Risk factors of hemodialysis catheter dysfunction in patients undergoing continuous renal replacement therapy: a retrospective study.

BACKGROUND: Continuous renal replacement therapy is a relatively common modality applied to critically ill patients with renal impairment. To maintain stable continuous renal replacement therapy, sufficient blood flow through the circuit is crucial, but catheter dysfunction reduces the blood flow by inadequate pressures within the circuit. Therefore, exploring and modifying the possible risk factors related to catheter dysfunction can help to provide continuous renal replacement therapy with minimal interruption. METHODS: Adult patients who received continuous renal replacement therapy at Seoul National University Hospital between January 2019 and December 2021 were retrospectively analyzed. Patients who received continuous renal replacement therapy via a temporary hemodialysis catheter, inserted at the bedside under ultrasound guidance within 12 h of continuous renal replacement therapy initiation were included. RESULTS: A total of 507 continuous renal replacement therapy sessions in 457 patients were analyzed. Dialysis catheter dysfunction occurred in 119 sessions (23.5%). Multivariate analysis showed that less prolonged prothrombin time (adjusted OR 0.49, 95% CI, 0.30-0.82, p = 0.007) and activated partial thromboplastin time (adjusted OR 1.01, 95% CI, 1.00-1.01, p = 0.049) were associated with increased risk of catheter dysfunction. Risk factors of re-catheterization included vascular access to the left jugular and femoral vein. CONCLUSIONS: In critically ill patients undergoing continuous renal replacement therapy, less prolonged prothrombin time was associated with earlier catheter dysfunction. Use of left internal jugular veins and femoral vein were associated with increased risk of re-catheterization compared to the right internal jugular vein.

Comparing the prediction performance of item response theory and machine learning methods on item responses for educational assessments.

To obtain more accurate and robust feedback information from the students' assessment outcomes and to communicate it to students and optimize teaching and learning strategies, educational researchers and practitioners must critically reflect on whether the existing methods of data analytics are capable of retrieving the information provided in the database. This study compared and contrasted the prediction performance of an item response theory method, particularly the use of an explanatory item response model (EIRM), and six supervised machine learning (ML) methods for predicting students' item responses in educational assessments, considering student- and item-related background information. Each of seven prediction methods was evaluated through cross-validation approaches under three prediction scenarios: (a) unrealized responses of new students to existing items, (b) unrealized responses of existing students to new items, and (c) missing responses of existing students to existing items. The results of a simulation study and two real-life assessment data examples showed that employing student- and item-related background information in addition to the item response data substantially increases the prediction accuracy for new students or items. We also found that the EIRM is as competitive as the best performing ML methods in predicting the student performance outcomes for the educational assessment datasets.

Myticusin-beta, antimicrobial peptide from the marine bivalve, Mytilus coruscus.

We isolated and purified an antimicrobial peptide (AMP) from the mantle of the hard-shelled mussel, Mytilus coruscus. The peptide was purified through C18 reversed-phase high-performance liquid chromatography, and displayed antibacterial activity. Total molecular mass of 11,182 Da was determined using matrix-assisted laser desorption ionization time-of-flight mass spectrophotometry. The N-terminal 23-amino acid sequence of its purified peak was obtained through Edman degradation, revealing 82% identity with myticusin-1 of M. coruscus. Complete sequence of the target peptide was determined through cDNA cloning and rapid amplification of cDNA ends. The complete sequence comprised 574 bp with a 387-bp open reading frame (ORF) encoding 24 amino acids of a signal peptide and 104 amino acids of a mature peptide, which was named myticusin-beta. Furthermore, we discovered two novel isoforms of myticusin-beta. We constructed and expressed recombinant myticusin-beta, which displayed antimicrobial activity against gram-positive (Bacillus cereus, Bacillus subtilis, Clostridium perfringens, Staphylococcus aureus, Streptococcus iniae, Streptococcus mutans) and gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Vibrio alginolyticus, Klebsiella pneumoniae). Purified recombinant myticusin-beta also showed anti-parasitic activity at various concentrations. A short AMP analog was designed and synthesized based on the sequence of myticusin-beta, with markedly improved antimicrobial activity. Expression of myticusin-beta was detected in the mantle at the highest level, followed by hemocytes. The results obtained in this work suggest that myticusin-beta is an immune-related AMP of M. coruscus and an effective alternative to antibiotics.

An explanatory item response theory method for alleviating the cold-start problem in adaptive learning environments.

