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.

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.

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.

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.

Effectiveness and safety of bivalirudin in elderly patients with coronary artery disease undergoing percutaneous coronary intervention: A real-world study.

OBJECTIVE: To assess the effectiveness and safety of bivalirudin compared with heparin monotherapy in elderly patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Bivalirudin is recommended for periprocedural use in patients undergoing PCI who are of high bleeding risk. However, its safe and efficacious use in elderly patients, a typical high bleeding risk cohort, in real world practice is yet to be reported. METHODS: In this single center, real-world observational study, 4736 consecutive elderly patients who underwent PCI were enrolled. Of these, 1240 were treated with bivalirudin and 3496 with heparin according to the periprocedural anticoagulation strategies of PCI. The primary outcome was 12-month net adverse clinical events (NACE) defined as a composite of cardiac death, myocardial infarction, stroke, revascularization, or any bleeding. Propensity score matching (PSM) was used to balance baseline characteristics between groups. RESULTS: After PSM, bivalirudin was found to be associated with lower rates of NACE (19.1% vs. 24.7%, p = 0.002), cardiac death (2.7% vs. 4.3%, p = 0.038), and any bleeding (10.0% vs. 12.9%, p = 0.023) compared to heparin monotherapy. No differences were found in the incidences of myocardial infarction, stroke, revascularization, stent thrombosis (0.1% vs. 0.1%, p = 1.000), and major bleedings (0.5% vs. 0.5%, p = 1.000) between the two patient groups. CONCLUSION: In this real-world observational study, periprocedural use of bivalirudin in elderly patients who underwent PCI was associated with less cardiac death and any bleeding compared to heparin monotherapy, without increased risk of stent thrombosis.

Predictors and long-term outcomes of in-hospital switching from clopidogrel to ticagrelor among patients with acute coronary syndrome undergoing percutaneous coronary intervention.

This study evaluated clinical outcomes of switching from clopidogrel to ticagrelor in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). The clinical benefit of in-hospital switching from clopidogrel to ticagrelor in these patients remains unclear. Among patients with ACS initially receiving clopidogrel, logistic regression was used to identify independent predictors of switching to ticagrelor. Multivariable Cox regression was used to compare efficacy and safety between switching to ticagrelor and continuing clopidogrel. The primary endpoint was net adverse clinical events (NACEs) at 12 months, a composite of major adverse cardiovascular events (MACE) and Bleeding Academic Research Consortium (BARC) type 2/3/5 bleeding. Among 10,519 patients initially receiving clopidogrel, 1405 (13.4%) were switched to ticagrelor at discharge. Stent number, left main artery lesions, diabetes, male sex, age, estimated glomerular filtration rate of <45 ml/min/1.73 m2 , and history of PCI or stroke were identified as independent predictors of switching to ticagrelor. The rate of NACE (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.18-1.91) or BARC type 2/3/5 bleeding (HR: 2.01; 95% CI: 1.52-2.66) was significantly higher in patients switching to ticagrelor than in those continuing clopidogrel. The risk of MACE was comparable between both the groups (HR: 0.71; 95% CI: 0.41-1.22). In real-world practice, in-hospital switching from clopidogrel to ticagrelor was independently associated with several clinical factors. Patients switching to ticagrelor had a higher rate of NACE or BARC type 2/3/5 bleeding than those continuing clopidogrel, without any reduction in the MACE rate.

Ticagrelor versus clopidogrel in patients with acute coronary syndrome undergoing complex percutaneous coronary intervention.

