Identification of hub modules and therapeutic targets associated with CD8+T-cells in HF and their pan-cancer analysis.

Heart failure (HF) is a terminal condition of multiple cardiovascular disorders. Cancer is a deadly disease worldwide. The relationship between HF and cancer remains poorly understood. The Gene Expression Omnibus database was used to download the RNA sequencing data of 356 patients with hypertrophic cardiomyopathy-induced HF and non-HF. A co-expression network was established through the weighted correlation network analysis (WGCNA) to identify hub genes of HF and cancer. Cox risk analysis was performed to predict the prognostic risks of HF hub genes in pan-cancer. HF was linked to immune response pathway by the analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A positive correlation was observed between the expression levels of 4 hub genes and the infiltration of CD8+T-cells in pan-cancer. 4 hub genes were identified as beneficial prognostic factors in several cancers. Western blotting and real-time polymerase chain reaction validated the high expression of GZMM, NKG7, and ZAP70 in both mice and patients with HF compared to control groups. Our study highlights the shared immune pathogenesis of HF and cancer and provides valuable insights for developing novel therapeutic strategies, offering new opportunities for improving the management and treatment outcomes of both HF and cancer.

Highly functional duodenal stent with photosensitizers enables photodynamic therapy for metabolic syndrome treatment: Feasibility and safety study in a porcine model.

Duodenal mucosal resurfacing (DMR) by thermal ablation of the duodenal mucosa is a minimally invasive endoscopic procedure for controlling metabolic syndrome (MS). However, thermal energy can cause adverse effects due to deep mucosal injury, necessitating an additional mucosal lifting process, which complicate the procedures. Therefore, we aimed to develop a similar procedure using non-thermal photodynamic therapy (PDT) for DMR using a highly functional metal stent covered with photosensitizers (PSs) to minimize the potential risks of thermal ablation injury. We developed a novel PS stent enabling the controlled release of radical oxygen species with specific structures to prevent stent migration and duodenal stricture after ablation and performed an animal study (n = 8) to demonstrate the feasibility and safety of PDT for DMR. The stents were placed for 7 days to prevent duodenal strictures after PDT. To confirm PDT efficacy, we stained for gastric inhibitory polypeptide (GIP) and glucose transporter isoform 1. The PS stents were deployed, and PDT was applied without evidence of duodenal stricture, pancreatitis, or hemorrhage in any of the pigs. Microscopic evaluation indicated apoptosis of the mucosal cells in the irradiated duodenum on days 7 and 14, which recovered after day 28. Immunohistochemistry revealed suppressed GIP expression in the mucosal wall of the irradiated duodenum. Endoscopic PDT for DMR using PS stents could be applied safely in a porcine model and may result in decreased GIP secretion, which is a crucial mechanism in MS treatment. Further clinical studies are required to explore its safety and efficacy in patients with MS.

Human adipose-derived stem cells genetically programmed to induce necroptosis for cancer immunotherapy.

Herein, we present human adipose-derived stem cells (ADSCs) inserted with the receptor-interacting protein kinase-3 (RIP3) gene (RP@ADSCs), which induces cell necroptosis, for tumor immunotherapy. Necroptosis has characteristics of both apoptosis, such as programmed cell death, and necrosis, such as swelling and plasma membrane rupture, during which damage-related molecular patterns are released, triggering an immune response. Therefore, necroptosis has the potential to be used as an effective anticancer immunotherapy. RP@ADSCs were programmed to necroptosis after a particular time after being injected in vivo, and various pro-inflammatory cytokines secreted during the stem cell death process stimulated the immune system, showing local and sustained anticancer effects. It was confirmed that RIP3 protein expression increased in ADSCs after RP transfection. RP@ADSCs continued to induce ADSCs death for 7 days, and various pro-inflammatory cytokines were secreted through ADSCs death. The efficacy of RP@ADSCs-mediated immunotherapy was evaluated in mouse models bearing GL-26 (glioblastoma) and K1735 (melanoma), and it was found that RP resulted in an increase in the population of long-term cytotoxic T cells and a decrease in the population of regulatory T cells. This shows that RP@ADSCs have potential and applicability as an excellent anticancer immunotherapy agent in clinical practice.