Electronic learning systems have received increasing attention because they are easily accessible to many students and are capable of personalizing the learning environment in response to students' learning needs. To that end, using fast and flexible algorithms that keep track of the students' ability change in real time is desirable. Recently, the Elo rating system (ERS) has been applied and studied in both research and practical settings (Brinkhuis & Maris, 2009; Klinkenberg, Straatemeier, & van der Maas in Computers & Education, 57, 1813-1824, 2011). However, such adaptive algorithms face the cold-start problem, defined as the problem that the system does not know a new student's ability level at the beginning of the learning stage. The cold-start problem may also occur when a student leaves the e-learning system for a while and returns (i.e., a between-session period). Because external effects could influence the student's ability level during the period, there is again much uncertainty about ability level. To address these practical concerns, in this study we propose alternative approaches to cold-start issues in the context of the e-learning environment. Particularly, we propose making the ERS more efficient by using an explanatory item response theory modeling to estimate students' ability levels on the basis of their background information and past trajectories of learning. A simulation study was conducted under various conditions, and the results showed that the proposed approach substantially reduces ability estimation errors. We illustrate the approach using real data from a popular learning platform.

PTPN6 regulates the cell-surface expression of TRPM4 channels in HEK293 cells.

Transient receptor-potential, cation channel, subfamily M, member 4 (TRPM4) channels regulate a variety of physiological and pathological processes; however, their roles as functional channels under diverse conditions remain unclear. In this study, cytosolic protein tyrosine phosphatase non-receptor type 6 (PTPN6) interacted with TRPM4 channels. We confirmed their interaction by performing co-immunoprecipitation (Co-IP) assays following heterologous PTPN6 and TRPM4 channel expression in HEK293 cells. Furthermore, biomolecular fluorescence complementation (BiFC) image analysis confirmed TRPM4-PTPN6 binding. In addition, immunoblotting and Co-IP analyses revealed that TRPM4 expression significantly decreased in the membrane fraction of cells after PTPN6 was silenced with a specific short-hairpin RNA (shRNA-PTPN6). In agreement, TRPM4-induced changes in whole-cell currents were not detected in PTPN6-silenced HEK cells, in contrast to cells transfected with a scrambled RNA (scRNA) or in naïve HEK cells. These data suggest that PTPN6 inhibits TRPM4 channel activity by disrupting TRPM4 expression. Furthermore, TRPM4 channels were expressed in the membrane of naïve cells and scRNA transfectants, but not in those of PTPN6-silenced cells. These results indicated that PTPN6 is critically associated with TRPM4 trafficking. This role of PTPN6 in TRPM4 membrane localization was also demonstrated in HeLa cells. TRPM4 overexpression significantly enhanced cell proliferation in untreated HeLa cells, but not in HeLa cells with silenced PTPN6 expression. These findings indicate that PTPN6-dependent TRPM4 expression and trafficking to the plasma membrane is critical for cell proliferation in both HEK293 and HeLa cells. Therefore, PTPN6 is a novel therapeutic target for treating pathologic diseases involving TRPM4.

Fidelity Criteria Development: Aligning Paralympic School Day With Contact Theory.

The purpose of this study was to address contact theory as the theoretical basis of the Paralympic School Day (PSD) disability awareness program using a newly created fidelity of implementation instrument (fidelity criteria) to measure a single construct (contact theory), seeking to control and explain the manner in which PSD satisfied the four components of contact theory. Participants were 145 sixth-grade students who took part in PSD. Results determined that the PSD intervention supported the four theoretical components of contact theory, with statistically significant differences in student responses across all four indicators (p < .001). In addition, results determined that the fidelity criteria had strong test-retest reliability with internal consistency that was strong across time points (r = .829; p < .001). Results also determined that the four indicators of the instrument measured a single construct (one indicator significant at the p ≤ .01 level and three indicators significant at the p ≤ .001 level), thus, determining strong construct validity.

Prenatal prediction of neonatal death in single ventricle congenital heart disease.

