Li Wang

Rheumatoid arthritis (RA) is a progressive autoimmune disease primarily characterized by persistent synovial inflammation and progressive bone erosion. Due to the complexity of its pathological microenvironment, pharmacological treatment of RA is often limited. This is primarily attributed to the fact that activated macrophages in the RA microenvironment secrete large amounts of pro-inflammatory cytokines, which further activate fibroblast-like synoviocytes (FLS), promoting a hypoxic synovial microenvironment and the release of inflammatory mediators. Inducing apoptosis in these inflammatory cells to mitigate inflammatory responses represents a potential therapeutic strategy for RA. Here, we developed microenvironment-responsive nanoparticles, ATKP-HA/CuS@Cel. Hyaluronic acid (HA) was first used to modify celastrol (Cel)-loaded octahedral copper sulfide nanoparticles (CuS NPs), forming HA/CuS@Cel NPs. Then, alendronate sodium (ALN), a potent osteoclast inhibitor, was conjugated to NH2-PEG-thioketal (TK)-COOH to obtain ALN-TK-PEG (ATKP). Self-assembly of ATKP onto HA/CuS@Cel resulted in the final ATKP-HA/CuS@Cel NPs. In vitro, this formulation enabled the release of Cel and ALN in response to reactive oxygen species, significantly inducing apoptosis of inflammatory macrophages and FLS. In vivo, ATKP-HA/CuS@Cel effectively accumulated at inflamed joint sites and markedly alleviated bone destruction and inflammatory responses in collagen-induced arthritis rats. Overall, our findings provided an innovative delivery strategy that enhanced RA therapeutic efficacy by inhibiting the abundance of various inflammatory cells through microenvironment-driven drug release.

To improve the theranostic efficacy of PSMA-targeted radiopharmaceuticals on patients with medium-to-low PSMA expression, we radiolabeled a series of novel designed PSMA-targeting dimer agents to improve tumor imaging and treatment outcomes under challenging conditions. All agents were successfully radiolabeled with ⁶⁸Ga in moderate decay-corrected labeling yield and high radiochemical purity. Among them, [⁶⁸Ga]Ga-TVS-PSMA-1 exhibited high tumor uptake in both LNCaP and 22RV1 models. [¹⁷⁷Lu]Lu-TVS-PSMA-1 demonstrated significantly improved treatment efficacy with a lower dose and good safety profile compared with [¹⁷⁷Lu]Lu-PSMA-617. A first-in-human [⁶⁸Ga]Ga-TVS-PSMA-1 PET/CT scan was performed in a 66-year-old male prostate cancer patient. Two metastatic lesions in the lumbar vertebrae were clearly visualized, and the primary tumor exhibited an SUVmax of 30.3. The [⁶⁸Ga]Ga-TVS-PSMA-1 showed lower salivary gland uptake compared with previously reported values for [⁶⁸Ga]Ga-PSMA-11; however, confirmation in larger patient cohorts is required. This study demonstrates that the dimer agent TVS-PSMA-1 holds great potential as a next-generation theranostic agent for prostate cancer.

Building upon our previous work on [68Ga]Ga/[177Lu]Lu-DOTA-Ibandronate and its demonstrated clinical applicability, this study investigates the biological behavior and translational potential of the novel therapeutic radiopharmaceutical terbium-161 (161Tb)-labeled DOTA-IBA. The radiolabeling parameters of [161Tb]Tb-DOTA-IBA were first optimized, followed by a systematic assessment of its physicochemical characteristics. Biodistribution, micro-SPECT/CT imaging, and therapeutic efficacy were evaluated in a 4T1 mouse model of bone metastasis to determine pharmacokinetics and bone-targeting capacity. Safety was verified through dose-escalation experiments. Furthermore, a preliminary clinical evaluation was performed in one volunteer with bone metastases to validate safety and initial therapeutic efficacy. [161Tb]Tb-DOTA-IBA was obtained with radiochemical purity exceeding 98%, demonstrating excellent bone-targeting selectivity and retention, with a 24 h bone uptake of 30.61 ± 4.61% ID/g, which is substantially higher than in soft tissues. In a patient receiving 370 MBq, marked pain relief was achieved, reflected by decreased VAS scores, with therapeutic benefit lasting 8–12 weeks and no observed toxic reactions. The compound exhibited favorable pharmacokinetics and safety, with no ≥ grade 3 adverse events. Overall, [161Tb]Tb-DOTA-IBA displayed high tumor-to-background ratios and excellent pharmacokinetic behavior. Early human data confirmed its safety and therapeutic potential. The complementary use of [68Ga]Ga/[161Tb]Tb-DOTA-IBA enables a unified diagnostic-therapeutic platform for the management of bone metastases, providing an innovative, targeted treatment option capable of improving both quality of life and survival in patients with advanced skeletal disease.

