Development of Peptide Paratope Mimics Derived from the Anti-ROR1 Antibody and Long-Acting Peptide-Drug Conjugates for Targeted Cancer Therapy.

Antibody-based targeted therapy in cancer faces a challenge due to uneven antibody distribution in solid tumors, hindering effective drug delivery. We addressed this by developing peptide mimetics with nanomolar-range affinity for Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using computational methods. These peptides showed both specific targeting and deep penetration in vitro and in vivo. Additionally, we created peptide-drug conjugates (PDCs) by linking targeting peptides to toxin drugs via various linkers and enhancing their in vivo half-life with fatty side chains for albumin binding. The antitumor candidate II-3 displayed exceptional affinity (KD = 1.72 × 10-9 M), internalization efficiency, anticancer potency (IC50 = 0.015 ± 0.002 µM), and pharmacokinetics (t1/2 = 2.6 h), showcasing a rational approach for designing PDCs with favorable tissue distribution and strong tumor penetration.

Novel CCR3-targeted cyclic peptides as potential therapeutic agents for age-related macular degeneration via inhibiting angiogenesis and reducing retinal photoreceptor damage.

The prolonged intravitreal administration of anti-vascular endothelial growth factor (VEGF) drugs is prone to inducing aberrant retinal vascular development and causing damage to retinal neurons. Hence, we have taken an alternative approach by designing and synthesizing a series of cyclic peptides targeting CC motif chemokine receptor 3 (CCR3). Based on the binding mode of the N-terminal region in CCR3 protein to CCL11, we used computer-aided identification of key amino acid sequence, conformational restriction through different cyclization methods, designed and synthesized a series of target cyclic peptides, and screened the preferred compound IB-2 through affinity. IB-2 exhibits excellent anti-angiogenic activity in HRECs. The apoptosis level of 661W cells demonstrated a significant decrease with the escalating concentration of IB-2. This suggests that IB-2 may have a protective effect on photoreceptor cells. In vivo experiments have shown that IB-2 significantly reduces retinal vascular leakage and choroidal neovascularization (CNV) area in a laser-induced mouse model of CNV. These findings indicate the potential of IB-2 as a safe and effective therapeutic agent for AMD, warranting further development.

Estrogen deficiency aggravates apical periodontitis by regulating NLRP3/caspase-1/IL-1ß axis.

Estrogen plays critical roles in apical periodontitis and subsequent bone loss, however the mechanism is not clear yet. In this study, we aimed to study the underlying mechanism of estrogen in apical periodontitis using both clinic samples and animal model. Clinically, as estrogen physiologically declines in elder female patients (premenopausal verses postmenopausal patients), we found that the expression level of NLRP3/Caspase-1/IL-1ß signaling pathway was elevated in the infected apical tissues of postmenopausal patients as compared to the premenopausal patients, suggesting that this pathway is involved in the estrogen-mediated apical periodontitis. Furthermore, by analyzing the well-established OVX (estrogen deficiency model) animal model, we confirmed that the expression level of NLRP3/Caspase-1/IL-1ß signaling pathway was also elevated in the infection areas of apical periodontitis in OVX animals. Importantly, as the periodontitis progressed, the subsequent bone loss was aggravated significantly. Thus, taken all these data together, our results demonstrated that the NLRP3/Caspase-1/IL-1ß signaling pathway is involved in the estrogen-mediated apical periodontitis and the consequent bone loss in both human being and animal model. This study may provide a potential target for female apical periodontitis therapy.

Epigenetic silencing of miR-137 induces resistance to bicalutamide by targeting TRIM24 in prostate cancer cells.