OBJECTIVES: To evaluate the effectiveness and safety of ticagrelor versus clopidogrel in patients with acute coronary syndromes (ACS) undergoing complex percutaneous coronary intervention (PCI). BACKGROUND: It remains inconclusive whether ticagrelor is superior to clopidogrel in ACS patients undergoing complex PCI in real-world practice. METHODS: Based on an all-comers PCI registry, we compared the long-term effectiveness and safety between ticagrelor and clopidogrel in ACS patients undergoing complex PCI, defined as PCI procedures for complex lesions including bifurcation, chronic total occlusion, ostial, tortuous, calcific, diffused, thrombus-containing, and restenotic lesions. The primary ischemic outcome was a composite of cardiac death, myocardial infarction, or stroke. The safety outcome comprised Bleeding Academic Research Consortium (BARC) types 2, 3, and 5 bleeding. Propensity score matching (PSM) was performed to reduce bias. RESULTS: Among ACS patients who underwent complex PCI, 4373 (35.2%) and 8065 (64.8%) received dual antiplatelet therapy based on ticagrelor and clopidogrel, respectively. The incidences of composite ischemic events (before PSM: 1.74% vs. 2.84%; after PSM: 1.50% vs. 2.65%; p < 0.01 for both) and all-cause death (before PSM: 1.23% vs. 2.12%, p < 0.01; after PSM: 1.09% vs. 1.81%, p = 0.02) were significantly lower in the ticagrelor-treated than in the clopidogrel-treated group. There was no significant difference in BARC types 2, 3, and 5 bleeding between groups. CONCLUSIONS: Whilst the risk of major bleeding was comparable between the two drugs, ticagrelor was associated with a significantly lower risk of ischemic events than clopidogrel in ACS patients undergoing complex PCI.

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.

Immune Stimulating Antibody-Photosensitizer Conjugates via Fc-Mediated Dendritic Cell Phagocytosis and Phototriggered Immunogenic Cell Death for KRAS-Mutated Pancreatic Cancer Treatment.

Although cetuximab (CTX) is a chimeric epidermal growth factor receptor (EGFR) antibody, the antitumor efficacy of CTX has a negligible effect in patients with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutated pancreatic adenocarcinoma. Given that all extant treatments are ineffective due to the undruggable characteristics of KRAS-mutated cancer, alternative strategies have been investigated. In this work, CTX-conjugated maleimide-polyethylene glycol-chlorin e6 (CMPC) is designed to strengthen its antitumor efficacy. With strong affinity for EGFR overexpressing Aspc-1 cells, CMPC with laser exerts the greatest cytotoxicity (90%) and induction of immunogenic cell death. Through a combination of fragment crystallizable region-mediated antigen uptake by CTX and danger-associated molecular patterns released by photodynamic therapy (PDT), phagocytosis and maturation of dendritic cells treated with CMPC plus laser show dramatic increases. In vivo biodistribution and antitumor effect also demonstrate that CMPC has significant tumor selectivity and tumor ablation efficacy upon laser irradiation. Furthermore, a large number of CD4+ , CD8+ T cells and mature DCs and natural killer cells are infiltrated in CMPC with laser-treated tumor tissues and tumor-draining lymph nodes, revealing both innate and adaptive cellular immune stimulation. This synergistic effect with CMPC and laser treatment provides an effective approach for pancreatic cancer immunotherapy attributed to both CTX and PDT.

Impact of 6- versus 12-month dual antiplatelet therapy on clinical prognosis in patients with high bleeding risk: Insights from the 4-year results of the I LOVE IT 2 study.

