wang Xiaozhu X Jiang Dawei D Sakheie Meelad M Kuo Hsiou-Ting HT Barnhart Todd E TE Cai Weibo W Radchenko Valery V Schaffer Paul P Lin Kuo-Shyan KS Engle Jonathan W JW Bénard François F Orvig Chris C

Inorganic chemistry 20200124 3

44Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc3+ ion with nonmacrocyclic chelator H4pypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques (1H, 13C, 1H-13C HSQC, 1H-13C HMBC, COSY, and NOESY). In aqueous sol ...[more]

PMID: 31976659

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Project description:BackgroundThe AAZTA chelator and in particular its bifunctional derivative AAZTA5 was recently investigated to demonstrate unique capabilities to complex diagnostic and therapeutic trivalent radiometals under mild conditions. This study presents a comparison of 68Ga, 44Sc and 177Lu-labeled AAZTA5-PSMA-617 with DOTA-PSMA-617 analogues. We evaluated the radiolabeling characteristics, in vitro stability of the radiolabeled compounds and evaluated their binding affinity and internalization behavior on LNCaP tumor cells in direct comparison to the radiolabeled DOTA-conjugated PSMA-617 analogs.ResultsAAZTA5 was synthesized in a five-step synthesis and coupled to the PSMA-617 backbone on solid phase. Radiochemical evaluation of AAZTA5-PSMA-617 with 68Ga, 44Sc and 177Lu achieved quantitative radiolabeling of >?99% after less than 5?min at room temperature. Stabilities against human serum, PBS buffer and EDTA and DTPA solutions were analyzed. While there was a small degradation of the 68Ga complex over 2?h in human serum, PBS and EDTA/DTPA, the 44Sc and 177Lu complexes were stable at 2?h and remained stable over 8?h and 1 day. For all three compounds, i.e. [natGa]Ga-AAZTA5-PSMA-617, [natSc]Sc-AAZTA5-PSMA-617 and [natLu]Lu-AAZTA5-PSMA-617, in vitro studies on PSMA-positive LNCaP cells were performed in direct comparison to radiolabeled DOTA-PSMA-617 yielding the corresponding inhibition constants (Ki). Ki values were in the range of 8-31?nM values which correspond with those of [natGa]Ga-DOTA-PSMA-617, [natSc]Sc-DOTA-PSMA-617 and [natLu]Lu-DOTA-PSMA-617, i.e. 5-7?nM, respectively. Internalization studies demonstrated cellular membrane to internalization ratios for the radiolabeled 68Ga, 44Sc and 177Lu-AAZTA5-PSMA-617 tracers (13-20%IA/106 cells) in the same range as the ones of the three radiolabeled DOTA-PSMA-617 tracers (17-20%IA/106 cells) in the same assay.ConclusionsThe AAZTA5-PSMA-617 structure proved fast and quantitative radiolabeling with all three radiometal complexes at room temperature, excellent stability with 44Sc, very high stability with 177Lu and medium stability with 68Ga in human serum, PBS and EDTA/DTPA solutions. All three AAZTA5-PSMA-617 tracers showed binding affinities and internalization ratios in LNCaP cells comparable with that of radiolabeled DOTA-PSMA-617 analogues. Therefore, the exchange of the chelator DOTA with AAZTA5 within the PSMA-617 binding motif has no negative influence on in vitro LNCaP cell binding characteristics. In combination with the faster and milder radiolabeling features, AAZTA5-PSMA-617 thus demonstrates promising potential for in vivo application for theranostics of prostate cancer.

Project description:Background44Sc/47Sc is an attractive theranostic pair for targeted in vivo positron emission tomographic (PET) imaging and beta-particle treatment of cancer. The 44Ti/44Sc generator allows daily onsite production of this diagnostic isotope, which may provide an attractive alternative for PET facilities that lack in-house irradiation capabilities. Early animal and patient studies have demonstrated the utility of 44Sc. In our current study, we built and evaluated a novel clinical-scale 44Ti/44Sc generator, explored the pharmacokinetic profiles of 44ScCl3, [44Sc]-citrate and [44Sc]-NODAGA (1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid) in naïve mice, and estimated the radiation burden of 44ScCl3 in humans.Methods44Ti/44Sc (101.2 MBq) in 6 M HCl solution was utilized to assemble a modular ZR resin containing generator. After assembly, 44Sc was eluted with 0.05 M HCl for further PET imaging and biodistribution studies in female Swiss Webster mice. Based on the biodistribution data, absorbed doses of 44/47ScCl3 in human adults were calculated for 18 organs and tissues using the IDAC-Dose software.Results44Ti in 6 M HCl was loaded onto the organic resin generator with a yield of 99.97%. After loading and initial stabilization, 44ScCl3 was eluted with 0.05 M HCl in typical yields of 82.9 ± 5.3% (N = 16), which was normalized to the estimated generator capacity. Estimated generator capacity was computed based on elution time interval and the total amount of 44Ti loaded on the generator. Run in forward and reverse directions, the 44Sc/44Ti ratio from a primary column was significantly improved from 1038 ± 440 to 3557 ± 680 (Bq/Bq) when a secondary, replaceable, ZR resin cartridge was employed at the flow outlet. In vivo imaging and ex vivo distribution studies of the reversible modular generator for 44ScCl3, [44Sc]-citrate and [44Sc]-NODAGA show that free 44Sc remained in the circulation significantly longer than the chelated 44Sc. The dose estimation of 44ScCl3 reveals that the radiation burden is 0.146 mSv/MBq for a 70 kg adult male and 0.179 mSv/MBq for a 57 kg adult female. Liver, spleen and heart wall will receive the highest absorbed dose: 0.524, 0.502, and 0.303 mGy/MBq, respectively, for the adult male.ConclusionsA clinical-scale 44Ti/44Sc generator system with a modular design was developed to supply 44ScCl3 in 0.05 M HCl, which is suitable for further radiolabeling and in vivo use. Our data demonstrated that free 44ScCl3 remained in the circulation for extended periods, which resulted in approximately 10 times greater radiation burden than stably chelated 44Sc. Stable 44Sc/47Sc-complexation will be more favorable for in vivo use and for clinical utility.

