Antioxidant and antibacterial hydrogel formed by protocatechualdehyde-ferric iron complex and aminopolysaccharide for infected wound healing.

To better treat bacteria-infected wounds and promote healing, new wound dressings must be developed. In this study, we obtained PA@Fe by chelating iron trivalent ions (Fe3+) with protocatechualdehyde (PA), which has a catechol structure. Subsequently, we reacted it with ethylene glycol chitosan (GC) via a Schiff base reaction and loaded vancomycin to obtain an antibacterial Gel@Van hydrogel with a photothermal response. The as-prepared Gel@Van hydrogel exhibited good injectability, self-healing, hemostasis, photothermal stability, biocompatibility, and antioxidant and antibacterial properties. Moreover, Gel@Van hydrogel achieved highly synergistic antibacterial efficacy through photothermal and antibiotic sterilization. In a mouse skin-damaged infection model, Gel@Van hydrogel had a strong ability to promote the healing of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds, indicating the great potential application value of Gel@Van hydrogel in the field of treating and promoting the healing of infected wounds.

Turning Polysaccharides into Injectable and Rapid Self-Healing Antibacterial Hydrogels for Antibacterial Treatment and Bacterial-Infected Wound Healing.

Great efforts have been devoted to the development of novel and multifunctional wound dressing materials to meet the different needs of wound healing. Herein, we covalently grafted quaternary ammonium groups (QAGs) containing 12-carbon straight-chain alkanes to the dextran polymer skeleton. We then oxidized the resulting product into oxidized quaternized dextran (OQD). The obtained OQD polymer is rich in antibacterial QAGs and aldehyde groups. It can react with glycol chitosan (GC) via the Schiff-base reaction to form a multifunctional GC@OQD hydrogel with good self-healing behavior, hemostasis, injectability, inherent superior antibacterial activity, biocompatibility, and excellent promotion of healing of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds. The biosafe and nontoxic GC@OQD hydrogel with a three-dimensional porous network structure possesses an excellent swelling rate and water retention capacity. It can be used for hemostasis and treating irregular wounds. The designed GC@OQD hydrogel with inherent antibacterial activity possesses good antibacterial efficacy on both S. aureus (Gram-positive bacteria) and Escherichia coli (Gram-negative bacteria), as well as MRSA bacteria, with antibacterial activity greater than 99%. It can be used for the treatment of wounds infected by MRSA and significantly promotes the healing of wounds. Thus, the multifunctional antibacterial GC@OQD hydrogel has the potential to be applied in clinical practice as a wound dressing.

Devastating the Supply Wagons: Multifaceted Liposomes Capable of Exhausting Tumor to Death via Triple Energy Depletion.

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2 O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.

Evaluation of brain function in adult patent ductus arteriosus surgery: A multimodal monitoring approach.

Adult patent ductus arteriosus (PDA) repair surgery often involves hypothermic cardiopulmonary bypass (CPB) and is associated with postoperative neurological complications. Our study evaluates brain function during PDA surgery using regional cerebral oxygen saturation (rSO2) and bispectral index (BIS) monitoring to mitigate these complications. Patients were categorized into moderate (26-31 â„ƒ) and mild (32-35 â„ƒ) hypothermia groups. Findings indicate a positive correlation between PDA diameter and pulmonary artery systolic blood pressure, and a strong correlation between delirium and average rSO2-AUC. The mild hypothermia group had longer extubation and hospitalization times. During CPB, rSO2 levels fluctuated significantly, and EEG analysis revealed changes in brain wave patterns. One case of nerve injury in the mild hypothermia group showed incomplete recovery after a year. Our results advocate for moderate hypothermia during CPB in adult PDA repair, suggesting that combined rSO2 and BIS monitoring can reduce neurological complications post-surgery.

Evaluation of the Clinical Efficacy of Heart Valve Surgery in Patients with a Cardiac Disorder and the Factors Contributing to Poor Patient Prognosis.

