Electrodiffusion versus Chemical Diffusion in Alkali Calcium Phosphate Glasses: Implication of Structural Changes

A long-term transport experiment has been performed on a bioactive calcium phosphate glass of the molar composition 30CaO*25Na₂O*45P₂O₅ using the technique of bombardment induced ion transport (BIIT) with potassium as foreign bombarder ion. Ion transport due to gradients of the electrical potential and the concentration lead to incorporation of K⁺ and depletion of both Na⁺ and Ca⁺⁺ by electrodiffusion in the forward direction. The resulting concentration profiles have been quantitatively analyzed by time-of-flight secondary ion mass spectrometry (ToF-SIMS). The concentration profiles of the P⁺ and PO_<i>x</i>⁺ signals (<i>x</i> = 1–4) resemble those of the K⁺, Na⁺, and Ca⁺⁺ signals, indicating a characteristic change of the local bonding situation. This is interpreted as an indirect hint of a change of local structure of the glass network. Because the concentration profiles imprinted by the BIIT constitute pronounced concentration gradients, these depletion profiles further evolve on a much longer time scale due to chemical diffusion (absence of electric potential gradients). The former depletion zone is partially refilled by chemical diffusion. At the same time, the structural changes of the glass network are demonstrated to be reversible. Numerical simulations on the basis of the coupled Nernst–Planck–Poisson equations allow one to derive the diffusion coefficients of sodium, potassium, and calcium for both cases, that is, electrodiffusion and chemical diffusion. The two experiments are sensitive to different aspects of the diffusion coefficients and thus are complementary. The analysis is sensitive to the concentration dependence of <i>D</i>(Na⁺) and <i>D</i>(Ca⁺⁺) for the electrodiffusion and of <i>D</i>(K⁺) for the chemical diffusion. For the chemical diffusion of Na⁺ and Ca⁺⁺ in the backward direction, <i>D</i>(Ca⁺⁺) is larger than <i>D</i>(Na⁺), indicating that the extra sites occupied by Ca⁺⁺ in the preceding electrodiffusion are energetically high-lying

Monomeric and Dimeric ⁶⁸Ga-Labeled Bombesin Analogues for Positron Emission Tomography (PET) Imaging of Tumors Expressing Gastrin-Releasing Peptide Receptors (GRPrs)

The GRPr, highly expressed in prostate PCa and breast cancer BCa, is a promising target for the development of new PET radiotracers. The chelator HBED-CC (<i>N</i>,<i>N</i>′-bis­[2-hydroxy-5-(carboxyethyl)­benzyl]­ethylenediamine-<i>N</i>,<i>N</i>′-diacetic acid) was coupled to the bombesin peptides: HBED-C-BN(2–14) <b>1</b>, HBED-CC-PEG₂-[d-Tyr⁶,β-Ala¹¹,Thi¹³,Nle¹⁴]-BN­(6–14) <b>2</b>, HBED-CC-Y-[d-Phe⁶,Sta¹³,Leu¹⁴]-BN­(6–14) (Y = 4-amino-1-carboxymethyl­piperidine) <b>3</b>, and HBED-CC-{PEG₂-Y-[d-Phe⁶,Sta¹³,Leu¹⁴]-BN­(6–14)}₂ <b>4</b> (homodimer). Compounds <b>1</b>–<b>4</b> presented high binding affinities for GRPr (T47D, 0.56–3.51 nM; PC-3, 2.12–4.68 nM). In PC-3 and T47D cells, agonists [⁶⁸Ga]<b>1</b> and [⁶⁸Ga]<b>2</b> were mainly internalized while antagonists [⁶⁸Ga]<b>3</b> and [⁶⁸Ga]<b>4</b> were surface bound. Cell-related radioactivity reached a maximum after 45 min, while tracer levels followed GRPr expression (PC-3 > T47D > LNCaP > MDA-MB-231). [⁶⁸Ga]<b>4</b> showed the highest cell-bound radioactivity (PC-3 and T47D). In vivo, tumor (PC-3) targeting for [⁶⁸Ga]<b>3</b> and [⁶⁸Ga]<b>4</b> increased over time, with dynamic μPET showing clearer tumors images at later time points. [⁶⁸Ga]<b>3</b> and [⁶⁸Ga]<b>4</b> can be considered suitable PET tracers for imaging PCa and BCa expressing GRPr

Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors

Since prostate-specific membrane antigen (PSMA) is up-regulated in nearly all stages of prostate cancer (PCa), PSMA can be considered as a viable diagnostic biomarker and treatment target in PCa. This project is focused on the development and evaluation of a series of compounds directed against PSMA. The modifications to the linker are designed to improve the binding potential and pharmacokinetics for theranostic application. In addition, the results help to further elucidate the structure–activity relationships (SAR) of the resulting PSMA inhibitors. Both <i>in vitro</i> and <i>in vivo</i> experiments of 18 synthesized PSMA inhibitor variants showed that systematic chemical modification of the linker has a significant impact on the tumor-targeting and pharmacokinetic properties. This approach can lead to an improved management of patients suffering from recurrent prostate cancer by the use of one radiolabeling precursor, which can be radiolabeled either with ⁶⁸Ga for diagnosis or with ¹⁷⁷Lu or ²²⁵Ac for therapy

⁶⁸Ga-Complex Lipophilicity and the Targeting Property of a Urea-Based PSMA Inhibitor for PET Imaging

Urea-based inhibitors of the prostate-specific membrane antigen (PSMA) represent low-molecular-weight pepidomimetics showing the ability to image PSMA-expressing prostate tumors. The highly efficient, acyclic Ga­(III) chelator <i>N,N</i>′-bis [2-hydroxy-5-(carboxyethyl)­benzyl] ethylenediamine-<i>N,N</i>′- diacetic acid (HBED-CC) was introduced as a lipophilic side chain into the hydrophilic pharmacophore Glu-NH-CO-NH-Lys which was found favorable to interact with the PSMA “active binding site”. This report describes the syntheses, in vitro binding analyses, and biodistribution data of the radiogallium labeled PSMA inhibitor Glu-NH-CO-NH-Lys­(Ahx)-HBED-CC in comparison to the corresponding DOTA conjugate. The binding properties were analyzed using competitive cell binding and enzyme-based assays followed by internalization experiments. Compared to the DOTA-conjugate, the HBED-CC derivative showed reduced unspecific binding and considerable higher specific internalization in LNCaP cells. The ⁶⁸Ga complex of the HBED-CC ligand exhibited higher specificity for PSMA expressing tumor cells resulting in improved in vivo properties. ⁶⁸Ga labeled Glu-NH-CO-NH-Lys­(Ahx)-HBED-CC showed fast blood and organ clearances, low liver accumulation, and high specific uptake in PSMA expressing organs and tumor. It could be demonstrated that the PET-imaging property of a urea-based PSMA inhibitor could significantly be improved with HBED-CC

Improving the Imaging Contrast of ⁶⁸Ga-PSMA-11 by Targeted Linker Design: Charged Spacer Moieties Enhance the Pharmacokinetic Properties

⁶⁸Ga-Glu-urea-Lys-(Ahx)-HBED-CC (⁶⁸Ga-PSMA-11) represents a successful radiopharmaceutical for PET/CT imaging of prostate cancer. Further optimization of the tumor-to-background contrast might significantly enhance the sensitivity of PET/CT imaging and the probability of detecting recurrent prostate cancer at low PSA values. This study describes the advantage of histidine (H)/glutamic acid (E) and tryptophan (W)/glutamic acid (E) containing linkers on the pharmacokinetic properties of ⁶⁸Ga-PSMA-11. The tracers were obtained by a combination of standard Fmoc-based solid-phase synthesis and copper­(I)-catalyzed azide–alkyne cycloaddition. Their ⁶⁸Ga complexes were compared to the clinical reference ⁶⁸Ga-PSMA-11 with respect to cell binding, effective internalization, and tumor targeting properties in LNCaP-bearing balb/c nu/nu mice. The introduction of (HE)_<i>i</i> (<i>i</i> = 1–3) or (WE)_<i>i</i> (<i>i</i> = 1–3) into PSMA-11 resulted in a significantly changed biodistribution profile. The uptake values in kidneys, spleen, liver, and other background organs were reduced for (HE)₃ while the tumor uptake was not affected. For (HE)₁ the tumor uptake was significantly increased. The introduction of tryptophan-containing linkers also modulated the organ distribution profile. The results clearly indicate that histidine is of essential impact in order to improve the tumor-to-organ contrast. Hence, the histidine/glutamic acid linker modifications considerably improved the pharmacokinetic properties of ⁶⁸Ga-PSMA-11 leading to a reduced uptake in dose limiting organs and a significantly enhanced tumor-to-background contrast. Glu-urea-Lys-(HE)₃-HBED-CC represents a promising ⁶⁸Ga complex ligand for PET/CT-imaging of prostate cancer