OBJECTIVE: The objective of this study was to determine whether prenatal ultrasound findings and cord blood N-terminal pro-B-type natriuretic peptide (NT pro-BNP) and cardiac troponin T (cTnT) can predict neonatal mortality in single ventricle congenital heart disease. METHODS: The association between neonatal mortality and prenatal ultrasound findings/cord blood biomarkers was evaluated in neonates delivered with a diagnosis of single ventricle congenital heart disease. The presence of prenatal ultrasound findings suggesting systemic outflow obstruction (ascending aorta < 2.5 percentile) or ventricular dysfunction (the presence of cardiomegaly or hydrops) was evaluated, and the total number of abnormal findings was converted to a numeric score called the 'single ventricle score'. In addition, NT pro-BNP and cTnT were measured in cord blood taken at the time of delivery. RESULTS: A total of 48 cases of single ventricle congenital heart disease were included. The rate of neonatal mortality was 31% (15/48). The presence of either abnormal ultrasound findings (single ventricle score ≥ 2) or elevated concentrations of NT pro-BNP or cTnT was associated with increased risk of neonatal death. CONCLUSION: The presence of either abnormal prenatal ultrasound findings or increased cord blood NT pro-BNP and cTnT concentrations was associated with the risk of neonatal death in single ventricle congenital heart disease.

The Impact of Paralympic School Day on Student Attitudes Toward Inclusion in Physical Education.

The purpose of this study was to determine if Paralympic School Day (PSD), a published disability awareness program, would have a positive impact on the attitudes of students without disabilities toward the inclusion of students with disabilities in physical education classes. Participants were 143 sixth-grade students who were divided into 2 groups (experimental n = 71, control n = 72), with the experimental group receiving the PSD treatment. Participants responded 2 times to Siperstein's Adjective Checklist and Block's Children's Attitudes Toward Integrated Physical Education-Revised (CAIPE-R) questionnaire. Four ANCOVA tests were conducted. Results indicated a significant PSD treatment effect across all 4 measures: Adjective Checklist (p = .046, η² = .03), CAIPE-R (p = .002, η² = .04), inclusion subscale (p = .001, η² = .05), and sport-modification subscale (p = .027, η² = .02).

Self-Assembled Tamoxifen-Selective Fluorescent Nanomaterials Driven by Molecular Structural Similarity.

Most supramolecular systems were discovered by using a trial-and-error approach, leading to numerous synthetic efforts to obtain optimal supramolecular building blocks for selective guest encapsulation. Here, we report a simple coassembly strategy for preparing tamoxifen-selective supramolecular nanomaterials in an aqueous solution. The synthetic amphiphile molecule, 1,1,2,2-tetraphenylethylene (TPE), promotes large tamoxifen aggregate disassembly into smaller, discrete aggregates such as ribbon-like and micellar assemblies in coassembled solutions, enhancing the solubility and dispersion. The TPE moiety exhibits enhanced emission upon tamoxifen interaction, enabling the observation of the coassembled species in an aqueous solution for cell imaging. The tamoxifen-selective fluorescent micelles in the presence of a 1:1 molar ratio of TPE derivative with tamoxifen show enhanced tamoxifen absorption and anticancer effects against MCF-7 breast cancer cells. These supramolecular approaches, based on the coassembly of building blocks with molecular structural similarity, can provide a novel strategy for the efficient development of selective molecular carriers with enhanced biological activities.

Light-Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy.

While proteolysis-targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment via targeted protein degradation, precisely activating them in tumor tissues and preventing uncontrolled proteolysis at off-target sites remain challenging. Herein, a light-triggered PROTAC nanoassembly (LPN) for photodynamic indoleamine 2,3-dioxygenase (IDO) proteolysis is reported. The LPN is derived from the self-assembly of prodrug conjugates, which comprise a PROTAC, cathepsin B-specific cleavable peptide linker, and photosensitizer, without any additional carrier materials. In colon tumor models, intravenously injected LPNs initially silence the activity of PROTACs and accumulate significantly in targeted tumor tissues due to an enhanced permeability and retention effect. Subsequently, the cancer biomarker cathepsin B begins to trigger the release of active PROTACs from the LPNs through enzymatic cleavage of the linkers. Upon light irradiation, tumor cells undergo immunogenic cell death induced by photodynamic therapy to promote the activation of effector T cells, while the continuous IDO degradation of PROTAC simultaneously blocks tryptophan metabolite-regulated regulatory-T-cell-mediated immunosuppression. Such LPN-mediated combinatorial photodynamic IDO proteolysis effectively inhibits tumor growth, metastasis, and recurrence. Collectively, this study presents a promising nanomedicine, designed to synergize PROTACs with other immunotherapeutic modalities, for more effective and safer cancer immunotherapy.

Mucoadhesive Mesalamine Prodrug Nanoassemblies to Target Intestinal Macrophages for the Treatment of Inflammatory Bowel Disease.