Objective: We aimed to investigate the clinical efficacy of heart valve surgery in patients with heart disease and the factors contributing to poor patient prognosis. Methods: This was a retrospective analysis of 172 patients with heart disease treated in Peking University International Hospital between January 2019 and December 2021, with surgical treatment in the study group (86 patients) and conservative treatment in the control group (86 patients), by comparing factors such as patient age, preoperative cardiac function status, type and degree of valve lesion, surgical method and time of aortic block and perioperative treatment in both groups with clinical cure rate. The risk factors for early postoperative death were analyzed by single-factor and multi-factor logistic regression methods. Results: Regression analysis showed that age, peripheral artery disease (PAD), diabetes mellitus (DM), hypertension (HTN), dietary habits and medical compliance were prognostic factors in patients after heart valve surgery. The incidence of complications was lower in the study group than in the control group (P < .05). The left anterior descending artery (LAD), left ventricular end-diastolic internal diameter (LVEDD), cardiothoracic ratio (CTR) and left ventricular end-systolic internal diameter (LVDS) was decreased in both groups, whereas the left ventricular ejection fraction (LVEF) and peak early diastolic flow rate/peak late diastolic flow rate (E/A) were increased. The changes were greater in the study group than in the control group (P < .05); life function scores and survival rates were higher in the study group than in the control group (P < .05). Conclusions: The analysis of relevant clinical risk factors identified some independent prognostic factors affecting early death after valve replacement. These can be used for preoperative risk assessment, identification of high-risk surgical patients and guiding daily clinical work. Rationalizing the indications for surgery, choosing the timing of surgery, myocardial protection and appropriate surgical approach can further reduce the rate of surgical morbidity and mortality and complications in this patient population.

Risk Factors of Prolonged Mechanical Ventilation in Patients Undergoing Redo Valve Surgery.

BACKGROUND: Prolonged mechanical ventilation (PMV) after cardiac surgery is associated with high morbidity and mortality. Patients following redo valve surgery possess many attributes that place them at risk for PMV, yet few studies particularly focused on them. The purpose of this study was to identify perioperative variables associated with PMV in redo valve surgery. METHODS: A retrospective study, including 117 patients who underwent redo valve surgery from November 2017 to September 2021, was performed. The potential perioperative risk factors for PMV were collected. PMV was defined as the need for intubation and mechanical ventilation for >24 h, after completion of the operation. The clinical data were analyzed with univariate and multivariate analyses to identify risk factors for PMV following redo valve surgery. RESULTS: The incidence of PMV was 38.5% (N = 45). Multiple logistic regression analysis showed perioperative risk factors for PMV included advanced age (age>57 years) [odds ratio (OR) 3.043, 95% confidence interval (CI) 1.172-7.905, P = 0.022], low weight (weight ≤58 kg) (OR 2.798, 95% CI: 1.088-7.199, P = 0.033), EuroSCORE II ≥6.8% (OR 3.467, 95% CI: 1.364-8.817, P = 0.009), and VIS at 12 hours post ICU admission (VIS12) >10 (OR 5.613, 95% CI: 2.211-14.249, P < 0.001). CONCLUSIONS: In adult patients undergoing redo valve surgery, advanced age, low weight, high EuroSCORE II and a high VIS at 12 hours post-ICU admission were associated with PMV. Hemodynamic status after operation were more important than preoperative and intraoperative variables in predicting PMV.

A Diuretic Response is Associated with the Early Prognosis of Patients Undergoing Repeat Tricuspid Valve Surgery Due to Severe Tricuspid Regurgitation After Left-Sided Valvular Surgery.