Comparison of early visual outcomes after SMILE using VISUMAX 800 and VISUMAX 500 for myopia: a retrospective matched case-control study.

VISUMAX 800 was introduced to improve the patient experience and clinical outcomes of small incision lenticule extraction (SMILE). This was a retrospective, matched, and case-control study (1:2) controlled for preoperative central corneal thickness and refractive error that compared early refractive and visual outcomes after SMILE using VISUMAX 800 and VISUMAX 500 to treat myopia. We included 50 eyes that underwent the VISUMAX 800 SMILE and 100 eyes that underwent the VISUMAX 500 SMILE. SMILE using VISUMAX 800 was performed using the CentraLign aid for vertex centration. Cyclotorsion was controlled by an OcuLign assistant in the VISUMAX 800 group after corneal marking. Corneal higher-order aberrations (HOAs) were evaluated using a Pentacam 1 month after surgery. No differences were observed in the pre- and post-operative refractive and visual outcomes at 1 day, 1 month, and 6 months after surgery. VISUMAX 800 induced less total HOAs than VISUMAX 500 (P = 0.036). No statistically significant differences were observed in the amounts of induced spherical aberrations or vertical and horizontal comas. No differences were observed in the 1 month and 6 months refractive and visual outcomes between two SMILE procedures, except for VISUMAX 800, which resulted in lower postoperative total HOAs than VISUMAX 500.

Identification of memory mechanism in tissue-resident stem cells via ANGPTL4 beyond immune cells upon viral antigen exposure.

Although memory functions of immune cells characterized by increased resistance to subsequent infections after initial pathogen exposure are well-established, it remains unclear whether non-immune cells, especially tissue-resident stem cells, exhibit similar memory mechanisms. The present study revealed that detrimental effects of initial viral antigen exposure (human papillomavirus [HPV]) on diverse stem cell functions were significantly exacerbated upon subsequent secondary exposure both in vitro and in vivo. Importantly, endometrial stem cells exhibited robust memory functions following consecutive HPV antigen exposures, whereas fully differentiated cells such as fibroblasts and vesicular cells did not show corresponding changes in response to the same antigen exposures. Deficiency of angiopoietin-like 4 (ANGPTL4) achieved through small hairpin RNA knockdown in vitro and knockout (KO) mice in vivo highlighted the critical role of ANGPTL4 in governing memory functions associated with various stem cell processes. This regulation occurred through histone H3 methylation alterations and PI3K/Akt signaling pathways in response to successive HPV antigen exposures. Furthermore, memory functions associated with various stem cell functions that were evident in wild-type mice following consecutive exposures to HPV antigen were not observed in ANGPTL4 KO mice. In summary, our findings strongly support the presence of memory mechanism in non-immune cells, particularly tissue-resident stem cells.

Localized Photodynamic Therapy Using a Chlorin e6-Embedded Silicone-Covered Self-Expandable Metallic Stent as a Palliative Treatment for Malignant Esophageal Strictures.

Localized photodynamic therapy (PDT) uses a polymeric-photosensitizer (PS)-embedded, covered self-expandable metallic stent (SEMS). PDT is minimally invasive and a noteworthy potential alternative for treating esophageal strictures, where surgery is not a viable option. However, preclinical evidence is insufficient, and optimized irradiation energy dose ranges for localized PDT are unclear. Herein, we validated the irradiation energy doses of the SEMS (embedded in a PS using chlorin e6 [Ce6] and covered in silicone) and PDT-induced tissue changes in a rat esophagus. Cytotoxicity and phototoxicity in the Ce6-embedded SEMS piece with laser irradiation were significantly higher than that of the silicone-covered SEMS with or without laser and the Ce6-embedded silicone-covered SEMS without laser groups (all p < 0.001). Moreover, surface morphology, atomic changes, and homogeneous coverage of the Ce6-embedded silicone-covered membrane were confirmed. The ablation range of the porcine liver was proportionally increased with the irradiation dose (all p < 0.001). The ablation region was identified at different irradiation energy doses of 50, 100, 200, and 400 J/cm2. The in vivo study in the rat esophagus comprised a control group and 100, 200, and 400 J/cm2 energy-dose groups. Finally, histology and immunohistochemistry (TUNEL and Ki67) confirmed that the optimized Ce6-embedded silicone-covered SEMS with selected irradiation energy doses (200 and 400 J/cm2) effectively damaged the esophageal tissue without ductal perforation. The polymeric PS-embedded silicone-covered SEMS can be easily placed via a minimally invasive approach and represents a promising new approach for the palliative treatment of malignant esophageal strictures.