OBJECTIVES: To explore the impact of 6- versus 12-month dual antiplatelet therapy (DAPT) on the clinical prognosis of high bleeding risk (HBR) patients. BACKGROUND: The optimal DAPT duration after percutaneous coronary intervention (PCI) in HBR patients is unclear. METHODS: This study is a post hoc analysis of the 4-year clinical follow-up results of the I LOVE IT 2 study. Prevalence and prognosis of HBR patients were explored, and clinical outcomes of HBR patients who underwent 6- versus 12-month DAPT were compared. The primary outcome was Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding. The secondary outcomes were BARC type 2-5 bleeding and net clinical adverse events (NACE), defined as a composite of all-cause death, myocardial infarction (MI), ischemia-driven revascularization, stroke, stent thrombosis, or any bleeding events. RESULTS: HBR occurred in 440 of 2,737 patients (16.0%). HBR patients were associated with a higher risk of BARC type 3 or 5 bleeding (2.95 vs. 1.52%, p = .03), NACE (31.82 vs. 25.99%, p = .01), all-cause death (5.68 vs. 3.13%, p = .008) and stroke (9.09 vs. 3.83%, p < .001) than non-HBR patients at 4 years. There were no significant differences in BARC type 3 or 5 bleeding (3.07 vs. 2.76%, p = 1.00) or NACE rate (31.9 vs. 33.8%, p = .72) between patients who underwent 6- and 12-month DAPT. CONCLUSIONS: HBR patients are at a higher risk of long-term bleeding and ischemic events than non-HBR patients. The safety and efficacy of 6- and 12-month DAPT were comparable in HBR patients.

Comparison of the efficacy and safety of ticagrelor and clopidogrel in patients with acute coronary syndrome after risk stratification.

OBJECTIVE: This study aimed at comparing the effectiveness and safety of ticagrelor and clopidogrel in acute coronary artery syndrome (ACS) patients stratified by the Optimal Antiplatelet Therapy for Chinese Patients with Coronary Artery Disease (OPT-CAD) risk score. BACKGROUND: Although they provide a promising basis for treatment decisions, risk scores have not been utilized to optimize P2Y12 inhibitors for ACS patients. METHODS: In 2016-2019, 16,343 ACS patients who underwent percutaneous coronary intervention at the General Hospital of Northern Theater Command were enrolled and classified as low-risk (n = 9,841) or intermediate- to high-risk (n = 6,502) according to OPT-CAD risk score. Clinical outcomes for patients receiving clopidogrel or ticagrelor were compared within risk levels. Primary endpoint was ischemic events at 12 months. Propensity score matching (PSM) was used to balance groups. RESULTS: The risk of ischemic events (2.73% vs. 3.89%, p = .02) and all-cause mortality (1.75% vs. 2.86%, p = .01) were lower in the intermediate- to high-risk patients treated with ticagrelor than those treated with clopidogrel, without an excessive risk of major bleeding (3.71% vs. 3.95%, p = .65). Among low-risk patients, ticagrelor was associated with significantly increased bleeding risk (4.13% vs. 2.85%, p < .01) compared to clopidogrel, with no difference in ischemic risk (1.04% vs. 1.25%, p = .36). Results were consistent in PSM cohorts. CONCLUSIONS: Ticagrelor improves ischemic prognosis in intermediate- to high-risk patients but shows worse safety in low-risk patients compared to clopidogrel, supporting the effectiveness of risk score-guided decision making.

Glycyrrhetinic Acid-Modified Silicon Phthalocyanine for Liver Cancer-Targeted Photodynamic Therapy.

To supplement shortcomings of existing treatments and enhance the therapeutic effect for liver cancer, a novel photosensitizer is designed using silicon phthalocyanine (SiPC) and a unique targeting moiety, glycyrrhetinic acid (GA). The SiPC is modified with a hydrophilic polymer and finally bound with GA. The solubility, fluorescence, singlet oxygen generation, and UV-vis absorbance are analyzed, and receptor-dependent intracellular influx is estimated in various cell lines. Using flow cytometry and confocal microscopy, intracellular fluorescence was detected in liver cancer because of GA receptor overexpression. To prove in vitro photodynamic therapeutic effects, the sample treated cells are irradiated and viability of liver cancer cells decreases in proportion to laser power. Then, it is confirmed that GA-modified SiPC effectively accumulated in liver cancer of HepG2 tumor-bearing mouse. Additionally, the PDT-combined therapeutic effect of GA-modified SiPC is observed in the tumor model and shown to have a tumor growth inhibition effect (60.36 times higher than the control group) and supported by histological analyses. These results demonstrate that the newly modified SiPC can be applied to liver cancer-specific treatment with high therapeutic efficacy. Consequently, novel SiPC has the potential to alter conventional liver cancer-targeted therapy and chemotherapy in clinical use.