OBJECTIVE: To analyze the factors affecting the early prognosis of patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery. METHOD: We retrospectively analyzed 76 patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery at Peking University International Hospital between October 2017 and February 2021. Patients were divided into two groups, according to preoperative weight control and whether the adjusted diuretic dose exceeded 40 mg of furosemide (or the equivalent dose). The factors affecting the early prognosis were analyzed through postoperative follow up. RESULTS: Thirty-five male patients (46.1%), aged 57±13 years, were enrolled in the study. For the patients who received a preoperative same dose of furosemide ≥40 mg/day and a same dose of furosemide <40 mg/day, the baseline data basically were the same. There were 76 patients (100%) who were followed up. Endpoint events during the follow up were as follows: Six patients (7.9%) died, two patients (2.6%) were admitted to the hospital or transferred to the intensive care unit due to cardiac insufficiency, and other conditions such as severe tricuspid regurgitation on repeat ultrasound, bilateral lower extremity edema, and inability to reduce or stop diuretics were found in five cases (6.6%). Compared with the group with the same dose of furosemide <40 mg/day group, the ≥40 mg/day group had a higher incidence of endpoints (12, 27.3% vs. 1, 3.1%, P = 0.006). CONCLUSION: In patients undergoing repeat tricuspid valve surgery due to severe tricuspid regurgitation after left-sided valvular surgery, a diuretic response was associated with surgical prognosis. Compared with the low-dose furosemide group, the high-dose group (≥40 mg/) had a significantly increased incidence of early events.

Feasibility analyses of virtual models and 3D printing for surgical simulation of the double-outlet right ventricle.

Accurate diagnosis and surgical selection of the double-outlet right ventricle (DORV) is both critical and difficult. Virtual models and three-dimensional (3D) printing have been used to provide morphological copies to doctors as reference. However, the existing methods have shortcomings in visualization of the surgical results, optimal surgical design, and accurate surgical scheme measurements. To overcome this problem, we performed surgical predictions by designing the intraventricular baffle and ventricular septal defect patch to evaluate surgical options and using 3D printing to guide the trimming of the baffle or patch. A complete set of processes including scanning, modeling, designing, 3D printing, and guiding the trimming of the baffle for the diagnosis and surgical planning of DORV was established. Six cases were used to evaluate the feasibility of this method. The average rate of misdiagnosis of the six cases by computed tomography and echocardiography was 42.5%, which was reduced to 4.6% when the diagnosis was established using the virtual models and 3D printing as auxiliary tools. The approach effectively improved diagnostic accuracy, guided the operation, and simplified the process of patch trimming. The proposed method can thus be used for improving the surgical simulation and guiding of the DORV surgery.

Risk Factors for Postoperative Acute Kidney Injury in Patients Undergoing Redo Cardiac Surgery Using Cardiopulmonary Bypass.

Objective: This paper aimed to investigate the incidence and risk factors of postoperative acute kidney injury (AKI) in adult patients undergoing redo cardiac surgery with cardiopulmonary bypass (CPB), and explore the impact of AKI on early outcomes. Methods: A total of 116 patients undergoing redo cardiac surgery with CPB between November 2017 and May 2021 were included. Patients were divided into two groups, AKI group and non-AKI group, according to the Kidney Disease Improving Global Outcomes criteria. Perioperative variables were retrospectively collected and analyzed. Risk factors for the development of AKI were investigated by univariate and multiple logistic regression models. Clinical outcomes were also compared between the groups. Results: Postoperative AKI occurred in 63 patients (54.3%), among whom renal replacement therapy was required in 12 patients (19.0%). The mechanical ventilation time (AKI: 43.00 (19.00, 72.00) hours; non-AKI: 18.00 (15.00, 20.00) hours; p < 0.001), ICU length of stay (AKI: 4.00 (2.00, 6.00) days; non-AKI: 3.00 (2.00, 4.00) days; p = 0.010), hospital length of stay since operation (AKI: 12.00 (8.00, 18.00) days; non-AKI: 9.00 (7.00, 12.50) days; p = 0.024), dialysis (AKI: 12.00 (19.05%); non-AKI: 0 (0%); p = 0.001), reintubation (AKI: 7.00 (11.11%); non-AKI: 0 (0%); p = 0.035), and hospital mortality (AKI: 8.00 (12.70%); non-AKI: 0 (0%); p = 0.020) were all higher in the AKI group than in the non-AKI group. Multivariate analysis revealed that high aspartate aminotransferase (OR, 1.028, 95% CI, 1.003 to 1.053, p = 0.025), coronary angiogram within 2 weeks before surgery (OR, 3.209, 95% CI, 1.307 to 7.878, p = 0.011) and CPB time (OR, 1.012, 95% CI, 1.005 to 1.019, p = 0.001) were independent risk factors for postoperative AKI. Conclusions: High aspartate aminotransferase, coronary angiogram within 2 weeks before surgery and CPB time seem to be associated with an increased incidence of postoperative AKI in patients with redo cardiac surgery.