While mesalamine, a 5-aminosalicylic acid (5-ASA), is pivotal in the management of inflammatory bowel disease (IBD) through both step-up and top-down approaches in clinical settings, its widespread utilization is limited by low bioavailability at the desired site of action due to rapid and extensive absorption in the upper gastrointestinal (GI) tract. Addressing mesalamine's pharmacokinetic challenges, here, we introduce nanoassemblies composed exclusively of a mesalamine prodrug that pairs 5-ASA with a mucoadhesive and cathepsin B-cleavable peptide. In an IBD model, orally administered nanoassemblies demonstrate enhanced accumulation and sustained retention in the GI tract due to their mucoadhesive properties and the epithelial enhanced permeability and retention (eEPR) effect. This retention enables the efficient uptake by intestinal pro-inflammatory macrophages expressing high cathepsin B, triggering a burst release of the 5-ASA. This cascade fosters the polarization toward an M2 macrophage phenotype, diminishes inflammatory responses, and simultaneously facilitates the delivery of active agents to adjacent epithelial cells. Therefore, the nanoassemblies show outstanding therapeutic efficacy in inhibiting local inflammation and contribute to suppressing systemic inflammation by restoring damaged intestinal barriers. Collectively, this study highlights the promising role of the prodrug nanoassemblies in enhancing targeted drug delivery, potentially broadening the use of mesalamine in managing IBD.

Photonic control of ligand nanospacing in self-assembly regulates stem cell fate.

Extracellular matrix (ECM) undergoes dynamic inflation that dynamically changes ligand nanospacing but has not been explored. Here we utilize ECM-mimicking photocontrolled supramolecular ligand-tunable Azo+ self-assembly composed of azobenzene derivatives (Azo+) stacked via cation-π interactions and stabilized with RGD ligand-bearing poly(acrylic acid). Near-infrared-upconverted-ultraviolet light induces cis-Azo+-mediated inflation that suppresses cation-π interactions, thereby inflating liganded self-assembly. This inflation increases nanospacing of "closely nanospaced" ligands from 1.8 nm to 2.6 nm and the surface area of liganded self-assembly that facilitate stem cell adhesion, mechanosensing, and differentiation both in vitro and in vivo, including the release of loaded molecules by destabilizing water bridges and hydrogen bonds between the Azo+ molecules and loaded molecules. Conversely, visible light induces trans-Azo+ formation that facilitates cation-π interactions, thereby deflating self-assembly with "closely nanospaced" ligands that inhibits stem cell adhesion, mechanosensing, and differentiation. In stark contrast, when ligand nanospacing increases from 8.7 nm to 12.2 nm via the inflation of self-assembly, the surface area of "distantly nanospaced" ligands increases, thereby suppressing stem cell adhesion, mechanosensing, and differentiation. Long-term in vivo stability of self-assembly via real-time tracking and upconversion are verified. This tuning of ligand nanospacing can unravel dynamic ligand-cell interactions for stem cell-regulated tissue regeneration.

Genetic structure of the Korean black scraper Thamnaconus modestus inferred from microsatellite marker analysis.

The Korean black scraper, Thamnaconus modestus, is one of the most economically important maricultural fish species in Korea. However, the annual catch of this fish has been continuously declining over the past several decades. In this study, the genetic diversity and relationships among four wild populations and two hatchery stocks of Korean black scraper were assessed based on 16 microsatellite (MS) markers. A total of 319 different alleles were detected over all loci with an average of 19.94 alleles per locus. The hatchery stocks [mean number of alleles (N(A)) = 12, allelic richness (A(R)) = 12, expected heterozygosity (He) = 0.834] showed a slight reduction (P > 0.05) in genetic variability in comparison with wild populations (mean N(A) = 13.86, A(R) = 12.35, He = 0.844), suggesting a sufficient level of genetic variation in the hatchery populations. Similarly low levels of inbreeding and significant Hardy-Weinberg equilibrium deviations were detected in both wild and hatchery populations. The genetic subdivision among all six populations was low but significant (overall F(ST) = 0.008, P < 0.01). Pairwise F(ST), a phylogenetic tree, and multidimensional scaling analysis suggested the existence of three geographically structured populations based on different sea basin origins, although the isolation-by-distance model was rejected. This result was corroborated by an analysis of molecular variance. This genetic differentiation may result from the co-effects of various factors, such as historical dispersal, local environment and ocean currents. These three geographical groups can be considered as independent management units. Our results show that MS markers may be suitable not only for the genetic monitoring of hatchery stocks but also for revealing the population structure of Korean black scraper populations. These results will provide critical information for breeding programs, the management of cultured stocks and the conservation of this species.

