In Vitro and In Vivo Study of Novel PSMA-Targeted Radioligands: Enhancing Tumor Uptake and Therapeutic Efficacy through Zwitterionization and Albumin-Binding Strategies
Bibliographic record
Abstract
Prostate-specific membrane antigen (PSMA) targeted radioligand therapy (TRT) for metastatic castration-resistant prostate cancer has demonstrated significant potential. This study aimed to develop an optimal radiotherapeutic agent suitable for high-level PSMA expression by optimizing the ligand structure with albumin-binding zwitterionic strategies to increase tumor uptake and retention time and to explore the effects of these strategies on the in vitro and in vivo properties of PSMA inhibitors. All precursors were synthesized based on PSMA-targeting agent Flu-1. The radioligands were investigated for their physicochemical properties, imaging, and biodistribution by means of gallium and lutetium labeling to evaluate their pharmacokinetic properties, as well as their affinity and specificity for PSMA. The therapeutic effect of radioligands was systematically evaluated in [ 177 Lu]Lu-Flu-1, [ 177 Lu]Lu-BWD, [ 177 Lu]Lu–P4–BWD, and [ 177 Lu]Lu–P4–PND. All PSMA ligands were of chemical purity >95%. The final radiochemical purity of the radioligands was achieved up to 99%. The cell-based and imaging study results showed that BWD had a high affinity for PSMA (IC 50 = 35.86 ± 0.56) and was significantly superior to the other radioligands in terms of tumor uptake and retention. The biodistribution study further confirmed that the tumor uptake of [ 177 Lu]Lu-BWD (64.28 ± 12.46%ID/g) was significantly higher than that of other [ 177 Lu]Lu-radioligands at 4 h postinjection, including [ 177 Lu]Lu-PSMA-617 (47.64 ± 11.39%ID/g). The TRT results showed that a single injection of 7.4 MBq of [ 177 Lu]Lu-BWD significantly inhibited the growth of PC3-PIP tumors, and it was superior to that of [ 177 Lu]Lu-PSMA-617 under the same conditions. [ 177 Lu]Lu-BWD with greatly enhanced tumor uptake and retention demonstrated remarkable therapeutic efficacy using significantly lower dosages for clinical translation to treat PCa with high level of PSMA expression.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".