Comparison of blood pool and myocardial 3D printing in the diagnosis of types of congenital heart disease.

The study aimed to evaluate the effectiveness of blood pool and myocardial models made by stereolithography in the diagnosis of different types of congenital heart disease (CHD). Two modeling methods were applied in the diagnosis of 8 cases, and two control groups consisting of experts and students diagnosed the cases using echocardiography with computed tomography, blood pool models, and myocardial models. The importance, suitability, and simulation degree of different models were analyzed. The average diagnostic rate before and after 3D printing was used was 88.75% and 95.9% (P = 0.001) in the expert group and 60% and 91.6% (P = 0.000) in the student group, respectively. 3D printing was considered to be more important for the diagnosis of complex CHDs (very important; average, 87.8%) than simple CHDs (very important; average, 30.8%) (P = 0.000). Myocardial models were considered most realistic regarding the structure of the heart (average, 92.5%). In cases of congenital corrected transposition of great arteries, Williams syndrome, coronary artery fistula, tetralogy of Fallot, patent ductus arteriosus, and coarctation of the aorta, blood pool models were considered more effective (average, 92.1%), while in cases of double outlet right ventricle and ventricular septal defect, myocardial models were considered optimal (average, 80%).

Perioperative Use of Pituitrin after Cardiac Defect Repair in Adult Patients with Severe Pulmonary Hypertension.

BACKGROUND: Vasopressin can constrict peripheral arteries without constricting the pulmonary artery. Theoretically, vasopressin is suitable for the perioperative treatment of pulmonary hypertension. Few studies have investigated the use of pituitrin (a substitute for vasopressin) after cardiac defect repair surgery. This study aimed to analyze the effect of pituitrin on hemodynamics and to determine whether pituitrin can be used after surgical repair in adult patients with pulmonary arterial hypertension-congenital heart disease (PAH-CHD). METHODS: A pulmonary artery catheter was used in all the patients for hemodynamic monitoring. Hemodynamic parameters were recorded before and at 0.5 h, 1 h, 6 h, 12 h and 24 h after pituitrin administration. The changes in the hemodynamic parameters before and after pituitrin use were analyzed through repeated measures analysis of variance. RESULTS: A total of 110 patients with PAH-CHD underwent repair surgery; 23 patients were included in further analysis, including 11 with atrial septal defect, 9 with ventricular septal defect, and 3 with patent ductus arteriosus. Ten (43.5%) were men, with a mean age of 29.4 ± 6.8 years. Hemodynamic parameters before and after the oxygen test were as follows: radial artery oxygen saturation, 91.5% ± 4.4 vs. 97.9 ± 2.4%; pulmonary vascular resistance, 10.5 ± 1.8 Wood units (wu) vs. 5 ± 1.2 wu; systemic-pulmonary blood flow ratio (QP/QS), 1.1 ± 0.2 vs. 2.1 ± 0.9. With prolonged use, the systolic blood pressure of the radial artery increased significantly (P = 0.001), that of the pulmonary artery decreased significantly (P = 0.009), and RP/s decreased significantly (P < 0.001). CONCLUSION: Pituitrin as an alternative to vasopressin can increase arterial pressure, decrease pulmonary artery pressure, and reduce the pulmonary artery pressure/arterial pressure ratio after repair surgery in adult patients with PAH-CHD.

Feasibility Analysis of 3D Printing With Prenatal Ultrasound for the Diagnosis of Fetal Abnormalities.

