Development of a novel sialic acid-conjugated camptothecin prodrug for enhanced cancer chemotherapy.

Camptothecin (CPT) is an attractive natural drug for cancer chemotherapy. However, the poor water solubility, non-targeting feature, and adverse side effects of CPT are significant obstacles to developing an effective anticancer drug. Here, for the first time, 9-thiol-sialic acid (9-SH-Sia) is coupled to CPT by forming a disulfide releasable carbonate linkage, resulting in a novel CPT prodrug (CPT-ss-Sia) that self-assembles into nanostructures in an aqueous solution. Strikingly, CPT-ss-Sia exhibited excellent in vitro properties, including enhanced water solubility, glutathione (GSH)-triggered CPT release, and increased E-lactone ring stability. Furthermore, CPT-ss-Sia had good cancer cell-killing ability comparable to CPT. Intravenous administration of CPT-ss-Sia significantly inhibited the growth of multiple types of tumors. Histological analysis showed that CPT-ss-Sia treatment significantly reduced lesions in tumor-bearing mice compared to CPT treatment. Notably, CPT-ss-Sia treatment did not adversely affect the body weight of the mice. This is the first report of the 9-SH-Sia conjugate-based prodrug. Overall, CPT-ss-Sia has broad clinical application prospects.

miR-140-3P Induces Chemotherapy Resistance in Esophageal Carcinoma by Targeting the NFYA-MDR1 Axis.

Esophageal carcinoma (EC) is recognized as the 6th most frequent carcinoma in China, with esophageal squamous cell carcinoma (ESCC) being the predominant histologic type. Currently, chemotherapy is one among the most important therapy modalities for patients with ESCC. However, resistance to chemotherapeutic drugs leads to limited treatment options and poor prognosis. In our study, the analysis of small RNA sequencing and digital gene expression (DGE) profiling was done to recognize the microRNAs (miRNAs) and key genes related with drug resistance in ESCC. It was noticed that the hsa-miRNA-140-3p (miR-140-3p) expression was considerably higher in drug-resistant cells than in sensitive cells. In addition, DGE identified target genes of miR-140-3p might perform key roles in ESCC. Furthermore, this work exhibited that miR-140-3p represents the nuclear transcription factor Y subunit alpha (NFYA) gene by targeting its 3'-untranslated regions. Such an interaction might influence the formation of the transcription factor NFY trimer, which in turn may inhibit the transcription of the multidrug resistance 1 gene and, ultimately, to multidrug resistance in ESCC. The inhibition of miR-140-3p decreased resistance to oxaliplatin in EC. Therefore, miR-140-3p may serve as a molecular marker for treatment response, efficacy, and prognosis of chemotherapy in ESCC patients.

Synthesis of sialic acid conjugates of the clinical near-infrared dye as next-generation theranostics for cancer phototherapy.

Cancer is a multifaceted global health problem that requires continuous action to develop next-generation cancer theranostics. Inspired by the emerging use of indocyanine green (ICG), the only clinically approved near-infrared (NIR) dye for cancer phototherapy, here we synthesized two ICG conjugate theranostics by coupling ICG to sialic acid (Sia) through the C2 and C9 positions of Sia, respectively, referred to as Sia-C2-ICG and Sia-C9-ICG. Encouragingly, Sia-C2/C9-ICGs show superior in vitro properties, including enhanced stability, reduced non-specific binding to serum proteins, and improved blood compatibility, highlighting the benefits of Sia coupling. Notably, in vivo NIR imaging shows that Sia-C9-ICG significantly promotes tumor targeting and effectively prolongs the circulation time in the body, while Sia-C2-ICG is superior to ICG but inferior to Sia-C9-ICG in targeting tumors. Furthermore, Sia-C9-ICG combined with NIR laser irradiation can lead to excellent photothermal and photodynamic therapies for cancer cells, resulting in superior solid tumor ablation. To our knowledge, this is the first report of Sia-NIR conjugates achieving significant tumor reduction in vivo. Together, these advances render Sia-C9-ICG an attractive lead as next-generation cancer theranostics that can be translated clinically to treat human patients.

Palbociclib Enhances Migration and Invasion of Cancer Cells via Senescence-Associated Secretory Phenotype-Related CCL5 in Non-Small-Cell Lung Cancer.