Modulating the folding and binding of peptides using a stimuli-responsive molecular tweezer.

This study presents the development of a ß-hairpin (tryptophan zipper, Trpzip)-based molecular tweezer (MT) that can control the folding and binding of α-helical peptides. When an α-helix isolated from the p53 protein was conjugated with Trpzip in an optimized macrocyclic structure, the folded ß-hairpin stabilized the helix conformation through the side chain-to-side chain stapling strategy, which notably enhanced target (hDM2) affinity of the peptide. On the other hand, the helicity and binding affinity were significantly reduced when the hairpin was unfolded by a redox stimulus. This stimulus-responsive property was translated into the effective capture and release of model multivalent biomaterials, hDM2-gold nanoparticle conjugates. Since numerous protein interactions are mediated by α-helical peptides, these results suggest that the ß-hairpin-based MT holds great potential to be utilized in various biomedical applications, such as protein interaction inhibition and cancer biomarker (e.g., circulating tumor cells and exosomes) detection.

Effect of collector speed and flow rate on morphology of Er doped TiO2 nanofibers.

The 0.5 mol% Er3+ doped TiO2 (Er(3+)-TiO2) nanofibers were synthesized by a sol-gel derived electrospinning and subsequent calcination for 3 h at 500 degrees C in air. The calcined fibers were examined to evaluate the effect of collector speed and flow rate on morphology of the fibers. The dynamic viscosity and surface tension of precursor solution were 34 cP and 22.7 mN/m, respectively. The Er(3+)-TiO2 nanofibers were electrospun horizontally on the drum rotated at 100-500 rpm and flow rate of 0.2-0.5 mL/h under a DC voltage of 10 kV. The grounded collector is a stainless mandrel placed 12 cm away from the tip of the needle. Beads were observed for the nanofibers prepared at flow rates from 0.2 mL/h to 0.5 mL/h when the collector speed was 100 rpm. The nanofibers increased in diameter slightly from 150 nm to 190 nm as the flow rate was raised from 0.2 mLh to 0.5 mL/h. No beads were found at the collector speed of above 300 rpm when the flow rate was 0.2 mL/h. The optimized flow rate and collector speed of the nanofibers were determined to be in the range of 0.2-0.3 mL/h and 300-400 rpm, respectively. Uniform, smooth and continuous fibers with diameters of 150 to 170 nm were detected. Crystallite size determined by the Scherrer formula was about 6 nm. It can be concluded that the collector speed and the flow rate are influential on the morphology of the Er(3+)-TiO2 nanofibers. The Er(3+)-TiO2 nanofibers, prepared at 0.2 mL/h and 300 rpm, had typical absorption peaks located at 490, 523 and 654 nm, corresponding to the transitions from 4I15/2 to 4F7/2, 2H11/2 and 4F9/2, respectively. The Er(3+)-TiO2 nanofibers showed enhanced photoresponses under visible light.

Patterns of intimacy crisis resolution and their associations with romantic loneliness in Polish and U.S. young adults.

In Erikson's model of development, intimacy and isolation denote polar outcomes of psychosocial crisis in young adulthood. Drawing on this model, the present study used three-wave longitudinal data to examine patterns of the success and lack of success in the resolution of Eriksonian crisis in relation to romantic loneliness as a negative outcome of the intimacy crisis, and compared across Poland and the United States. The data were collected from Polish and U.S. individuals aged 18-40 for Wave 1 (N = 763). Four patterns of the Eriksonian intimacy crisis were identified: (a) stable partnered status; (b) stable single status; (c) transition from single to partnered status; (d) transition from partnered to single status. In both countries, transition from single to partnered status was related to decreased romantic loneliness. Greater initial romantic loneliness was observed among Polish single adults who transited to partnered status in contrast to stable single adults. In turn, the U.S. partnered adults who transited to single status initially experienced lower romantic loneliness than stable single adults. Bivariate latent growth curve models pairing romantic loneliness with relationship satisfaction revealed that higher initial relationship satisfaction was associated with lower initial romantic loneliness, and a greater increase in relationship satisfaction was associated with smaller increases in romantic loneliness. The findings highlight that different resolutions of the intimacy crisis are related to diverse romantic loneliness and relationship satisfaction trajectories and these associations also appear to differ as a function of various marital and loneliness contexts in Poland and the United States. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A Joint Modeling Approach for Longitudinal Outcomes and Non-ignorable Dropout under Population Heterogeneity in Mental Health Studies.