OBJECTIVE: To assess the feasibility and accuracy of 3D printing with prenatal three-dimensional ultrasound (3DUS) in the diagnosis of fetal abnormalities. METHODS: Fetuses initially diagnosed with various abnormalities were included in this retrospective study. The fetuses were examined by 3DUS, modeled, and 3D printed, and the dimensional accuracy of the 3D prints was analyzed. The effectiveness, demand, necessity of 3D printing, and the diagnostic accuracy of different methods were analyzed based on questionnaire responses from 40 senior ultrasound doctors and 40 postgraduate students. RESULTS: A total of 12 fetuses with cleft lip and palate, spinal, heart, or brain abnormalities were included for detailed assessment. All deviations (mean deviation: 0.1 mm) between the original images and the final 3D prints lay within the consistency boundary (-1.12, 1.31 mm) (P > .05). In the subsequent analyses, 90.8% of the doctors and 94.2% of the students strongly agreed that 3D printing could precisely represent and depict fetal abnormalities. The average misdiagnosis rate of the doctors decreased from 5% to 0.4% after the application of 3D printing combined with 3DUS in comparison with 3DUS alone, and the corresponding value for the students dropped from 17.9% to 5.2%. CONCLUSIONS: The errors in modeling and 3D printing based on 3DUS were within acceptable limits, and 3D printing improved the diagnosis of various fetal abnormalities.

Targeting and imaging colorectal cancer by activatable cell-penetrating peptides.

While it has been a great challenge to determine the positive status of metastasis lesions, intraoperative tumor imaging, which can show tumor localization and facilitate intraoperative staging of nodal metastases, have enabled surgeons to quickly and accurately perform radical resections. However, to date, there is no accurate method for evaluating nodal status intraoperatively. In this study, we synthesized activatable cell-penetrating peptides (ACPPs) that can specifically recognize colorectal cancer and their nodal status. ACPPs were labeled with Cy5 dye at the C-terminal, and named ACPP-Cy5. Laser scanning confocal microscopy and flow cytometry were used to measure the change in intracellular fluorescence intensity between cancer cells and normal cells. The results showed while the intracellular Cy5 fluorescent intensity can be visualized in both cancer and normal cells by 8 h after adding ACPP-Cy5, the relative fluorescence intensity of colorectal cancer cells was significantly higher than the normal cells. In addition, IVIS spectrum in vivo imaging system was used to observe the fluorescence intensity of ACPP-Cy5 after tail vein injection of mice with subcutaneous tumor or orthotopic colorectal cancer and liver metastasis. We found in mice with colorectal cancer and liver metastasis the Cy5 fluorescence intensity of cancer was significantly increased compared to the organs including liver, colorectum, lung, spleen, and heart. It is demonstrated here, this ACPPs can target colorectal cancer and liver metastasis, therefore ACPP-Cy5 may be a promising tool used for the diagnoses of colorectal cancer and to assist in tumor localization during surgery.

Mitochondria-acting nanomicelles for destruction of cancer cells via excessive mitophagy/autophagy-driven lethal energy depletion and phototherapy.

Mitophagy is a specific self-protective autophagic process that degrades damaged or dysfunctional mitochondria, and is generally considered to reduce the effectiveness of mitochondria-targeted therapies. Here, we report an energy depletion-based anticancer strategy by selectively activating excessive mitophagy in cancer cells. We fabricate a type of mitochondria-targeting nanomicelles via the self-assembly of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and dc-IR825 (a near-infrared cyanine dye and a photothermal agent). The TPGS/dc-IR825 nanomicelles enable mitochondrial damage in cancer cells, which, for self-protection, activate two autophagic pathways, (1) mitophagy and (2) adenosine triphosphate (ATP) shortage-triggered autophagy. However, the excessive mitophagy/autophagy activities far surpass the degradative capacity of autolysosomes, leading to the formation of micrometer-sized vacuoles and degradation blockage. Immunofluorescence staining and Western blot analysis reveal that the nanomicelle-treated cancer cells are under severe ATP shortage, which eventually causes substantial cell death. Moreover, the nanomicelles intravenously injected into tumor-bearing mice show high tumor accumulation, long tumor retention, and inhibit the tumor growth by inducing excessive mitophagy/autophagy and energy depletion in tumor cells. Additional near-infrared laser irradiation treatment further enhances the in vitro and in vivo anticancer efficiencies of the nanomicelles, due to the excellent photothermal and photodynamic effects of dc-IR825. We believe that this work highlights the important role of mitophagy/autophagy in treating cancers.

Construction of Dually Responsive Nanotransformers with Nanosphere-Nanofiber-Nanosphere Transition for Overcoming the Size Paradox of Anticancer Nanodrugs.