A Multiligand Architectural Photosensitizer That Targets Hemagglutinin on Envelope of Influenza Virus for Photodynamic Inactivation.

The efficacy of current antiviral drugs used to treat influenza has been declining because of mutations and resistance of the virus. Herein, a light-sensitive multiligand architecture is developed consisting of chitosan conjugated to a photosensitizer and 6'-sialyllactose (SL) to develop an antiviral agent against influenza with a different mechanism of action (SL-chitosan-Chlorin e6, SCC). Saturation transfer difference-nuclear magnetic resonance determined that the ability of SCC to bind to viral hemagglutinin is stronger than that of the monomeric substance. Virus recognition is confirmed by immunofluorescence and transmission electron microscope imaging. SCC induces viral inactivation by causing permanent membrane damage through its photoactivity. Viral membrane is oxidized by the photoactivity of SCC, thus, the virus membrane collapses. Furthermore, using the plaque reduction assay to evaluate the inhibitory effect of SCC on influenza A and B, it is found that its antiviral effects are 23% and 50% higher than the conventional antiviral drug. Additionally, SCC prevents infection by influenza in 100% of mice subjected to laser irradiation. These results indicate that this photodynamic multiligand structure can overcome the limitations of existing antiviral agents and suggest a pertinent methodology of prophylaxis and treatment by preemptively attacking the virus before it enters the host cell.

pH-Sensitive Carbon Dots for Enhancing Photomediated Antitumor Immunity.

Recent cancer immunotherapy has attracted much attention due to high specificity and recurrence prevention of tumor. Nevertheless, its therapeutic effects are still challenging in solid cancer. To establish superior antitumor immunity, chlorin e6 (Ce6)-loaded pH sensitive carbon dots were investigated (Ce6@IDCDs). At tumoral pH 6.5, Ce6 was released four times compared with the release at physiological pH 7.4 due to an imbalance between hydrophilic and hydrophobic forces via protonation of imidazole groups in Ce6@IDCDs. This result led to the superior singlet oxygen generating activity of Ce6@IDCDs without Ce6 quenching. The maturation effects of dendritic cells after co-incubation with supernatant media obtained from Ce6@IDCDs with laser-treated cells at pH 6.5 were much higher than at physiological pH. Furthermore, Ce6@IDCDs following a laser at pH 6.5 significantly promoted calreticulin exposure and high-mobility group box 1 release, as major immunogenic cell death markers. In bilateral CT-26-bearing mice model, the Ce6@IDCDs elicited significant antitumoral effects at laser treated-primary tumor regions via therapeutic reactive oxygen species. Furthermore, Ce6@IDCDs upon laser irradiation induced a large amount of activated CD8+ T cells, natural killer cells, and mature dendritic cells recruitment into tumoral tissue and hampered tumor growth even at untreated sites approximately four-fold compared with those of others. Overall, this pH-sensitive immunoinducer can accomplish primary and distant tumor ablation via photomediated cancer immunotherapy.

Exploration of cryptic organic photosensitive compound as Zincphyrin IV in Streptomyces venezuelae ATCC 15439.