Nectin-4, a cell adhesion molecule frequently overexpressed in non-small cell lung cancer (NSCLC), has emerged as a promising target for theranostic applications due to its involvement in tumor progression and association with poor prognosis. This study aimed to develop radiolabeled agents based on bicyclic peptides for both imaging and targeted therapy for Nectin-4 positive tumors. We designed and synthesized ⁶⁸Ga-labeled probes ([⁶⁸Ga]Ga-3 and [⁶⁸Ga]Ga-5) for PET imaging and ¹⁷⁷Lu-labeled agents ([¹⁷⁷Lu]Lu-6) for targeted radionuclide therapy. Radiochemical yields and purity were optimized, and the agents were evaluated for cellular uptake, internalization, and biodistribution in Nectin-4-expressing cell lines (H1975, ABC-1, HEK293_nectin4) and xenograft models. Target specificity was confirmed through blocking studies with the Nectin-4 specific inhibitor peptide N188. The ⁶⁸Ga-labeled probes exhibited high radiochemical yields (78–81%) and purity (>95%), with specific uptake observed in Nectin-4-positive cells (e.g., 69.20 ± 2.31%ID/10⁶ cells for [⁶⁸Ga]Ga-3 at 120 min) and tumors. Blocking studies resulted in significant reductions in uptake, with 39-fold and 22-fold decreases for [⁶⁸Ga]Ga-3 and [⁶⁸Ga]Ga-5, respectively, confirming Nectin-4 specificity. [¹⁷⁷Lu]Lu-6 showed superior tumor retention (13% uptake) and internalization (3.5%) compared to [¹⁷⁷Lu]Lu-FAP-2286/N188, with sustained tumor growth suppression in xenograft models. PET/SPECT imaging revealed high tumor-to-background ratios and favorable pharmacokinetics, highlighting the potential of these agents for clinical application.

Purpose Since prostate-specific membrane antigen (PSMA) is widely expressed in nearly all stages of prostate cancer (PCa), PSMA tracers can be considered a viable diagnostic tool for PCa. Compared to ⁶⁸Ga-labeled PSMA agents, ¹⁸F-labeled analogues have various advantages, including the ability to achieve large scale production; easy to commercialize due to its longer half-life; and the ability to image late time points. Because [¹⁸F]vinyl sulfone (VS) is a good intermediate for labeling thiol groups in mild conditions with high labeling yield, we explored the use of various VS groups for PSMA modifications in this study. Procedures We developed six ¹⁸F-labeled radiotracers targeting PSMA from radioactive intermediates to explore targeting ability and distribution in vivo in LNCaP and 22RV1 tumor-bearing mice. Different labeling methods were compared on their ability to lead to PSMA agents with high contrast and uptake. Results In vitro stability assay showed that the tracer [¹⁸F]4a had high stability, with more than 95% of the radiochemical purities remaining as intact forms after 0.5, 1, and 2 h incubation, respectively. In vitro binding assays showed that [¹⁸F]4a has a low-micromole binding affinity of 9.45 µM. Cell uptake and internalization assays found that [¹⁸F]4a exhibited the highest cell uptake and internalization in 22RV1 cells (1.25 ± 0.06, 1.32 ± 0.11, 1.73 ± 0.08, and 2.03 ± 0.14%ID/10⁶ cells after 10 min, 30 min, 1 h, and 2 h incubation, respectively for cell uptake assay; 0.52 ± 0.02, 0.70 ± 0.11, 0.78 ± 0.04, and 0.98 ± 0.15%ID/10⁶ cells after 10 min, 30 min, 1 h, and 2 h incubation, respectively for cell internalization assay.) Analysis of the PET images showed that the tracer [¹⁸F]4a had the highest tumor uptake (3.38 ± 0.35%ID/g at 2 h p. i. in 22RV1 tumor-bearing mice; 30.16 ± 13.00%ID/g at 2 h p. i. in LNCaP tumor-bearing mice.) Of note, the tracer [¹⁸F]4a showed an approximately threefold increase in tumor uptake compared to [⁶⁸Ga]PSMA-11 in LNCaP tumor-bearing mice at 2 h p. i. The biodistribution experiment verified the accuracy of the in vivo distribution of [¹⁸F]4a in LNCaP and 22RV1 tumor-bearing mice by PET/CT imaging. Conclusions PSMA-targeted radiotracer [¹⁸F]4a is a promising PET agent for prostate cancer diagnosis.

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 [¹⁷⁷Lu]Lu-Flu-1, [¹⁷⁷Lu]Lu-BWD, [¹⁷⁷Lu]Lu-P4-BWD, and [¹⁷⁷Lu]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 (IC₅₀ = 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 [¹⁷⁷Lu]Lu-BWD (64.28 ± 12.46%ID/g) was significantly higher than that of other [¹⁷⁷Lu]Lu-radioligands at 4 h postinjection, including [¹⁷⁷Lu]Lu-PSMA-617 (47.64 ± 11.39%ID/g). The TRT results showed that a single injection of 7.4 MBq of [¹⁷⁷Lu]Lu-BWD significantly inhibited the growth of PC3-PIP tumors, and it was superior to that of [¹⁷⁷Lu]Lu-PSMA-617 under the same conditions. [¹⁷⁷Lu]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.