An ALP-responsive, anionic iridium complex for specific recognition of osteosarcoma cells.

Poor cellular permeability greatly hampers the utilization of anionic Ir(III) complexes, though efficiently emissive and remarkably stable, in cell-based diagnosis. To overcome this barrier, we present the development of an alkaline phosphatase (ALP)-responsive, anionic, and aggregation-induced emission (AIE)-active Ir(III) complex (Ir1) for specific recognition of osteosarcoma cells. Containing phosphate moieties, Ir1 exhibits a net -1 charge, enabling charge repulsion from the cell membrane and resulting in low cellular uptake and good biocompatibility in normal osteoblast cells. Upon ALP-mediated hydrolysis of phosphate groups, the resulting dephosphorylated product, Ir2, demonstrates a positive charge and increased lipophilicity, promoting cellular uptake and activating its AIE properties for specific recognition of osteosarcoma cells that express elevated levels of ALP. This study elucidates the role of ALP as an ideal trigger for enhancing the cellular permeability of phosphate ester-containing Ir(III) complexes, thus expanding the potential of anionic Ir(III) complexes for biomedical applications.

Self-Assembly of Sulfate-Containing Peptides Sequesters VEGF for Inhibiting Cancer Cell Invasion.

Heparan sulfate proteoglycans (HSPGs) play a crucial role in regulating cancer growth and migration by mediating interactions with growth factors. In this study, we developed a self-assembling peptide (S1) containing a sulfate group to simulate the contiguous sulfated regions (S-domains) in heparan sulfate for growth factor binding, aiming to sequester growth factors like VEGF. Spectral and structural studies as well as simulation studies suggested that S1 self-assembled into nanostructures similar to the heparan sulfate chains and effectively bound to VEGF. On cancer cell surfaces, S1 self-assemblies sequestered VEGF, leading to a reduction in VEGF levels in the medium, consequently inhibiting cancer cell growth, invasion, and angiogenesis. This study highlights the potential of self-assembling peptides to emulate extracellular matrix functions, offering insights for future cancer therapeutic strategies.

"On/off"-switchable crosslinked PTX-nanoformulation with improved precise delivery for NSCLC brain metastases and restrained adverse reaction over nab-PTX.

Non-small cell lung cancer (NSCLC) brain metastases present a significant treatment challenge due to limited drug delivery efficiency and severe adverse reactions. In this study, we address these challenges by designing a "on/off" switchable crosslinked paclitaxel (PTX) nanocarrier, BPM-PD, with novel ultra-pH-sensitive linkages (pH 6.8 to 6.5). BPM-PD demonstrates a distinct "on/off" switchable release of the anti-cancer drug paclitaxel (PTX) in response to the acidic extratumoral microenvironment. The "off" state of BPM-PD@PTX effectively prevents premature drug release in the blood circulation, blood-brain barrier (BBB)/blood-tumor barrier (BTB), and normal brain tissue, surpassing the clinical PTX-nanoformulation (nab-PTX). Meanwhile, the "on" state facilitates precise delivery to NSCLC brain metastases cells. Compared to nab-PTX, BPM-PD@PTX demonstrates improved therapeutic efficacy with a reduced tumor area (only 14.6%) and extended survival duration, while mitigating adverse reactions (over 83.7%) in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), offering a promising approach for the treatment of NSCLC brain metastases. The precise molecular switch also helped to increase the PTX maximum tolerated dose from 25 mg/kg to 45 mg/kg This research contributes to the field of cancer therapeutics and has significant implications for improving the clinical outcomes of NSCLC patients.

Proteomic and Phosphoproteomic Analyses Reveal the Oncogenic Role of PTK7-NDRG1 Axis in Non-small-cell Lung Cancer Cell Resistance to AZD9291.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the most important chemotherapeutics for non-small-cell lung cancer (NSCLC) therapy. The resistance to EGFR-TKIs is one of the biggest obstacles to NSCLC outcome. In this study, taking advantage of phospho- and proximal proteomic techniques, we analyzed the network rearrangement in cell lines responding to AZD9291 treatment and found that cell-cell adhesion was dramatically enhanced in AZD9291-resistant cells. Further analysis revealed that protein tyrosine kinase 7 (PTK7) expression was significantly elevated. Knockdown or overexpression assays showed that PTK7 played a critical role in improving cell adhesion, which enhanced drug resistance. Because PTK7 is a membrane-localized pseudokinase, the proximal labeling probe BirA* was fused to reveal PTK7-interacting proteins. We found that PTK7 interacted with and stabilized NDRG1, which is located predominantly adjacent to adherens junctions. Downregulation of PTK7 or NDRG1 eliminated the resistance of H1975-resistant (H1975-R) and PC9-resistant (PC9-R) cells to AZD9291, suggesting that the PTK7-NDRG1 axis might be a potential target to eliminate the EGFR-TKI resistance during NSCLC therapy.

Mapping Tyrosine Kinases Based on a TK Activity-Representing Peptide Library Reveals a Role for SRC in H1975 Drug Resistance.

Tyrosine kinases (TKs) are prominent targets in cancer therapies, and more than 30 TK inhibitors have been approved for treatments in tumors with abnormal TK. Disappointingly, an incomplete response can occur with the long-term use of TK inhibitors, known as cancer drug resistance, which can be caused by kinome reprogramming. Hence, monitoring the status of TKs is crucial for revealing the underlying drug resistance mechanism. Here, we describe a TK activity-representing peptide library-based multiple reaction monitoring (TARPL-MRM) strategy for directly inferring TK activities. The strategy facilitated the assay of 87 human TKs through target quantification of 301 phosphorylation sites. Using this strategy, we demonstrated the heterogeneity of TK activity in different non-small cell lung cancer (NSCLC) cell lines and assessed the response of TK activities to the EGFR inhibitor AZD9291 in NSCLC cells. We found that the acquired resistance of H1975 cells to AZD9291 requires SRC activity, and inhibition of SRC plays potential roles in overcoming this resistance. In summary, our work reveals that this strategy has the potential to become a powerful tool for TK studies, clinical diagnostics, and the discovery of new therapeutic targets.

Chromosome-Level Reference Genome and Population Genomic Analysis Provide Insights into the Evolution and Improvement of Domesticated Mulberry (Morus alba).

Mulberry (Morus spp.) is the sole plant consumed by the domesticated silkworm. However, the genome of domesticated mulberry has not yet been sequenced, and the ploidy level of this species remains unclear. Here, we report a high-quality, chromosome-level domesticated mulberry (Morus alba) genome. Analysis of genomic data and karyotype analyses confirmed that M. alba is a diploid with 28 chromosomes (2n = 2x = 28). Population genomic analysis based on resequencing of 134 mulberry accessions classified domesticated mulberry into three geographical groups, namely, Taihu Basin of southeastern China (Hu mulberry), northern and southwestern China, and Japan. Hu mulberry had the lowest nucleotide diversity among these accessions and demonstrated obvious signatures of selection associated with environmental adaptation. Further phylogenetic analysis supports a previous proposal that multiple domesticated mulberry accessions previously classified as different species actually belong to one species. This study expands our understanding of genome evolution of the genus Morus and population structure of domesticated mulberry, which would facilitate mulberry breeding and improvement.