Tumor microenvironment (TME)-responsive nanosystems represent a category of intelligent nanomaterials for precise anticancer drug delivery. Herein, we report a smart size-/morphology-switchable nanodrug that can respond to the acidic TME and near-infrared (NIR) laser irradiation for effective tumor ablation and tumor metastasis inhibition. The nanoagent is physically assembled by a cytolytic peptide, melittin (MEL), an NIR-absorbing molecule, cypate, and a tumor-targeting polymer, hyaluronic acid (HA). At pH 7.4, the as-formed MEL/Cypate@HA complexes are negatively charged nanospheres (∼50 nm), which are suitable for long-term systemic circulation. When these nanospheres actively target tumors, the weakly acidic TME triggers an in situ transformation of the nanospheres to net-like nanofibers. Compared with the nanospheres, the nanofibers not only exhibit an inhibitory effect on tumor cell mobility but also significantly prolong the retention time of MEL/Cypate@HA in tumor tissues for MEL-based chemotherapy. Moreover, the nanofibers can be photodegraded into small nanospheres (∼25 nm) by NIR laser irradiation during cypate-mediated photothermal therapy, which enables deep tumor penetration of the loaded MEL and thus achieves effective tumor eradication. This work provides a facile strategy for converting naturally occurring therapeutic peptides into a TME-responsive drug delivery system and may inspire the development of nanomaterials with changeable structures for therapeutic purposes.

Molecular Targeting-Mediated Mild-Temperature Photothermal Therapy with a Smart Albumin-Based Nanodrug.

Photothermal therapy (PTT) usually requires hyperthermia >50 °C for effective tumor ablation, which inevitably induces heating damage to the surrounding normal tissues/organs. Moreover, low tumor retention and high liver accumulation are the two main obstacles that significantly limit the efficacy and safety of many nanomedicines. To solve these problems, a smart albumin-based tumor microenvironment-responsive nanoagent is designed via the self-assembly of human serum albumin (HSA), dc-IR825 (a cyanine dye and a photothermal agent), and gambogic acid (GA, a heat shock protein 90 (HSP90) inhibitor and an anticancer agent) to realize molecular targeting-mediated mild-temperature PTT. The formed HSA/dc-IR825/GA nanoparticles (NPs) can escape from mitochondria to the cytosol through mitochondrial disruption under near-infrared (NIR) laser irradiation. Moreover, the GA molecules block the hyperthermia-induced overexpression of HSP90, achieving the reduced thermoresistance of tumor cells and effective PTT at a mild temperature (<45 °C). Furthermore, HSA/dc-IR825/GA NPs show pH-responsive charge reversal, effective tumor accumulation, and negligible liver deposition, ultimately facilitating synergistic mild-temperature PTT and chemotherapy. Taken together, the NIR-activated NPs allow the release of molecular drugs more precisely, ablate tumors more effectively, and inhibit cancer metastasis more persistently, which will advance the development of novel mild-temperature PTT-based combination strategies.

Efficient cell surface labelling of live zebrafish embryos: wash-free fluorescence imaging for cellular dynamics tracking and nanotoxicity evaluation.

Imaging the dynamics and behaviors of plasma membranes is at the leading edge of life science research. We report here the development of a universal red-fluorescent probe Chol-PEG-Cy5 for wash-free plasma membrane labelling both in vitro and in vivo. In aqueous solutions, the fluorescence of Chol-PEG-Cy5 is significantly quenched due to the intermolecular resonance energy transfer (RET) between neighbouring Cy5 moieties; however, upon membrane anchoring, the probes undergo lateral diffusion in lipid bilayers, resulting in weakened RET and turn-on fluorescence emission. We demonstrate that Chol-PEG-Cy5 enables rapid, stable and high-quality in vitro cell surface imaging in a variety of mammalian cells. Additionally, with the assistance of three-dimensional (3D) image reconstruction, we achieve for the first time the whole-mount in situ fluorescence imaging of the epidermal cell surfaces of live zebrafish embryos, which cannot be realized by conventional plasma membrane probes due to the presence of the surface-covering mucus barrier. This novel technique encourages us to track the cellular dynamics of the epidermis during embryonic development with 3D visualization. Moreover, we also develop a new method to evaluate the epidermal toxicity of nanomaterials (e.g., gold nanoparticles and graphene oxide nanosheets) toward zebrafish embryos using this fluorescent probe.