Intranasal mRNA Delivery via Customized RNA-Polyplex Nanoparticles Enhancing Gene Expression through Photochemical Mechanisms.

Achieving effective mRNA expression in vivo requires careful selection of an appropriate delivery vehicle and route of administration. Among the various routes of administration, intranasal administration has received considerable attention due to its ability to induce potent immune responses. In this context, we designed a specialized cationic polymer tailored for delivery of mRNA into the nasal cavity. These polymers are designed with varying degrees of substitution in different amine groups to allow for identification of the most suitable amine moiety for effective mRNA delivery. We also incorporated a photosensitizer within the polymer structure that can trigger the generation of reactive oxygen species when exposed to light. The synthesized cationic polymer is complexed with anionic mRNA to form a polyplex. Illuminating these polyplexes with laser light enhances their escape from intracellular endosomes, stimulating mRNA translocation into the cytoplasm, followed by increased mRNA expression at the cellular level. Through intranasal administration to C57BL/6 mice, it was confirmed that these photoactive polyplexes effectively induce mRNA expression and activate immune responses in vivo using photochemical effects. This innovative design of a photoactivated cationic polymer presents a promising and reliable strategy to achieve efficient intranasal mRNA delivery. This approach has potential applications in the development of mRNA-based vaccines for both prophylactic and therapeutic purposes.

Bioinformatics analyses of potentially common pathogenic networks for primary Sjögren's syndrome complicated with acute myocardial infarction.

Both primary Sjögren's syndrome (pSS) and acute myocardial infarction (AMI) are intricately linked. However, their common mechanism is not fully understood. Herein, we examined the underlying network of molecular action associated with developing this complication. Datasets were downloaded from the GEO database. We performed enrichment and protein-protein interaction analyses and screened key genes. We used external datasets to confirm the diagnostic performance for these hub genes. Transcription factor and microRNA regulatory networks were constructed for the validated hub genes. Finally, drug prediction and molecular docking validation were performed. We identified 62 common DEGs, many of which were enriched regarding inflammation and immune response. 5 DEGs were found as key hub genes (IGSF6, MMP9, S100A8, MNDA, and NCF2). They had high diagnostic performance in external datasets. Functional enrichment of these five hub genes showed that they were associated with the adaptive immune response. The Type 1T helper cell showed the most association among all cell types related to AMI and pSS. We identified 36 common TFs and 49 identical TF-miRNAs. The drugs, including Benzo, dexamethasone, and NADP, were predicted as potential therapeutic agents. Herein, we revealed common networks involving pSS and AMI etiologies. Knowledge of these networks and hub genes can enhance research into their associated mechanism and the development of future robust therapy.

Stem Cell-Derived Extracellular Vesicles for Cancer Therapy and Tissue Engineering Applications.

Recently, stem cells and their secretomes have attracted great attention in biomedical applications, particularly extracellular vesicles (EVs). EVs are secretomes of cells for cell-to-cell communication. They play a role as intercellular messengers as they carry proteins, nucleic acids, lipids, and therapeutic agents. They have also been utilized as drug-delivery vehicles due to their biocompatibility, low immunogenicity, stability, targetability, and engineerable properties. The therapeutic potential of EVs can be further enhanced by surface engineering and modification using functional molecules such as aptamers, peptides, and antibodies. As a consequence, EVs hold great promise as effective delivery vehicles for enhancing treatment efficacy while avoiding side effects. Among various cell types that secrete EVs, stem cells are ideal sources of EVs because stem cells have unique properties such as self-renewal and regenerative potential for transplantation into damaged tissues that can facilitate their regeneration. However, challenges such as immune rejection and ethical considerations remain significant hurdles. Stem cell-derived EVs have been extensively explored as a cell-free approach that bypasses many challenges associated with cell-based therapy in cancer therapy and tissue regeneration. In this review, we summarize and discuss the current knowledge of various types of stem cells as a source of EVs, their engineering, and applications of EVs, focusing on cancer therapy and tissue engineering.