The paper proposes a joint mixture model to model non-ignorable drop-out in longitudinal cohort studies of mental health outcomes. The model combines a (non)-linear growth curve model for the time-dependent outcomes and a discrete-time survival model for the drop-out with random effects shared by the two sub-models. The mixture part of the model takes into account population heterogeneity by accounting for latent subgroups of the shared effects that may lead to different patterns for the growth and the drop-out tendency. A simulation study shows that the joint mixture model provides greater precision in estimating the average slope and covariance matrix of random effects. We illustrate its benefits with data from a longitudinal cohort study that characterizes depression symptoms over time yet is hindered by non-trivial participant drop-out.

Psychometric Analysis of the Dating Anxiety Scale for Adolescents in Samples of Polish and U.S. Young Adults: Examining the Factor Structure, Measurement Invariance, Item Functioning, and Convergent Validity.

This study explored whether the Dating Anxiety Scale for Adolescents (DAS-A), which was originally developed in the United States to assess dating anxiety in adolescents, is appropriate for use in samples of young adults from Poland and the United States. The factor structure, measurement invariance across country, gender and relationship status, degree of precision across latent levels of the DAS and the functioning of individual items, and convergent validity were examined in a sample of 309 Polish and 405 U.S. young adults. The confirmatory factor analysis (CFA) supported the original three-factor measurement model of the DAS. Invariance tests revealed factor loadings and item thresholds that differed across subgroups, supporting partial metric and partial scalar invariance. The MIRT analysis showed that all items adequately discriminated participants with low and high anxiety. Dating anxiety latent factor correlations with mental health and interpersonal competence were significant in the expected negative directions. The results call for careful interpretation of research involving the DAS in cultural, gender, and relationship status groups, particularly when the primary goal is to compare mean levels of dating anxiety. Further development of the scale is recommended before it can be used across country, gender, and relationship status groups.

Selective Anticancer Materials by Self-Assembly of Synthetic Amphiphiles Based on N-Acetylneuraminic Acid.

N-Acetylneuraminic acid (Neu5Ac), one of the abundant types of sialic acid, is an emerging anticancer agent owing to its ability to target selectins in the plasma membrane of cancer cells. Considering the functionality of Neu5Ac, obtaining novel Neu5Ac-conjugated materials with a selective and an enhanced antitumor activity has remained a challenge. Herein, we report the supramolecular materials of three novel amphiphiles composed of Neu5Ac as a hydrophilic segment and pyrene or adamantane as a hydrophobic segment. The synthetic amphiphiles 1, 2, and 3 self-assembled into ribbons, vesicles, and irregular aggregates in an aqueous solution, respectively. Among the materials, vesicles of amphiphile 2 showed the most substantial selectivity toward cancer cells, followed by cell death due to the production of reactive oxygen species by the pyrene group. The dual advantage of Neu5Ac-selectivity and the pyrene-cytotoxicity of vesicles of amphiphile 2 can provide a strategy for effective anticancer materials.

Anti-PD-L1 peptide-conjugated prodrug nanoparticles for targeted cancer immunotherapy combining PD-L1 blockade with immunogenic cell death.

Rationale: Cancer immunotherapy combining immune checkpoint blockade (ICB) with chemotherapeutic drugs has provided significant clinical advances. However, such combination therapeutic regimen has suffered from severe toxicity of both drugs and low response rate of patients. In this study, we propose anti-PD-L1 peptide-conjugated prodrug nanoparticles (PD-NPs) to overcome these obstacles of current cancer immunotherapy. Methods: The functional peptide, consisted of anti-PD-L1 peptide and cathepsin B-specific cleavable peptide, is conjugated to a doxorubicin (DOX), resulting in prodrug nanoparticles of PD-NPs via intermolecular interactions. The antitumor efficacy and immune responses with minimal side effects by PD-NPs combining PD-L1 blockade and ICD are evaluated in breast tumor models. Results: The PD-NPs are taken up by PD-L1 receptor-mediated endocytosis and then induce ICD in cancer cells by DOX release. Concurrently, PD-L1 blockade by PD-NPs disrupt the immune-suppressing pathway of cancer cells, resulting in proliferation and reinvigoration of T lymphocytes. In tumor models, PD-NPs accumulate within tumor tissues via enhanced permeability and retention (EPR) effect and induce immune-responsive tumors by recruiting a large amount of immune cells. Conclusions: Collectively, targeted tumor delivery of anti-PD-L1 peptide and DOX via PD-NPs efficiently inhibit tumor progression with minimal side effects.