Zincphyrin IV is a potential organic photosensitizer which is of significant interest for applications in biomedicine, materials science, agriculture (as insecticide), and chemistry. Most studies on Zincphyrin are focused on Zincphyrin III while biosynthesis and application of Zincphyrin IV is comparatively less explored. In this study, we explored Zincphyrin IV production in Streptomyces venezuelae ATCC 15439 through combination of morphology engineering and "One strain many compounds" approach. The morphology engineering followed by change in culture medium led to activation of cryptic Zincphyrin IV biosynthetic pathway in S. venezuelae with subsequent detection of Zincphyrin IV. Morphology engineering applied in S. venezuelae increased the biomass from 7.17 to 10.5 mg/mL after 48 h of culture. Moreover, morphology of engineered strain examined by SEM showed reduced branching and fragmentation of mycelia. The distinct change in color of culture broth visually demonstrated the activation of the cryptic biosynthetic pathway in S. venezuelae. The production of Zincphyrin IV was found to be initiated after overexpression ssgA, resulting in the increase in titer from 4.21 to 7.54 µg/mL. Furthermore, Zincphyrin IV demonstrated photodynamic antibacterial activity against Bacillus subtilis and photodynamic anticancer activity against human ovarian carcinoma cell lines.

Local Delivery of Gemcitabine Inhibits Pancreatic and Cholangiocarcinoma Tumor Growth by Promoting Epidermal Growth Factor Receptor Degradation.

Gemcitabine is clinically used to treat certain types of cancers, including pancreatic and biliary cancer. We investigated the signal transduction pathways underlying the local antitumor effects of gemcitabine-eluting membranes (GEMs) implanted in pancreatic/biliary tumor-bearing nude mice. Here, we report that GEMs increased the E3 ubiquitin ligase c-CBL protein level, leading to degradation of epidermal growth factor receptor (EGFR) in SCK and PANC-1 cells. GEMs decreased the RAS and PI3K protein levels, leading to a reduction in the protein levels of active forms of downstream signaling molecules, including PDK, AKT, and GSK3ß. GEM reduced proliferation of cancer cells by upregulating cell cycle arrest proteins, particularly p53 and p21, and downregulating cyclin D1 and cyclin B. Moreover, GEMs reduced the levels of proangiogenic factors, including VEGF, VEGFR2, CD31, and HIF-1α, and inhibited tumor cell migration and invasion by inducing the expression of E-cadherin and reducing that of N-cadherin, snail, and vimentin. We demonstrated that local delivery of gemcitabine using GEM implants inhibited tumor cell growth by promoting c-CBL-mediated degradation of EGFR and inhibiting the proliferation, angiogenesis, and epithelial-mesenchymal transition of pancreatic/biliary tumors. Use of gemcitabine-eluting stents can improve stent patency by inhibiting the ingrowth of malignant biliary obstructions.

Nonpolymeric pH-Sensitive Carbon Dots for Treatment of Tumor.

Nonpolymer, pH-sensitive carbon dots (pSCDs) were developed to overcome the disadvantages of pH-sensitive polymers such as inevitable synthesis, wide distribution of molecular weight, uncontrolled loading and release rate of drugs, and toxicity by biodegradation. The pSCDs were synthesized via one spot synthesis for 3 min using citric acid (CA) and 1-(3-aminopropyl) imidazole (API). Imidazole groups were present on pSCD surfaces and facilitated DOX loading via hydrophobic interactions (loading efficiency: 78.55%). The DOX-loaded pSCDs collapsed at tumoral pH (pH ∼ 6.5) due to protonation of the imidazole groups, and DOX was released about 7 times higher than the control group. The therapeutic effect was confirmed in vitro using HCT-116 (human colon cancer), PANC-1 (human pancreatic cancer), and SKBR-3 (human breast cancer) cells. Additionally, the DOX-loaded pSCDs successfully inhibited tumor growth in an HCT-116-bearing mouse model and did not show toxicity. These results indicate that a nonpolymeric pSCDs platform has the potential to be used as a cancer targeting therapeutic material.

Photoresponsive Micelle-Incorporated Doxorubicin for Chemo-Photodynamic Therapy to Achieve Synergistic Antitumor Effects.