Development of a Light-Controlled Nanoplatform for Direct Nuclear Delivery of Molecular and Nanoscale Materials.

Research on nanomedicines has rapidly progressed in the past few years. However, due to the limited size of nuclear pores (9-12 nm), the nuclear membrane remains a difficult barrier to many nucleus-targeting agents. Here, we report the development of a general platform to effectively deliver chemical compounds such as drug molecules or nanomaterials into cell nuclei. This platform consists of a polyamine-containing polyhedral oligomeric silsesquioxane (POSS) unit, a hydrophilic polyethylene glycol (PEG) chain, and the photosensitizer rose bengal (RB), which can self-assemble into nanoparticles (denoted as PPR NPs). Confocal fluorescence imaging showed that PPR NPs mainly located in lysosomes after cellular internalization. After mild light irradiation, however, PPR NPs effectively disrupted lysosomal structures by singlet oxygen (1O2) oxidation and substantially accumulated on nuclear membranes, which enabled further disruption of the membrane integrity and promoted their final nuclear entry. Next, we selected two chemotherapeutic agents (10-hydroxycamptothecine and docetaxel) and a fluorescent dye (DiD) as payloads of PPR NPs and successfully demonstrated that this nanocarrier could efficiently deliver them into cell nuclei in a light-controlled manner. In addition to molecular compounds, we have also demonstrated that PPR NPs could facilitate the nuclear entry of nanomaterials, including Prussian blue NPs as well as gold nanorods. Compared to traditional strategies for nuclear delivery, this highly controllable nanoplatform avoids complicated modification of nucleus-targeting ligands and is generally applicable to both molecular compounds and nanomaterials.

Turning double hydrophilic into amphiphilic: IR825-conjugated polymeric nanomicelles for near-infrared fluorescence imaging-guided photothermal cancer therapy.

Developing biocompatible and photodegradable photothermal agents (PTAs) holds great promise for potential clinical applications in photothermal cancer therapy. Herein, a new PTA was innovatively constructed by conjugating the hydrophobic near-infrared (NIR) heptamethine cyanine molecule IR825-NH2 with a double hydrophilic block copolymer methoxypoly(ethylene glycol)5k-block-poly(l-aspartic acid sodium salt)10 (abbreviated as PEG-PLD) via amine-carboxyl reaction. The as-designed PEG-PLD(IR825) was amphiphilic and could self-assemble into polymeric nanomicelles in aqueous solutions. Benefiting from the chemical conjugation strategy, PEG-PLD(IR825) nanomicelles realized a considerably high drug loading rate (∼21.0%) and substantially avoided the premature release of IR825 during systemic circulation. Confocal imaging revealed that the nanomicelles mainly located at mitochondria and endoplasmic reticulum after cellular internalization. In vitro photothermal therapy demonstrated the excellent cancer killing efficiency of PEG-PLD(IR825) nanomicelles due to their high light-to-heat conversion efficiency upon NIR laser irradiation. In addition, PEG-PLD(IR825) nanomicelles showed polarity-sensitive fluorescence at ∼610 nm (under 552 nm excitation) and 830 nm (under 780 nm excitation), which was especially useful for both in vitro visible fluorescence imaging and in vivo near-infrared fluorescence imaging-guided photothermal therapy (PTT). At the in vivo level, PEG-PLD(IR825) nanomicelles exhibited an excellent tumor-homing ability and a long retention time in tumor tissues as evidenced by the in vivo fluorescence imaging results. The desirable properties of PEG-PLD(IR825) nanomicelles ensured their effective tumor ablation during PTT treatment. More importantly, the PEG-PLD(IR825) nanomicelles underwent degradation after laser irradiation, which ensured their post-treatment biosafety. Therefore, the nanomicelles are promising to serve as an efficient and safe PTA for imaging-guided photothermal cancer therapy.