Project description:Both scandium-44 and yttrium-86 are popular PET isotopes with appropriate half-lives for immuno-positron emission tomography (immuno-PET) imaging. Herein, a new bifunctional H4pypa ligand, H4pypa-phenyl-NCS, is synthesized, conjugated to a monoclonal antibody, TRC105, and labeled with both radionuclides to investigate the long-term in vivo stability of each complex. While the 44Sc-labeled radiotracer exhibited promising pharmacokinetics and stability in 4T1-xenograft mice (n = 3) even upon prolonged interactions with blood serum proteins, the progressive bone uptake of the 86Y-counterpart indicated in vivo demetallation, obviating H4pypa as a suitable chelator for Y3+ ion in vivo. The solution chemistry of [natY(pypa)]- was studied in detail and the complex found to be thermodynamically stable in solution with a pM value 22.0, ≥3 units higher than those of the analogous DOTA- and CHX-A''-DTPA-complexes; the 86Y-result in vivo was therefore most unexpected. To explore further this in vivo lability, Density Functional Theory (DFT) calculation was performed to predict the geometry of [Y(pypa)]- and the results were compared with those for the analogous Sc- and Lu-complexes; all three adopted the same coordination geometry (i.e. distorted capped square antiprism), but the metal-ligand bonds were much longer in [Y(pypa)]- than in [Lu(pypa)]- and [Sc(pypa)]-, which could indicate that the size of the binding cavity is too small for the Y3+ ion, but suitable for both the Lu3+ and Sc3+ ions. Considered along with results from [86Y][Y(pypa-phenyl-TRC105)], it is noted that when matching chelators with radionuclides, chemical data such as the thermodynamic stability and in vitro inertness, albeit useful and necessary, do not always translate to in vivo inertness, especially with the prolonged blood circulation of the radiotracer bound to a monoclonal antibody. Although H4pypa is a nonadentate chelator, which theoretically matches the coordination number of the Y3+ ion, we show herein that its binding cavity, in fact, favors smaller metal ions such as Sc3+ and Lu3+ and further exploitation of the Sc-pypa combination is desired.

Project description:BackgroundRecently, 44Sc (T1/2 = 3.97 h, Eβ+av = 632 keV, I = 94.3 %) has emerged as an attractive radiometal candidate for PET imaging using DOTA-functionalized biomolecules. The aim of this study was to investigate the potential of using NODAGA for the coordination of 44Sc. Two pairs of DOTA/NODAGA-derivatized peptides were investigated in vitro and in vivo and the results obtained with 44Sc compared with its 68Ga-labeled counterparts.DOTA-RGD and NODAGA-RGD, as well as DOTA-NOC and NODAGA-NOC, were labeled with 44Sc and 68Ga, respectively. The radiopeptides were investigated with regard to their stability in buffer solution and under metal challenge conditions using Fe3+ and Cu2+. Time-dependent biodistribution studies and PET/CT imaging were performed in U87MG and AR42J tumor-bearing mice.ResultsBoth RGD- and NOC-based peptides with a DOTA chelator were readily labeled with 44Sc and 68Ga, respectively, and remained stable over at least 4 half-lives of the corresponding radionuclide. In contrast, the labeling of NODAGA-functionalized peptides with 44Sc was more challenging and the resulting radiopeptides were clearly less stable than the DOTA-derivatized matches. 44Sc-NODAGA peptides were clearly more susceptible to metal challenge than 44Sc-DOTA peptides under the same conditions. Instability of 68Ga-labeled peptides was only observed if they were coordinated with a DOTA in the presence of excess Cu2+. Biodistribution data of the 44Sc-labeled peptides were largely comparable with the data obtained with the 68Ga-labeled counterparts. It was only in the liver tissue that the uptake of 68Ga-labeled DOTA compounds was markedly higher than for the 44Sc-labeled version and this was also visible on PET/CT images. The 44Sc-labeled NODAGA-peptides showed a similar tissue distribution to those of the DOTA peptides without any obvious signs of in vivo instability.ConclusionsAlthough DOTA revealed to be the preferred chelator for stable coordination of 44Sc, the data presented in this work indicate the possibility of using NODAGA in combination with 44Sc. In view of a clinical study, thorough investigations will be necessary regarding the labeling conditions and storage solutions in order to guarantee sufficient stability of 44Sc-labeled NODAGA compounds.