Palbociclib is the first CDK4/6 inhibitor approved by FDA and has been studied in many types of cancer. However, some studies showed that it could induce epithelial-mesenchymal transition (EMT) of cancer cells. To test the effect of palbociclib on non-small-cell lung cancer (NSCLC) cells, we treated NSCLC cells with different concentrations of palbociclib and detected its effects via MTT, migration and invasion assays, and apoptosis test. Further RNA sequencing was performed in the cells treated with 2 µM palbociclib or control. And Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and protein-protein interaction network (PPI) were analyzed to explore the mechanism of palbociclib. The results showed that palbociclib significantly inhibited the growth of NSCLC cells and promoted apoptosis of cells, however, enhanced the migration and invasion abilities of cancer cells. RNA sequencing showed that cell cycle, inflammation-/immunity-related signaling, cytokine-cytokine receptor interaction, and cell senescence pathways were involved in the process, and CCL5 was one of the significantly differential genes affected by palbociclib. Further experiments showed that blocking CCL5-related pathways could reverse the malignant phenotype induced by palbociclib. Our results revealed that palbociclib-induced invasion and migration might be due to senescence-associated secretory phenotype (SASP) rather than EMT and suggested that SASP could act as a potential target to potentiate the antitumor effects of palbociclib in cancer treatment.

Atypical Response in Metastatic Non-Small Cell Lung Cancer Treated with PD-1/PD-L1 Inhibitors: Radiographic Patterns and Clinical Value of Local Therapy.

PURPOSE: To explore the clinical characteristics, management, and survival outcomes of advanced NSCLC patients treated with PD-1/PD-L1 inhibitors who presented with an atypical response (AR). METHODS: A total of 926 PD-1/PD-L1-inhibitor-treated patients with metastatic NSCLC from three academic centers were retrospectively reviewed. All measurable lesions were evaluated by RECIST version 1.1. RESULTS: Fifty-six (6.1%) patients developed AR. The median time to the occurrence of AR was 2.0 months. Patients with no fewer than 3 metastatic organs at baseline were more prone to develop AR in advanced NSCLC (p = 0.038). The common sites of progressive lesions were lymph nodes (33.8%) and lungs (29.7%). The majority (78.2%) of patients with AR had only 1-2 progressive tumor lesions, and most (89.1%) of the progressive lesions developed from originally existing tumor sites. There was no significance in terms of survival between patients with AR and those with typical response (TR). Local therapy was an independent predictor for PFS of patients with AR (p = 0.025). CONCLUSIONS: AR was not an uncommon event in patients with metastatic NSCLC treated with PD-1/PD-L1 inhibitors, and it had a comparable prognosis to those with TR. Proper local therapy targeting progressive lesions without discontinuing original PD-1/PD-L1 inhibitors may improve patient survival.

Developing Acid-Responsive Glyco-Nanoplatform Based Vaccines for Enhanced Cytotoxic T-lymphocyte Responses Against Cancer and SARS-CoV-2.

Cytotoxic T-lymphocytes (CTLs) are central for eliciting protective immunity against malignancies and infectious diseases. Here, for the first time, partially oxidized acetalated dextran nanoparticles (Ox-AcDEX NPs) with an average diameter of 100 nm are fabricated as a general platform for vaccine delivery. To develop effective anticancer vaccines, Ox-AcDEX NPs are conjugated with a representative CTL peptide epitope (CTLp) from human mucin-1 (MUC1) with the sequence of TSAPDTRPAP (referred to as Mp1) and an immune-enhancing adjuvant R837 (referred to as R) via imine bond formation affording AcDEX-(imine)-Mp1-R NPs. Administration of AcDEX-(imine)-Mp1-R NPs results in robust and long-lasting anti-MUC1 CTL immune responses, which provides mice with superior protection from the tumor. To verify its universality, this nanoplatform is also exploited to deliver epitopes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to prevent coronavirus disease 2019 (COVID-19). By conjugating Ox-AcDEX NPs with the potential CTL epitope of SARS-CoV-2 (referred to as Sp) and R837, AcDEX-(imine)-Sp-R NPs are fabricated for anti-SARS-CoV-2 vaccine candidates. Several epitopes potentially contributing to the induction of potent and protective anti-SARS-CoV-2 CTL responses are examined and discussed. Collectively, these findings shed light on the universal use of Ox-AcDEX NPs to deliver both tumor-associated and virus-associated epitopes.

Synthesis of Carbon Quantum Dot Nanoparticles Derived from Byproducts in Bio-Refinery Process for Cell Imaging and In Vivo Bioimaging.

The carbon quantum dot (CQD), a fluorescent carbon nanoparticle, has attracted considerable interest due to its photoluminescent property and promising applications in cell imaging and bioimaging. In this work, biocompatible, photostable, and sustainably sourced CQDs were synthesized from byproducts derived from a biorefinery process using one-pot hydrothermal treatment. The main components of byproducts were the degradation products (autohydrolyzate) of biomass pretreated by autohydrolysis. The as-synthesized CQDs had a size distribution from 2.0⁻6.0 nm and had high percentage of sp² and sp³ carbon groups. The CQDs showed blue-green fluorescence with a quantum yield of ~13%, and the fluorescence behaviors were found to be stable with strong resistance to photobleaching and temperature change. In addition, it is found that the as-synthesized CQDs could be used for imaging of cells and tumors, which show potential applications in bioimaging and related fields such as phototherapy and imaging.