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Stimuli responsive polymers are an efficient means of targeted therapy.  Compared to conventional agents, they increase bioavailability and efficacy.  In particular, polymer hydrogel nanoparticles (NPs) can be designed to respond when exposed to a specific environmental stimulus such as pH or temperature. However, targeting a specific metabolite as the trigger for stimuli response could further elevate selectivity and create a new class of bioresponsive materials.  In this work we describe an N-isopropylacrylamide (NIPAm) NP that responds to a specific metabolite characteristic of a hypoxic environment found in cancerous tumors.  NIPAm NPs were synthesized by copolymerization with an oxamate derivative, a known inhibitor of lactate dehydrogenase (LDH).  The oxamate functionalized NPs (OxNP) efficiently sequestered LDH to produce an OxNP-protein complex.  When exposed to elevated concentrations of lactic acid, a substrate of LDH and a metabolite characteristic of hypoxic tumor microenvironments, OxNP-LDH complexes swelled (65%).  The OxNP-LDH complexes were not responsive to structurally related small molecules.  This work demonstrates a proof of concept for tuning NP responsiveness by conjugation with a key protein to target a specific metabolite of disease.

Peptide and protein-based cancer vaccines usually fail to elicit efficient immune responses against tumors. However, delivery of these peptides and proteins as components within caged protein nanoparticles has shown promising improvements in vaccine efficacy. Advantages of protein nanoparticles over other vaccine platforms include their highly organized structures and symmetry, biodegradability, ability to be specifically functionalized at three different interfaces (inside and outside the protein cage, and between subunits in macromolecular assembly), and ideal size for vaccine delivery. In this review, we discuss different classes of virus-like particles and caged protein nanoparticles that have been used as vehicles to transport and increase the interaction of cancer vaccine components with the immune system. We review the effectiveness of these protein nanoparticles towards inducing and elevating specific immune responses, which are needed to overcome the low immunogenicity of the tumor microenvironment.

Photodynamic therapy shows promise for glioma treatment with powerful efficacy and low resistance, however, its effectiveness is significantly lowered by inadequate light delivery through the skull. Herein, a needle‐type implantable microLED device and cathepsin B‐responsive prodrug nanoparticles (PNPs) are newly exploited for glioma's chemo‐photodynamic combination therapy. The microLED containing four small LEDs on the tip of its guide needle can be implanted into the center of glioma tissues without large area opening of skull, uniformly irradiating light to deep glioma tissues. PNPs are formulated via self‐assembly of heterobifunctional prodrug composed of doxorubicin, verteporfin, and cathepsin B‐cleavable peptide linker, wherein they stably maintain inactive nanoparticle structures in normal physiological conditions and specifically deliver therapeutic age to cathepsin B‐overexpressed glioma tissues. In vitro cellular assays, PNPs irradiated with showed the synergistic cytotoxicity of DOX and VFP only in cathepsin B‐overexpressed cancer cells rather than normal cells. In tumor‐bearing mice, PNPs showed high tumor accumulation via the nanoparticle‐driven enhanced permeation and retention (EPR) effect and they also exhibited remarkable therapeutic efficacy against glioma under microLED‐mediated light irradiation via chemo‐photodynamic combination therapy. Accordingly, applying microLED with PNPs is an outstanding strategy to defeat glioma with cooperative chemo‐photodynamic effects, minimal invasiveness, and desirable systemic/local safety. [ABSTRACT FROM AUTHOR]