Prostate cancer is an important hormone-dependent cancer affecting men. In the initial stages, prostate cancer is often treated using hormone therapy, including bicalutamide. Despite the initial effectiveness of this therapy, the tumor eventually acquires resistance, resulting in recurrence of castration-resistant prostate cancer (CRPC). Dysregulation of microRNA (miRNA) function is one of the putative underlying mechanisms of hormone therapy resistance. Reports have shown that miRNAs act as tumor suppressors in patients with prostate cancer, but the role of these molecules in bicalutamide resistance in prostate cancer cell lines remains unclear. We performed lentiviral miRNA library screening to identify novel miRNAs that modulate the response of human prostate cancer LNCaP cells to the antiandrogen bicalutamide. We found that the tumor suppressor miRNA miR-137 silenced signaling in a spectrum of human cancers and selectively targeted tripartite motif-containing 24 (TRIM24) to suppress tumor proliferation. Silencing of TRIM24 recapitulated the effect of miR-137 on cell proliferation, whereas overexpression of TRIM24 reversed this effect. Real-time reverse transcription PCR analysis revealed a reciprocal relationship between miR-137 and TRIM24 in prostate cancer cell lines and tissues. Mechanistic studies indicated that methyl CpG-binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) cooperate to promote methylation of the miR-137 promoter and the consequent decreased transcription, leading to enhanced TRIM24 expression and glutamine metabolism. These findings describe a novel mechanism that affects TRIM24 deregulation in human cancers and provide a molecular link between miR-137, TRIM24, and tumor proliferation in CRPC.

Detection of Prostate Cancer Metastasis by Whole Body Magnetic Resonance Imaging Combined with Bone Scintigraphy and PSA Levels.

BACKGROUND/AIMS: The combined role of whole-body magnetic resonance imaging (WB-MRI), bone scintigraphy and prostate specific antigen (PSA) were considered in predicting metastases and prognosis of prostate cancer (PCa). METHODS: Totally 38 PCa patients underwent WB-MRI, bone scintigraphy and PSA detections, and 34 benign prostate hyperplasia (BPH) patients were checked with PSA. Pearson correlations were performed to determine associations among PSA, apparent diffusion coefficient (ADC) and Gleason scoring. Specificity and sensitivity were for comparison of diagnostic accuracies. Patients' baseline PSA, PSA nadir and time to the prostate-specific antigen nadir (TTPN) were analyzed, and Kaplan-Meier survival curves were also established. RESULTS: ADC values were negatively correlated with PSA levels (rs = -0.389, P = 0.016) and Gleason scores (rs = -0.432, P = 0.006), while PSA levels were positively correlated with Gleason scoring (rs = 0.493, P = 0.002). Diagnostic efficacy of whole body-diffusion weighted imaging (WB-DWI) combined with PSA seemed the most favorable, and bone scintigraphy was advantageous in identifying bone metastasis. PSA levels (> 61.60 µg/L), Gleason scores (> 6) and ADC (< 0.81 × 10-3 mm2/s) could all predict pessimistic prognosis (HR = 7.65; HR = 6.09; HR = 7.28). Smaller PSA nadir (≤ 1.0 µg/L) and longer TTPN (> 3 months) were associated with increased 5-year survival rate (P < 0.05). CONCLUSIONS: The combined efficacies of WB-MRI, bone scintigraphy and PSA levels were desired in identifying PCa lesions and prognosis.

New insight into the binding interaction of hydroxylated carbon nanotubes with bovine serum albumin.

In order to understand the effects of carbon nanotubes on the structural stability of proteins, the ligand-binding ability, fibrillation, and chemical denaturation of bovine serum albumin in the presence of a multi-walled hydroxylated carbon nanotubes (HO-MWCNTs) was characterized by UV-vis, circular dichroism, fluorescence spectroscopy and molecule modeling methods at the molecular level. The experiment results indicated that the fluorescence intensity of BSA was decreased obviously in presence of HO-MWCNTs. The binding interaction of HO-MWCNTs with BSA led to the secondary structure changes of BSA. This interaction could not only affect the ligand-binding ability of BSA, but also change the rate of fibrillation and denaturation of BSA. This work gave us some important information about the structures and properties of protein induced by carbon nanotubes.