Stem cell-derived paracrine factors by modulated reactive oxygen species to enhance cancer immunotherapy.

Herein, we present an approach for manipulating paracrine factors and signaling pathways in adipose-derived stem cells (ADSCs) to achieve highly effective tumor immunotherapy. Our method involves precise control of reactive oxygen species concentration using the CD90-maleimide-pluronic F68-chlorin e6 conjugate (CPFC) to create ACPFC, which is then attached to ADSCs through the CD90 receptor-specific interaction. By regulating the irradiated laser power, ACPFC promotes signaling pathways such as cascade-3, VEGFR2, α2ß1, C3AR1, CR1-4, and C5AR1, leading to the secretion of various inflammatory cytokines such as IFN-γ, TGF-ß, and IL-6, while inhibiting AKT, ERK, NFkB, PAR1, and PAR3/4 signaling pathways to reduce the secretion of cell growth factors like TIMP-1, TIMP-2, VEGF, Ang-2, FGF-2, and HGF. When ACPFC is injected intravenously into a tumor animal model, it autonomously targets and accumulates at the tumor site, and upon laser irradiation, it generates various anti-inflammatory factors while reducing angiogenesis growth factors. The resulting antitumor response recruits CD3+CD8+ cytotoxic T cells and CD3+CD4+ helper T cells into the tumor and spleen, leading to highly effective melanoma and pancreatic tumor treatment in mice. Our technology for regulating stem cell paracrine factors holds significant promise for the treatment of various diseases.

Synergistic Approach of Antibody-Photosensitizer Conjugate Independent of KRAS-Mutation and Its Downstream Blockade Pathway in Colorectal Cancer.

Here, a novel approach is presented to improve the efficacy of antibody-drug conjugates (ADC) by integrating antibody-mediated immunotherapy and photodynamic therapy (PDT) in a combination therapy system utilizing an antibody-photosensitizer conjugate (APC) platform based on a poloxamer polymer linker. To specifically target Kirsten rat sarcoma 2 viral oncogene homolog (KRAS)-mutated cancer cells, an antibody antiepidermal growth factor receptor (EGFR), cetuximab, with a poloxamer linker coupled with the photosensitizer chlorin e6 through click chemistry (cetuximab-maleimide-poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)-chlorine e6 conjugate, CMPXC) is synthesized. CMPXC is cytotoxic upon laser treatment, achieving a 90% cell death by suppressing KRAS downstream signaling pathways associated with ERK and AKT proteins, confirmed using RNA sequencing analysis. In KRAS-mutated colorectal cancer mouse models, CMPXC significantly enhances antitumor efficacy compared with cetuximab treatment alone, resulting in an 86% reduction in tumor growth. Furthermore, CMPXC treatment leads to a 2.24- and 1.75-fold increase in dendritic and priming cytotoxic T cells, respectively, highlighting the immune-activating potential of this approach. The findings suggest that the APC platform addresses the challenges associated with ADC development and EGFR-targeted therapy, including the synergistic advantages of antibody-mediated immunotherapy and PDT.

pH-Responsive Zinc Ion Regulating Immunomodulatory Nanoparticles for Effective Cancer Immunotherapy.

Herein, we introduce a novel approach involving the utilization of a human serum albumin-coated zeolite imidazolate framework-8 containing a photosensitizer (HPZ) that exhibits targeted recognition of the tumor microenvironment, enabling the rapid elevation of zinc ion concentrations while facilitating the controlled release of an encapsulated photosensitizer (PS). At a physiological pH of 7.4, HPZ demonstrates a size of approximately 170 nm, significantly decreasing to less than 10 nm under pH 6.5 acidic conditions. Acid-induced decomposition of HPZ triggers a rapid increase in zinc ion concentration, eliciting potent cytotoxic effects against colorectal, breast, and pancreatic cancers. Additionally, upon laser irradiation, the encapsulated PS within HPZ initiates the generation of reactive oxygen species, synergistically augmenting the cytotoxicity induced by zinc ions. Intravenous administration of HPZ in a CT26 tumor-bearing mouse model resulted in a notable expansion of CD3+CD4+ helper T cells and CD3+CD8+ cytotoxic T cells, accompanied by a reduction in the CD4+CD25+Foxp3+ regulatory T-cell population. These changes led to significant inhibition of tumor growth, highlighting the efficacy of HPZ in this experimental model. Importantly, HPZ exhibits favorable safety characteristics, displaying no toxicity toward vital organs and inducing no weight loss. Thus, HPZ holds immense promise as a standalone treatment or in combination with diverse anticancer immunotherapies, underscoring its potential in the field of anticancer immunotherapy.