Project description:BackgroundDespite the development of positron emission tomography (PET), single photon emission computed tomography (SPECT) still accounts for around 80% of all examinations performed in nuclear medicine departments. The search for new radiotracers or chelating agents for Technetium-99m is therefore still ongoing. O-TRENSOX and O-TRENOX two synthetic siderophores would be good candidates for this purpose as they are hexadentate ligands based on the very versatile and efficient 8-hydroxyquinoline chelating subunit. First, the radiolabeling of O-TRENOX and O-TRENSOX with 99mTc was investigated. Different parameters such as the quantity of chelating agent, type of reducing agent, pH and temperature of the reaction mixture were adjusted in order to find the best radiolabeling conditions. Then an assessment of the partition coefficient by measuring the distribution of each radiosynthesized complex between octanol and phosphate-buffered saline was realized. The complex's charge was evaluated on three different celluloses (neutral, negatively charged P81 and positively charged DE81), and finally in vivo studies with biodistribution and SPECT imaging of [99mTc]Tc-O-TRENOX and [99mTc]Tc-O-TRENSOX were performed.ResultsThe radiolabeling studies showed a rapid and efficient complexation of 99mTc with both chelating agents. Using tin pyrophosphate as the reducing agent and a minimum of 100 nmol of ligand, we obtained the [99mTc]Tc-O-TRENOX complex with a radiochemical purity of more than 98% and the [99mTc]Tc-O-TRENSOX complex with one above 97% at room temperature within 5 min. [99mTc]Tc-O-TRENOX complex was lipophilic and neutral, leading to a hepatobiliary elimination in mice. On the contrary, the [99mTc]Tc-O-TRENSOX complex was found to be hydrophilic and negatively charged. This was confirmed by a predominantly renal elimination in mice.ConclusionsThese encouraging results allow us to consider the O-TRENOX/99mTc and O-TRENSOX/99mTc complexes as serious candidates for SPECT imaging chelators. This study should be continued by conjugating these tris-oxine ligands to peptides or antibodies and comparing them with the other bifunctional agents used with Tc.

Project description:Nanomaterial based drug delivery systems allow for the independent tuning of the surface chemical and physical properties that affect their biodistribution in vivo and the therapeutic payloads that they are intended to deliver. Additionally, the added therapeutic and diagnostic value of their inherent material properties often provides extra functionality. Iron based nanomaterials with their magnetic properties and easily tailorable surface chemistry are of particular interest as model systems. In this study the core radius of the iron oxide nanoparticles (NPs) was 14.08 ± 3.92 nm while the hydrodynamic radius of the NPs, as determined by Dynamic Light Scattering (DLS), was between 90-110 nm. In this study, different approaches were explored to create radiolabeled NPs that are stable in solution. The NPs were functionalized with polycarboxylate or polyamine surface functional groups. Polycarboxylate functionalized NPs had a zeta potential of -35 mV and polyamine functionalized NPs had a zeta potential of +40 mV. The polycarboxylate functionalized NPs were chosen for in vivo biodistribution studies and hence were radiolabeled with (14)C, with a final activity of 0.097 nCi mg(-1) of NPs. In chronic studies, the biodistribution profile is tracked using low level radiolabeled proxies of the nanoparticles of interest. Conventionally, these radiolabeled proxies are chemically similar but not chemically identical to the non-radiolabeled NPs of interest. This study is novel as different approaches were explored to create radiolabeled NPs that are stable, possess a hydrodynamic radius of <100 nm and most importantly they exhibit an identical surface chemical functionality as their non-radiolabeled counterparts. Identical chemical functionality of the radiolabeled probes to the non-radiolabeled probes was an important consideration to generate statistically similar biodistribution data sets using multiple imaging and detection techniques. The radiolabeling approach described here is applicable to the synthesis of a large class of nanomaterials with multiple core and surface functionalities. This work combined with the biodistribution data suggests that the radiolabeling schemes carried out in this study have broad implications for use in pharmacokinetic studies for a variety of nanomaterials.

Dataset Information

[^nat/44Sc(pypa)]^-: Thermodynamic Stability, Radiolabeling, and Biodistribution of a Prostate-Specific-Membrane-Antigen-Targeting Conjugate.

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[<sup>nat/44</sup>Sc(pypa)]<sup>-</sup>: Thermodynamic Stability, Radiolabeling, and Biodistribution of a Prostate-Specific-Membrane-Antigen-Targeting Conjugate.

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