Abstract. In this study, we evaluated the ability of 8.8 mT static magnetic fields (SMF) to enhance the in vitro action of a chemotherapeutic agent, paclitaxel, against K562 human leukemia cells. We analyzed the cell proliferation, cell cycle distribution, DNA damage and alteration of cell surface and cell organelle ultrastructure after K562 cells were exposed to paclitaxel in the presence or absence of 8.8 mT SMF. The results showed that in the presence of SMF, the efficient concentration of paclitaxel on K562 cells was decreased from 50 to 10 ng/ml. Cell cycle analysis indicated that K562 cells treated with SMF plus paclitaxel were arrested at the G2 phase, which was mainly induced by paclitaxel. Through comet assay, we found that the cell cycle arrest effect of paclitaxel with or without SMF on K562 cells was correlated with DNA damage. The results of atomic force microscopy and transmission electron microscopy observation showed that the cell ultrastructure was altered in the group treated with the combination of SMF and paclitaxel, holes and protuberances were observed, and vacuoles in cytoplasm were augmented. Our data indicated that the potency of the combination of SMF and paclitaxel was greater than that of SMF or paclitaxel alone on K562 cells, and these effects were correlated with DNA damage induced by SMF and paclitaxel. Therefore, the alteration of cell membrane permeability may be one important mechanism underlying the effects of SMF and paclitaxel on K562 cells.

PurposeThere is increasing evidence for convincing efficacy and safety of 177Lu-labled prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) for metastatic castration-resistant prostate cancer (mCRPC). However, data are not available regarding the feasibility of 177Lu-labled PSMA-targeted RLT in East Asians. The present study summarized the first experience with 177Lu-PSMA-I&T therapy for mCRPC in China.MethodsForty consecutive patients with mCRPC were enrolled from December 2019 to September 2021. Eligible patients received 177Lu-PSMA-I&T RLT at intervals of 8-12 weeks. Toxicity was assessed based on standardized physicians’ reports and the Common Toxicity Criteria for Adverse Events criteria. Response to PRLT was evaluated according to the changes of prostate specific antigen (PSA) response and imaging response. Quality of life (QOL), Karnofsky performance status (KPS) and pain (visual analogue scale, VAS) were also evaluated. The impacts of baseline parameters on the therapeutic effects were explored by univariate and multivariate logistic regression analyses.ResultsAll patients underwent a total of 86 cycles of 177Lu-PSMA-I&T (range: 1-5 cycles) with dosages of 3.70-14.43GBq per cycle, with a median of 8 months followed up. Six patients (15%) developed mild reversible xerostomia during follow-up, and 28 patients (70%) experienced grade 1-4 bone marrow dysfunction. Changes in PSA were assessed after therapy, accompanied by the partial response (PR) in 25 patients (62.5%), the stable disease (SD) in 5 patients (12.5%), and the progressive disease (PD) in 10 patients (25%), respectively. QOL, KPS (%) and VAS scores were improved significantly due to treatment (P<0.05). Overweight and elevated AST, ALP, and LDH were associated with poor outcomes.Conclusions177Lu-PSMA-I&T achieves the favourable response and well tolerance in mCRPC, which associates with not only PSA decline but also with tumor remission including lymphadenopathy and bone metastasis. We also find that patients with overweight and high AST, ALP, and LDH should be cautious to undergo the PRLT. Large-cohort studies are warranted to confirm the initial findings and elucidate the survival benefit of the treatment.

In this study, we explored the mechanism of the killing effects of a moderate-intensity static magnetic field (SMF) and cisplatin (DDP) on K562 cells. We analyzed the metabolic activity of cells, the extracellular DDP content, and P-glycoprotein (P-gp) expression after K562 cells were exposed continuously to a uniform 8.8 mT SMF for 8 h, with or without DDP. We found that SMF combined with DDP (10 µg/ml) significantly inhibited the metabolic activity of K562 cells (P < 0.05), while neither DDP nor SMF alone affected the metabolic activity of these cells. In the SMF + DDP group, extracellular DDP content was significantly reduced (P < 0.05). DDP also induced the expression of P-gp (P < 0.05). By contrast, in the SMF + DDP group, P-gp expression decreased compared with the DDP group (P < 0.05). Taken together, our results showed that 8.8 mT SMF enhanced the killing potency of DDP on K562 cells by decreasing the expression of P-gp.

PSMA-negative neuroendocrine prostate cancer (NEPC) is likely to be a lethal subtype of prostate cancer (PCa) with limited clinical diagnostic and therapeutic options. High expression of neurotensin receptor subtype 1 (NTR1) associated with neuroendocrine differentiation of PCa, which makes NTR1 a potential target for NEPC. In this study, NTR1-targeted tracer 68 Ga-DOTA-NT-20.3 was synthesized and evaluated by determining its affinity to androgen-dependent (LNCap) and androgen-independent (PC3) xenografts.Methods: 68 Ga-DOTA-NT-20.3 was labeled with an automated iQS-theranostics synthesizer module and its stability, labeling yield, and radiochemical purity were analyzed by radio-HPLC. Receptor binding affinity was evaluated in NTR1-positive PC3 cells by competitive binding assay. The biodistribution of 68 Ga-DOTA-NT-20.3 in vivo was evaluated in PC3 and LNCap xenografts by micro-PET imaging. NTR1 expression was identified by immunohistochemistry and immunofluorescence. Results: 68 Ga-DOTA-NT-20.3 was synthesized successfully with a yield rate of 88.07 ± 1.26 %, radiochemical purity ≥ 99% and favorable stability. The NTR1 affinity (IC50) for 68 Ga-DOTA-NT-20.3 was 7.59 ± 0.41 nM. Micro-PET/CT in PC3 xenografts showed high contrast images with intense tumor uptake, which revealed specific NTR1 expression. The tumor showed significant radioactivity (4.95 ± 0.67 percentage of injected dose per gram of tissue [%ID/g]) at 1h, which fell to 1.95 ± 0.17 %ID/g (P < 0.01, t = 8.72) after specific blockage by neurotensin.LNCap xenografts had no significant accumulation (0.81 ± 0.06 %ID/g) of 68 Ga-DOTA-NT-20.3 at 1 h. In contrast, 68 Ga-PSMA-11 was mainly concentrated in LNCap xenografts (8.60 ± 2.11 %ID/g), with no significant uptake in PC3 tumors (0.53 ± 0.05 %ID/g), consistent with the in vitro immunohistochemistry findings. Biodistribution showed rapid clearance from the blood and main organs (brain, heart, lung, liver, muscle, bone) with significantly high tumor/liver (4.41 ± 0.73) and tumor/muscle ratios (12.34 ± 1.32) at 60 min post-injection. Conclusion: 68 Ga-DOTA-NT-20.3 can be efficiently prepared with a high yield and radiochemical purity. Its favorable biodistribution and prominent NTR1 affinity make 68 Ga-DOTA-NT-20.3 a potential radiopharmaceutical for the detection of PSMA-negative PCa and identification of neuroendocrine differentiation.