Nanoparticle platform comprising lipid-tailed pH-sensitive carbon dots with minimal drug loss.

Herein, we synthesized a lipid-mimicking organic material (PCD_FA) that can surpass the efficacy of lipid-based nanoparticles and demonstrated its potential as a delivery vehicle for various hydrophilic drugs. PCD_FA is a conjugate of pH-sensitive carbon dots (PCDs) and fatty acids (FAs) and has potential applications in several fields owing to various combinations of carbon dots (CDs) and FAs. Similar to phospholipids, PCD-FAs have hydrophilic heads and hydrophobic tails that allow them to self-form nanoparticles (Coposomes) in the aqueous phase. Coposomes can easily combine various hydrophilic head and hydrophobic tail combinations, and several drugs can be encapsulated, or drug release patterns can be controlled according to each property. We analyzed the differences in size, drug loading efficiency, and drug release patterns of Coposomes depending on the type of FAs and characteristics of the encapsulated drugs. Additionally, cell entry and intracellular drug release mechanisms of the Coposomes were identified. The applicability of Coposomes as drug delivery carriers for tumor treatment has been demonstrated in comparison with that of liposomes formulation in tumor-bearing mouse models. Consequently, this study presents possibilities for the synthesis and application of various amphiphilic lipid-mimicking organic materials via the combination of CDs and FAs with various functions.

Photoactive intragastric satiety-inducing device using polymeric photosensitizers for minimally invasive weight loss treatment.

An intragastric satiety-inducing device (ISD) located in the stomach induce satiety and fullness in the absence of food by continuously pressing on the distal esophagus and cardia of the stomach. To improve the therapeutic function of ISD, Chlorin e6 (Ce6) was embedded in a disk portion of ISD, generating reactive oxygen species and stimulating endocrine cells under the laser irradiation. Since Ce6 has remarkable light efficiency but poor solubility in various solvents, it is essential to use a polymeric photosensitizer and optimize a suitable coating solution composition. Methoxy polyethylene glycol-Ce6 was uniformly coated and the spontaneous release amount of the Ce6 from the device could be reduced, which induced photo-responsive cell death and reduced ghrelin levels in vitro. In mini pigs operated single therapy (PDT or ISD) or combination therapy (Photoreactive ISD), there were differences in body weight (control: 28% vs. Photoreactive ISD: 4%, P < 0.001), ghrelin (control: 4% vs. Photoreactive ISD: 35%, P < 0.001), and leptin levels (control: 8% vs. Photoreactive PDT: 35%, P < 0.001) at 4 weeks.

Effect of paclitaxel priming on doxorubicin penetration in a multicellular layer model of human colorectal cancer cells.

Tumor priming is considered a promising strategy for improving drug distribution in malignant tissues. Multicellular layers (MCLs) of human cancer cells are potentially useful models for evaluating tumor-priming agents. We evaluated the priming effects of paclitaxel (PTX) on doxorubicin (DOX) penetration using MCLs of the human colorectal cancer cell lines including DLD-1, HCT-116, and HT-29. The penetration of DOX treated at 50 µM for 3 h was highly limited in all three MCLs. The penetration of the priming agent PTX into MCLs was determined using rhodamine-labeled PTX and appeared to be cell line-dependent: full penetration was observed in HCT-116 and HT-29 MCLs, whereas only limited penetration occurred in DLD-1 MCLs. PTX pretreatment at 20 µM for 24 or 48 h induced a tumor-priming effect in DOX distribution, with a 3 to 5.6-fold-increase in HCT-116 and HT-29 MCLs but a less than two-fold increase in DLD-1 MCLs. PTX treatment decreased fibronectin expression in HCT-116 and HT-29 MCLs but not in DLD-1, suggesting that the prominent priming effect of PTX in HCT-116 and HT-29 MCLs may be associated with the downregulation of fibronectin expression. Our study demonstrated that MCLs of human cancer cells are a useful model not only for the study of drug penetration into tumor tissues but also for screening and evaluating tumor-priming agents.