A combination of chemo-photodynamic therapy has been manifested as a promising strategy for efficient cancer treatment due to the enhanced therapeutic efficacy. Here, we designed doxorubicin (DOX)-loaded photoresponsive micelles (DPRMs) based on a combination of chlorin e6 (Ce6) and lipoic acid (LA) conjugated methoxy-poly(ethylene) glycol (mPEG-Ce6, mPEG-LA) to achieve effective drug delivery using a single system. DPRMs were optimized with different molar ratios of mPEG-Ce6 and mPEG-LA which showed uniformly spherical morphology of size ∼130 nm and approximately 9% of DOX loading contents. Photoresponsive lipoyl ring of mPEG-LA was incorporated in DPRMs in order to induce photomediated reduction resulting in 2-3-fold accelerated DOX release according to higher molar ratio of mPEG-LA and enhancement of light dose. The photoresponsive DOX release and ROS generation by Ce6 mediated cytotoxic effect of DPRMs were demonstrated in vitro using CT-26 (mouse colon cancer) and HCT-116 (human colon cancer) cells. We observed both the photosensitizer and the anticancer drug are colocalized in the tumor cells to achieve effective enhancement. Additionally, the DPRMs with laser irradiation successfully inhibited tumor growth in CT-26 tumor bearing mouse model and immunohistochemical staining verified apoptosis-mediated tumor growth inhibition. These observations demonstrated that the DPRMs showed a higher therapeutic effect than the other systems and PDT maximized the antitumor effect. Thus, DPRMs confirmed the advantages as a chemo-photodynamic dual-therapy with a synergistic therapeutic effect and great potential for cancer treatment.

Effect of Ambient Light Exposure on Ocular Fatigue during Sleep.

BACKGROUND: To investigate the influence of nocturnal ambient light on visual function and ocular fatigue. METHODS: Sixty healthy subjects (30 men and 30 women) aged 19 through 29 years with no history of ocular disease were recruited. All subjects spent 3 consecutive nights in the sleep laboratory. During the first and second nights, the subjects were not exposed to light during sleep, but during the third night, they were exposed to ambient light, measuring 5 or 10 lux at the eye level, which was randomly allocated with 30 subjects each. The visual function and ocular fatigue were assessed at 7 a.m. on the 3rd and 4th mornings, using best-corrected visual acuity, refractive error, conjunctival hyperemia, tear break-up time, maximal blinking interval, ocular surface temperature, and subjective symptoms reported on a questionnaire. RESULTS: Three men and three women subjects failed to complete the study (4 in the 5 lux; 2 from the 10 lux). For the entire 54 subjects, tear break-up time and maximal blinking interval decreased (P = 0.015; 0.010, respectively), and nasal and temporal conjunctival hyperemia increased significantly after sleep under any ambient light (P < 0.001; 0.021, respectively). Eye tiredness and soreness also increased (P = 0.004; 0.024, respectively). After sleep under 5 lux light, only nasal conjunctival hyperemia increased significantly (P = 0.008). After sleep under 10 lux light, nasal and temporal conjunctival hyperemia, eye tiredness, soreness, difficulty in focusing, and ocular discomfort increased significantly (P < 0.05). CONCLUSION: Nocturnal ambient light exposure increases ocular fatigue. Avoiding ambient light during sleep could be recommended to prevent ocular fatigue.

Intermolecular Structural Change for Thermoswitchable Polymeric Photosensitizer.

We developed a thermoswitchable polymeric photosensitizer (T-PPS) by conjugating PS (Pheophorbide-a, PPb-a) to a temperature-responsive polymer backbone of biocompatible hydroxypropyl cellulose. Self-quenched PS molecules linked in close proximity by π-π stacking in T-PPS were easily transited to an active monomeric state by the temperature-induced phase transition of polymer backbones. The temperature-responsive intermolecular interaction changes of PS molecules in T-PPS were demonstrated in synchrotron small-angle X-ray scattering and UV-vis spectrophotometer analysis. The T-PPS allowed switchable activation and synergistically enhanced cancer cell killing effect at the hyperthermia temperature (45 °C). Our developed T-PPS has the considerable potential not only as a new class of photomedicine in clinics but also as a biosensor based on temperature responsiveness.