Immune-modulating peptides have shown potential as novel immune-stimulating agents which enhance the secretion of anticancer cytokines in vitro. However, fast clearance from blood hampers the ability of such peptides to accumulate in the tumour and results in limited therapeutic efficacy in animal studies. To address the fast blood clearance, this work reports the development and validation of a novel polymeric nanoparticle delivery system for the efficient localization of an immunomodulating peptide in the tumour microenvironment (TME). To identify the optimal polymeric nanoparticle for this study, two types of nanoparticles were developed as either branched polymers or micelles that have similar chemical functionality but different sizes. The effect of targeting the nanomedicine to the tumour-specific antigen, glycoprotein GPC-1, was explored using a bispecific antibody (BsAb) that shows an affinity for the cell protein (GPC-1) and the nanoparticle. These systems were evaluated for targeting efficiency and tumour penetration using tumour spheroids of Lewis Lung Cancer (LLC) cells and it was shown that the targeted system significantly enhanced cell association compared to the untargeted control with minor differences in penetration. The lead micelle-peptide conjugates were identified and using in vivo allograft models they were demonstrated to have high delivery efficiency of the peptide to tumours, prolonged blood circulation, enhanced tumour accumulation and tumour suppression that was associated with immune cell recruitment to the tumour.

Linker for activation of T cells (LAT) is an essential adaptor protein in early T cell receptor (TCR) signaling that propagates multiple signaling pathways. However, how LAT spatial organization facilitates signal initiation and propagation after TCR triggering is not clear. To differentiate de novo assembly in the plasma membrane from pre-existing LAT vesicles and clusters, we developed imaging protocols and analyses to capture the organization and dynamics of single LAT molecules immediately after TCR engagement. We could observe individual LAT molecules in the plasma membrane that assembled into immobile signaling entities requiring LAT phosphorylation. This step-wise assembly process was temporally highly coordinated via the zeta-chain-associated protein kinase 70 (Zap70)-LAT-growth factor receptor-bound protein 2 (Grb2) pathway. While multiple spatial organization co-existed even within the plasma membrane, our data suggest that de novo plasma membrane assemblies facilitated signal propagation.

AbstractIn this contribution, we designed a new xanthate RAFT agent by introducing (5,6,7,8‐tetrahydro‐2‐naphthalenyl)oxy (TNO) as the Z group, namely 2‐[(((5,6,7,8‐Tetrahydro‐2‐naphthalenyl)oxycarbonothioyl)thio)ethyl propanoate] (TNXEP). Due to the presence of the TNO group, TNXEP enabled highly controlled and ultrafast photoiniferter RAFT polymerization under violet (λ=405 nm) and blue (λ=450 nm) light. This approach was effectively extended to aqueous media for polymerization‐induced self‐assembly (PISA), facilitating the synthesis of polymeric nanoparticles. Leveraging the rapid photolysis and extended absorption of TNXEP, we demonstrated the first photoiniferter PISA system realizing ultrafast polymerization (>90 % monomer conversion in minutes) under visible light irradiation. Enhanced visible light penetration improved photopolymerization uniformity, enabling rapid and scalable production of polymeric nanoparticles at a 30 g scale in just 10 minutes, with tunable morphologies, including spheres, worms, and vesicles.

In this contribution, we designed a new xanthate RAFT agent by introducing (5,6,7,8-tetrahydro-2-naphthalenyl)oxy (TNO) as the Z group, namely 2-[(((5,6,7,8-Tetrahydro-2-naphthalenyl)oxycarbonothioyl)thio)ethyl propanoate] (TNXEP). Due to the presence of the TNO group, TNXEP enabled highly controlled and ultrafast photoiniferter RAFT polymerization under violet (λ=405 nm) and blue (λ=450 nm) light. This approach was effectively extended to aqueous media for polymerization-induced self-assembly (PISA), facilitating the synthesis of polymeric nanoparticles. Leveraging the rapid photolysis and extended absorption of TNXEP, we demonstrated the first photoiniferter PISA system realizing ultrafast polymerization (>90 % monomer conversion in minutes) under visible light irradiation. Enhanced visible light penetration improved photopolymerization uniformity, enabling rapid and scalable production of polymeric nanoparticles at a 30 g scale in just 10 minutes, with tunable morphologies, including spheres, worms, and vesicles.

There is currently no reference standard test for the detection of the extra-esophageal manifestations of gastroesophageal reflux disease (GERD). The current suite of diagnostic tests principally assesses reflux events in the esophagus. A new scintigraphic technique has been developed and validated against reference standards. It allows direct visualization of refluxate in the laryngopharynx and lungs. Fifty patients were assessed by scintigraphy before and after fundoplication at a single nuclear medicine facility. Standardized reflux symptomindices (RSIs) were obtained from each patient before and after surgery. Patients were scanned after oral 99 m technetium Fyton administration with early dynamic images and delayed SPECT/CT images of the head, neck, and lungs. ANOVA, Spearman correlation, and the Student's t-test were utilized for analysis. The study population (35F, 15 M) had a mean age of 63.9 years. Mean BMI was 26.8 with 67% being overweight or obese. All patients had significant reflux. SPECT/CT showed LPR events in 45/50 and pulmonary micro-aspiration (PMA) in 45/50 preoperatively and in 36/50 and 20/50 postoperatively, respectively. The RSI, cough, and throat clearing indices showed a significant fall postoperatively (p < 0.001). Frequency of scintigraphic reflux events was reduced from a mean of 4.5 in 30 min to 2.9 (t = 9.1, p = 0.004). The novel scintigraphic test detects esophageal and extra-esophageal reflux events and permits direct visualization of refluxate in the head and neck structures and lungs. It correlates well with symptoms of reflux in the esophagus and extra-esophageal structures and the response to therapy. Although prospective, the study did not randomize patients and in effect each patient became their own control following an intervention (fundoplication). Thus, the study is Level 3 evidence Laryngoscope, 135:73-79, 2025.