bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.04.25.591165

Exploring the PET in vivo generator 134Ce as a theranostic match for 225Ac

Bauer, D.·De Gregorio, R.·Pratt, E. C.·Bell, A.·Michel, A.·Lewis, J. S.
View original source ↗Export metadata ↓

Abstract

PurposeThe radionuclide pair cerium-134/lanthanum-134 (134Ce/134La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (225Ac). The unique properties of 134Ce offer perspectives for developing innovative in vivo investigations not possible with 225Ac. In this work, 225Ac- and 134Ce-labeled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, 134Ce/134La has limitations to the setting of quantitative positron emission tomography imaging. MethodsThe precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with 225Ac or 134Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The 225Ac and 134Ce-labeled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody. ResultsIn vitro and in vivo studies with both 225Ac and 134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the 134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of 134Ces PET-compatible daughter 134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing 225Ac-labelled tracers are not quantitatively represented by 134Ce PET imaging. ConclusionWhen employing slow-internalizing vectors, 134Ce might not be an ideal match for 225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of 134La. However, this same characteristic makes it possible to estimate the redistribution of 225Acs progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/591165v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@ca3cb6org.highwire.dtl.DTLVardef@157eac6org.highwire.dtl.DTLVardef@f6ac6dorg.highwire.dtl.DTLVardef@b24d87_HPS_FORMAT_FIGEXP M_FIG C_FIG Redistribution of progeny. Investigating the 225Ac and 134Ce decay chain. This figure was created with BioRender.

Explore related subjects

pharmacology and toxicologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Bauer, D., De Gregorio, R., Pratt, E. C., Bell, A., Michel, A., Lewis, J. S.. 2024-04-28. Exploring the PET in vivo generator 134Ce as a theranostic match for 225Ac. https://doi.org/10.1101/2024.04.25.591165

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Lipid-ASO therapeutics exhibit differential tissue targeted delivery upon systemic or local CNS administration

Antisense oligonucleotides (ASOs) are a powerful therapeutic modality, but their full potential is hindered by pharmacokinetic properties that affect tissue and cellular delivery. Lipid conjugation is increasingly used to modulate ASO's biodistribution and promote extrahepatic activity, yet lipid dependent effects on in vivo functional delivery, particularly in the central nervous system (CNS), remain less explored. Here, we performed a side by side in vivo comparison of cholesterol, palmitic acid (C16:0), docosanoic acid (C22:0), and eicosapentaenoic acid (C20:5) conjugated to a fully phosphorothioated 3 10 3 LNA gapmer ASO targeting the Malat1 long non coding RNA. Lipid-ASO conjugates were administered systemically or locally in the brain of mice and evaluated for tissue level and cellular level distribution by imaging, qPCR and single-cell RNA sequencing, simultaneously annotating cell origin and global transcriptional changes within the cell. Following systemic administration in mice, lipid conjugation improved overall multi organ efficacy compared to unconjugated ASO, but with pronounced tissue specific differences. Single cell sequencing of liver and heart transcriptomes revealed lipid dependent cellular uptake patterns and transcriptional responses distinct from administration of unconjugated ASO. After intracerebroventricular administration, selected fatty acid conjugates enhanced silencing in deep brain regions such as the striatum, whereas cholesterol conjugation impaired functional delivery despite increased CNS retention. Light-sheet microscopy showed restricted parenchymal penetration of cholesterol ASOs compared with broader but heterogeneous distribution of palmitic acid conjugate. Together, these findings demonstrate that lipid identity critically determines ASO efficacy, productive cellular uptake, and regional CNS engagement, emphasizing the need for context specific lipid design in ASO therapeutic development.

pharmacology and toxicology↗
bioRxiv2026

Novel Dissymmetric Ionizable Lipid-Assembled Lipid Nanoparticles for Delivery of Ferroptosis-Related siRNA in Diabetic Treatment

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

pharmacology and toxicology↗
bioRxiv2025

Screening for cryoprotective agent toxicity and toxicity reduction in mixtures at subambient temperatures

Organ transplantation faces major challenges in preserving and transporting organs due to the limitations of existing cold storage methods. Cryopreservation offers a promising alternative for extending preservation time, but it remains a challenge to avoid toxicity from the high concentrations of cryoprotective agents (CPAs) required to prevent ice formation. In this study, we expanded a previously reported high-throughput CPA toxicity screening platform by retrofitting an automated liquid handling system with subambient cooling capabilities. This enabled systematic assessment of CPA toxicity at 4 {degrees}C, a temperature commonly used for CPA equilibration in tissue and organ cryopreservation. Overall, we screened 22 individual CPAs and a wide range of binary mixtures at concentrations up to 12 mol/kg, allowing us to identify CPA combinations that reduce toxicity. Our findings revealed that at 4 {degrees}C, CPA toxicity was significantly reduced compared to room temperature. Several CPA combinations resulted in significantly lower toxicity than their constituent CPAs at the same concentration, including 12 CPA mixtures at 6 mol/kg and 8 CPA mixtures at 12 mol/kg. Toxicity neutralization was also observed in 9 cases, especially in combinations involving formamide, acetamide, dimethyl sulfoxide, and glycerol. For example, exposure to 6 mol/kg formamide alone resulted in 20% viability, but the addition of 6 mol/kg glycerol to create a mixture with a total concentration of 12 mol/kg eliminated this toxicity, resulting in a viability of 97%. These findings support the rationale for using multi-CPA cocktails and underscore the potential of rational mixture design to reduce toxicity.

pharmacology and toxicology↗