Click Chemistry-Mediated Polymannose Surface-Engineering of Natural Killer Cells for Immunotherapy of Triple-Negative Breast Cancer.

Natural killer (NK) cells, serve as the frontline defense of the immune system, and are capable of surveilling and eliminating tumor cells. Their significance in tumor immunotherapy has garnered considerable attention in recent years. However, the absence of specific receptor-ligand interactions between NK cells and tumor cells hampers their selectivity, thereby limiting the therapeutic effectiveness of NK cell-based tumor immunotherapy. Herein, this work constructs polymannose-engineered NK (pM-NK) cells via metabolic glycoengineering and copper-free click chemistry. Polymannose containing dibenzocyclooctyne terminal groups (pM-DBCO) is synthesized and covalently modified on the surface of azido-labeled NK cells. Compared to the untreated NK cells, the interactions between pM-NK cells and MDA-MB-231 cells, a breast tumor cell line with overexpression of mannose receptors (MRs), are significantly increased, and lead to significantly enhanced killing efficacy. Consequently, intravenous administration of pM-NK cells will effectively inhibit the tumor growth and will prolong the survival of mice bearing MDA-MB-231 tumors. Thus, this work presents a novel strategy for tumor-targeting NK cell-based tumor immunotherapy.

Click-Chemistry-Mediated Cell Membrane Glycopolymer Engineering to Potentiate Dendritic Cell Vaccines.

Dendritic cell vaccine (DCV) holds great potential in tumor immunotherapy owing to its potent ability in eliciting tumor-specific immune responses. Aiming at engineering enhanced DCV, we report the first effort to construct a glycopolymer-engineered DC vaccine (G-DCV) via metabolicglycoengineering and copper-free click-chemistry. Model G-DCV was prepared by firstly delivering tumor antigens, ovalbumin (OVA) into dendritic cells (DC) with fluoroalkane-grafted polyethyleneimines, followed by conjugating glycopolymers with a terminal group of dibenzocyclooctyne (DBCO) onto dendritic cells. Compared to unmodified DCV, our G-DCV could induce stronger T cell activation due to the enhanced adhesion between DCs and T cells. Notably, such G-DCV could more effectively inhibit the growth of the mouse B16-OVA (expressing OVA antigen) tumor model after adoptive transfer. Moreover, by combination with an immune checkpoint inhibitor, G-DCV showed further increased anti-tumor effects in treating different tumor models. Thus, our work provides a novel strategy to enhance the therapeutic effectiveness of DC vaccines.

Biocompatible cationic polypeptoids with antibacterial selectivity depending on hydrophobic carbon chain length.

The overuse of antibiotics has triggered a new infection crisis and natural antimicrobial peptides (AMPs) have been extensively studied as an alternative to fight microorganisms. Polypeptoids, or polypeptide-biomimetics, offer similar properties to polypeptides and a highly tunable structure that has been synthesized by various methods such as ring opening polymerization (ROP) using N-carboxyanhydride monomers. Simultaneous high antibacterial activity and biocompatibility of a structure by efficient synthesis is desired in the application of those materials. Herein, a series of cationic polypeptoids (PNBs) with variable side chain lengths was obtained by introducing positive charges to the main chain in one step and preserving the backbone structure, namely polypeptoids (PNBM, PNBE, PNBB) with different end groups (methyl (M), ethyl (E), butyl (B)). To address the issue of infection in interventional biomedical implants, we report cost-effective modified polyurethane (PU) films (PU-PNBM, PU-PNBE, PU-PNBB) as physical-biological synergistic antibacterial surfaces that overcome problems such as steric hindrance and the solubility of the materials. Antibacterial selectivity was achieved by regulating the different side chain lengths. When methyl and ethyl were used as hydrophobic side chains, they can only selectively kill Gram-positive Staphylococcus aureus. PNBB, the most hydrophobic and with a butyl side chain can kill both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus and inhibit the growth of bacterial biofilms. Effective in both solution and modified substrate, its biocompatibility is not compromised while the antibacterial properties are substantially improved. Furthermore, PU-PNBB films demonstrated their potential in vivo antimicrobial efficiency in a model of S. aureus infection established on mouse skin. The synthesis route and the surface modification strategies are convenient, providing a solution to the problem of poor biocompatibility in antimicrobial surface applications and a strategy for the use of peptide polymers for targeted therapy after specific infections in the biomedical field.

Evaluation of MADRS severity thresholds in patients with bipolar depression.

BACKGROUND: The Montgomery-Åsberg Depression Rating Scale (MADRS) is commonly used to assess depression symptom changes in clinical trials; however, the score itself can be difficult to interpret without clinical context. Categories of depression severity corresponding to MADRS total score have not been established for bipolar depression, which was the objective of this study. METHODS: Data were pooled from 3 randomized, double-blind, placebo-controlled trials of cariprazine in patients with bipolar I depression; placebo and cariprazine arms were pooled. An anchor-based approach was used to map MADRS total score to the clinician-rated, 7-category Clinical Global Impression of Severity scale (CGI-S). Spearman's correlation coefficient was used to assess associations between MADRS total and CGI-S scores. Optimal MADRS severity thresholds for each CGI-S category was determined via Youden index using receiver operating characteristic (ROC) analyses. RESULTS: Using data from 1523 patients with bipolar depression, mean MADRS total scores were positively correlated with mean CGI-S scores at week 6 (r = 0.87; P<.0001). Using ROC curves, MADRS severity thresholds corresponding to each CGI-S category were estimated with high sensitivity and specificity: 0-6 for "normal, not at all ill", 7-12 for "borderline mentally ill", 13-18 for "mildly ill", 19-23 for "moderately ill", 24-36 for "markedly ill", 37-39 for "severely ill", and ≥40 for "extremely ill". CONCLUSIONS: Utilizing data from 3 clinical trials of patients with bipolar depression, MADRS severity thresholds were identified. These empirical findings may help clinicians contextualize MADRS results from bipolar clinical research and apply to their practice. TRIAL REGISTRATION: clinicaltrials.gov NCT01396447, NCT02670538, NCT02670551.