Nanocracker capable of simultaneously reversing both P-glycoprotein and tumor microenvironment.

Here, we describe a multidrug-resistant nanocracker (MDRC) that can treat multi-drug resistant (MDR) cancer by recognizing the acidic microenvironment and inhibiting two mechanisms of MDR such as P-glycoprotein (P-gp) and vacuolar-type ATPase (V-ATPase). MDRC is a liposome formulation co-loading pantoprazole (PZ) and paclitaxel (PTX). PZ acts as a chemosensitizer that enhances the MDR cancer treatment effect of PTX by disrupting the pH gradient and inhibiting P-gp. MDRC-encapsulated PZ and PTX have different release rates, with PZ released within 12 h and PTX sustained release for 48 h in the plasma. MDRC could increase cell uptake by inhibiting the P-gp overexpressed MCF-7/mdr cells and UV-2237M cells, which are human breast MDR cancer cells and murine fibrosarcoma cells, respectively. MDRC can also increase the cytotoxic efficacy of PTX by increasing intracellular pH. MDRC has a 10.5-fold reduced IC50 value in the P-gp overexpressed human breast adenocarcinoma and a 6.3- to 9.5-fold reduced IC50 value in the P-gp non-expressed human breast adenocarcinoma compared to the mixture of PZ and PTX, respectively. Intravenous injection of MDRC did not cause weight loss, liver dysfunction, or major organ toxicity. MDRC exhibited 80% complete remission of murine fibrosarcoma. The excellent therapeutic effect of MDRC on MDR tumors was accompanied by an increase in dendritic cell maturation and cytotoxic T cells. In other words, MDRC has the potential to terminate MDR therapy through the complete remission of MDR tumors.

Loranthus tanakae Franch. & Sav. Suppresses Inflammatory Response in Cigarette Smoke Condensate Exposed Bronchial Epithelial Cells and Mice.

Loranthus tanakae Franch. & Sav. found in China, Japan, and Korea is traditionally used for managing arthritis and respiratory diseases. In this study, we analyzed the components of L. tanakae 70% ethanol extract (LTE) and investigated the therapeutic effects of LTE on pulmonary inflammation using cells exposed to cigarette smoke condensate (CSC) and lipopolysaccharide (LPS) in vitro and in vivo in mice and performed a network analysis between components and genes based on a public database. We detected quercitrin, afzelin, rhamnetin 3-rhamnoside, and rhamnocitrin 3-rhamnoside in LTE, which induced a significant reduction in inflammatory mediators including interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and inflammatory cells in CSC exposed H292 cells and in mice, accompanied by a reduction in inflammatory cell infiltration into lung tissue. In addition, LTE increased translocation into the nuclei of nuclear factor erythroid-2-related factor 2 (Nrf2). By contrast, the activation of nuclear factor (NF)-κB, induced by CSC exposure, decreased after LTE application. These results were consistent with the network pharmacological analysis. In conclusion, LTE effectively attenuated pulmonary inflammation caused by CSC+LPS exposure, which was closely involved in the enhancement of Nrf2 expression and suppression of NF-κB activation. Therefore, LTE may be a potential treatment option for pulmonary inflammatory diseases including chronic obstructive pulmonary disease (COPD).

Intracellular pH-Regulating Nanoparticles to Improve Anticancer Drug Efficacy for Cancer Treatment.