Background/Aims: The impact of vaccination on inflammatory bowel disease (IBD) patients is still unknown, and no studies have assessed the changes in patient-reported outcomes (PROs) after vaccination in patients with IBD. Therefore, in this study, we investigated the impact of vaccines on the PROs of patients with IBD. Methods: We conducted a questionnaire survey of patients with IBD who visited outpatient clinics at 4 specialized IBD clinics of referral university hospitals from April 2022 to June 2022. A total of 309 IBD patients were included in the study. Patient information was collected from a questionnaire and their medical records, including laboratory findings, were reviewed retrospectively. Risk factors associated with an increase in PROs after COVID-19 vaccination were analyzed using logistic regression analyses. In addition, we assessed whether there were differences in variables by vaccine order using the linear mixed model. Results: In multivariate analysis, young age (< 40 years) and ulcerative colitis (UC) were found to be independent risk factors for aggravation of PROs in patients with IBD. In all patients, platelet count significantly increased with continued vaccination in multiple pairwise comparisons. In UC patients, PROs such as the short health scale, UC-abdominal signs and symptoms, and UC-bowel signs and symptoms were aggravated significantly with continued vaccination. There was no significant increase in the variables of patients with Crohn's disease. Conclusions: Therefore, there may be a need to counsel patients with IBD younger than 40 years of age, and patients with UC before they receive COVID-19 vaccinations. [ABSTRACT FROM AUTHOR]

Nanoparticles have attracted considerable interest as cancer vaccine delivery vehicles for inducing sufficient CD8+ T cell-mediated immune responses to overcome the low immunogenicity of the tumor microenvironment. Our studies described here are the first to examine the effects of clinically-tested human cancer-testis (CT) peptide epitopes within a synthetic nanoparticle. Specifically, we focused on two significant clinical CT targets, the HLA-A2 restricted epitopes of NY-ESO-1 and MAGE-A3, using a viral-mimetic packaging strategy. Our data shows that simultaneous delivery of a NY-ESO-1 epitope (SLLMWITQV) and CpG using the E2 subunit assembly of pyruvate dehydrogenase (E2 nanoparticle), resulted in a 25-fold increase in specific IFN-γ secretion in HLA-A2 transgenic mice. This translated to a 15-fold increase in lytic activity toward target cancer cells expressing the antigen. Immunization with a MAGE-A3 epitope (FLWGPRALV) delivered with CpG in E2 nanoparticles yielded an increase in specific IFN-γ secretion and cell lysis by 6-fold and 9-fold, respectively. Furthermore, combined delivery of NY-ESO-1 and MAGE-A3 antigens in E2 nanoparticles yielded an additive effect that increased lytic activity towards cells bearing NY-ESO-1+ and MAGE-A3+. Our investigations demonstrate that formulation of CT antigens within a nanoparticle can significantly enhance antigen-specific cell-mediated responses, and the combination of the two antigens in a vaccine can preserve the increased individual responses that are observed for each antigen alone.

Background and Aim: Although age at disease onset is considered to be a significant factor in the prognosis of Crohn's disease, little is known about its influence on the long‐term prognosis of those with intestinal Behçet's disease (BD). This study aimed to evaluate the long‐term clinical outcomes of patients with intestinal BD according to age of disease onset. Methods: Patients diagnosed with intestinal BD at < 18, 18–60, and > 60 years of age were classified into early‐onset, adult‐onset, and late‐onset groups, respectively. The influence of disease onset time on clinical prognosis, including specific medical requirements, BD‐related intestinal surgery, hospitalization, and emergency room visits, was compared using the log–rank test in a large cohort of patients with intestinal BD. Results: Among 780 patients, 21 (2.7%), 672 (86.2%), and 87 (11.1%) comprised the early‐onset, adult‐onset, and late‐onset groups, respectively. Patients in the early‐onset group were more likely to require immunosuppressants than those in the adult‐onset group (P = 0.048). Nine (42.9%), 158 (23.5%), and 18 (20.7%) patients in the early‐onset, adult‐onset, and late‐onset groups, respectively, underwent intestinal resection. The early‐onset group exhibited a higher risk for intestinal resection than the late‐onset (P = 0.043) and adult‐onset (P = 0.030) groups. The late‐onset group exhibited a higher risk for BD‐related hospitalization than the adult‐onset group (P = 0.023). Conclusions: Age at diagnosis affected the clinical course of intestinal BD, including intestinal surgery, hospitalization, and specific medical requirements. Different treatment strategies should be established according to age at diagnosis. [ABSTRACT FROM AUTHOR]