Here, we describe an intracellular pH-regulating nanoparticle (IPRN), coencapsulated with chemosensitizers and anticancer agents for effective and safe cancer treatment. IPRN contains a tubulysin derivative (TUB), a hydrophobic anticancer drug, and pantoprazole (PTZ), a hydrophilic proton-pump inhibitor. IPRN with a size of 62 nm has an anionic surface charge and is stable for at least two weeks under storage conditions, though PTZ and TUB encapsulated in IPRN showed different drug release patterns. PTZ was released before TUB, controlling the cancer's intracellular pH, maintaining a pH at which TUB can work well. The encapsulated PTZ increased the pH of endolysosomes and inhibited ion trapping, with TUB ionization, thereby exhibiting increased cytotoxicity compared with free TUB observed in various cancer cell lines, such as human liver adenocarcinoma, human glioblastoma, and human pancreatic carcinoma. IPRN exhibited a 1.9-fold improved tumor growth inhibitory effect in a human liver adenocarcinoma-bearing mouse model, while minimizing the hepatotoxicity of free TUB. Thus, nanomedicines that contain both a chemosensitizer and an anticancer agent, such as IPRN, are expected to be next-generation anticancer agents that reduce the side effects of anticancer drugs and increase the therapeutic effect.

Ovalbumin and Poly(i:c) Encapsulated Dendritic Cell-Targeted Nanoparticles for Immune Activation in the Small Intestinal Lymphatic System.

Here, antigen and adjuvant encapsulated dendritic cell-targeted nanoparticles for immune activation in the small intestinal lymphatic system to inhibit melanoma development are described. This strategy is demonstrated using chondroitin sulfate-coated nanoparticles (OPGMN) grafted with glycocholic acid and mannose for cationic liposomes encapsulated with ovalbumin as an antigen and polyinosine-polycytidylic acid as a cancer-specific adjuvant. OPGMN is absorbed in the gastrointestinal tract and delivered to the lymph nodes when orally administered. Oral delivery of OPGMN induces increased dendritic cell maturation compared to the intradermal route in the lymph node and induces T helper type 1 and type 2 responses, such as immunoglobulin G1 and G2c, interferon-gamma, and interleukin-2, in the blood. Repeated oral administration of OPGMN increases the population of CD3+ CD8+ T cells, CD44high CD62Llow memory T cells, and CD11b+ CD27+ natural killer cells in the blood. OPGMN completely prevents melanoma development in the B16F10-bearing C57BL/6 mouse model by reducing the population of CD4+ CD25+ Foxp3+ regulatory T cells in the blood. This strategy is expected to prevent the recurrence of tumors after various cancer treatments.

Solubilized chlorin e6-layered double hydroxide complex for anticancer photodynamic therapy.

BACKGROUND: Layered double hydroxides (LDHs) are one type of 2-dimensional material with unique structure and strongly positive surface charge. Particularly, LDHs can be exfoliated by mono-layered double hydroxides (MLHs) as a single layer, showing an increased surface area. Therefore, there is a large focus on LDHs for drug delivery applications. Furthermore, most photosensitizers are hydrophobic that they cannot be soluble in aqueous solvents. Herein, we designed a simple way to solubilize hydrophobic photosensitizers by MLH with electrostatic interactions for anticancer photodynamic therapy (PDT), which has tremendous therapeutic advantages. The photosensitizer solubilized via loading on the MLH exhibited fluorescence and singlet oxygen-generation activities in aqueous solvent without chemical modification, resulting in photo-mediated anticancer treatment. METHODS: Negatively charged hydrophobic photosensitizers, chlorin e6 (Ce6) were solubilized by loading on the MLHs through the electrostatic interaction between positively charged MLHs. MLH/Ce6 complexes evaluated for physico-chemical characterization, pH-sensitive release property, in vitro photocytotoxicity, and in vivo tumor ablation. RESULTS: The photosensitizer solubilized via MLH exhibited fluorescence intensity and singlet-oxygen generation activities in aqueous solvent without chemical modification, resulting photocytotoxicity in cancer cells. The encapsulation efficiency of Ce6 increased to 21.2% through MLH compared to 0.6% when using LDH. In tumor-bearing mice, PDT with solubilized MLH/Ce6 indicated a tumor-suppressing effect approximately 3.4-fold greater than that obtained when Ce6 was injected alone. CONCLUSIONS: This study provided the solubilized Ce6 by the MLH in a simple way without chemical modification. We demonstrated that MLH/Ce6 complexes would have a great potential for anticancer PDT.