Cascade-Targeting of Charge-Reversal and Disulfide Bonds Shielding for Efficient DOX Delivery of Multistage Sensitive MSNs-COS-SS-CMC.

BACKGROUND: Although pH and redox sensitiveness have been extensively investigated to improve therapeutic efficiency, the effect of disulfide bonds location and pH-triggered charge-reversal on cascade-targeting still need to be further evaluated in cancer treatment with multi-responsive nanoparticles. PURPOSE: The aim of this study was to design multi-responsive DOX@MSNs-COS-NN-CMC, DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS and systematically investigate the effects of disulfide bonds location and charge-reversal on the cancer cell specificity, endocytosis mechanisms and antitumor efficiency. RESULTS: In vitro drug release rate of DOX@MSNs-COS-SS-CMC in tumor environments was 7-fold higher than that under normal physiological conditions after 200 h. Furthermore, the fluorescence intensity of DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS was 1.9-fold and 1.3-fold higher than free DOX at pH 6.5 and 10 mM GSH. In addition, vesicular transport might be a factor that affects the uptake efficiency of DOX@MSNs-COS-SS-CMC and DOX@MSNs-COS-CMC-SS. The clathrin-mediated endocytosis and endosomal escape of DOX@MSNs-COS-SS-CMC enhanced cellular internalization and preserved highly controllable drug release into the perinuclear of HeLa cells. DOX@MSNs-COS-SS-CMC exhibited a synergistic chemotherapy in preeminent tumor inhibition and less side effects of cardiotoxicity. CONCLUSION: The cascade-targeting of charge-reversal and disulfide bonds shielding would be a highly personalized strategy for cervical cancer treatment.

Use of high-fidelity 3-dimensional-printed models for training novice residents in basic nasal endoscopic skills.

BACKGROUND: The use of 3-dimensional (3D)-printed models is promising in nasal endoscopic technique training. Here, we aimed to develop postsurgical simulants for use in conjunction with 3D-printed nasal models and to assess their usefulness in helping residents transfer basic endoscopic skills acquired during simulation training to clinical situations. METHODS: The secretion simulant was prepared via a crosslinked reaction between sodium alginate and acrylamide, whereas the packing simulant was prepared using a superabsorbent polymer. After the simulants' fidelity and utility were evaluated by 5 rhinologists using a 5-point Likert scale, 46 novice residents were trained using the 3D-printed nasal models and postsurgical simulants for 2 weeks. A checklist and Global Rating Scale (GRS) were used to assess their performances before and after training, and the time to finish each task was also recorded. Following training, the qualified trainees operated on real patients and were reevaluated. RESULTS: The simulants' similarity and usefulness scored ≥4.0, and the training cost was 28 CNY ($4 USD) per session. Following training, the checklist and GRS scores increased, and the operation time decreased (all p < 0.05). There were no statistical differences between the trainees' performances on the models with the simulants and on patients (all p > 0.05). CONCLUSION: The low-cost simulated secretion and dressing are safe to use. The application of the simulants in conjunction with that of 3D-printed nasal models in a simulated task setting can help residents in transferring endoscopic skills acquired during simulation teaching to real patients.

Cell Type-Dependent Specificity and Anti-Inflammatory Effects of Charge-Reversible MSNs-COS-CMC for Targeted Drug Delivery in Cervical Carcinoma.

The surface charge of nanocarriers inevitably affects drug delivery efficiency; however, the cancer cell specificity, anti-inflammatory effects, and charge-reversal points remain to be further addressed in biomedical applications. The aim of this study was to comprehensively assess the cancer cell specificity of DOX-loaded mesoporous silica-chitosan oligosaccharide-carboxymethyl chitosan nanoparticles (DOX@MSNs-COS-CMC) in MCF-7 and HeLa cells, inhibit the production of inflammatory cytokines, and improve the drug accumulation in the tumor site. Intracellular results reveal that the retention time prolonged to 48 h in both HeLa and MCF-7 cells at pH 7.4. However, DOX@MSNs-COS-CMC exhibited a cell type-dependent cytotoxicity and enhanced intracellular uptake in HeLa cells at pH 6.5, due to the clathrin-mediated endocytosis and macropinocytosis in HeLa cells in comparison with the vesicular transport in MCF-7 cells. Moreover, Pearson's correlation coefficient value significantly decreased to 0.25 after 8 h, prompting endosomal escape and drug delivery into the HeLa nucleus. After the treatment of MSNs-COS-CMC at 200 µg/mL, the inflammatory cytokines IL-6 and TNF-α level decreased by 70% and 80%, respectively. Tumor inhibition of DOX@MSNs-COS-CMC was 0.4 times higher than free DOX, alleviating cardiotoxicity and inflammation in the HeLa xenograft tumor model. Charge-reversible DOX@MSNs-COS-CMC could be a possible candidate for clinical therapy of cervical carcinoma.

Amphiphilic poly(caprolactone-b-N-hydroxyethyl acrylamide) micelles for controlled drug delivery.

To increase the bioavailability and water solubility of hydrophobic medicine, an amphiphilic block copolymer, polycaprolactone-block-polyhydroxyethyl acrylamide (PCL-b-PHEAA), was synthesized. The copolymer can self-assemble into micelles by dialysis. The micelles were characterized by the Tyndall effect, static drop method, fluorescence spectrometry, dynamic light scattering, scanning electron microscopy and transmission electron microscopy. Ibuprofen was encapsulated inside the micelles by dialysis as a model medicine. The results show that the amphiphilic copolymer forms a uniform micelle system, with spherical micelles dispersed well in solution which have a low critical micelle concentration. In addition, the system shows good amphipathic behavior. Average particle size of a micelle is 104 nm, which increases a lot after drug loading and standing for half a month. In the first few hours, the cumulative release of the drug increases gradually; the rate of increase in the first ten hours is faster, then reaching a plateau which tends to be flat finally. It is similar under two different pH conditions. This biocompatible, biodegradable amphiphilic block copolymer has potential applications in the biomedical field.

pH-Triggered Charge-Reversal Mesoporous Silica Nanoparticles Stabilized by Chitosan Oligosaccharide/Carboxymethyl Chitosan Hybrids for Effective Intracellular Delivery of Doxorubicin.

Surface modification of mesoporous silica nanoparticles (MSNs) is a promising way to enhance therapeutic efficacy and minimize side effects of anticancer drugs. In this work, MSNs with reduced particle size and optimum pore diameter were obtained and catalyzed by ammonia/triethanolamine. In view of the negatively charged carboxymethyl chitosan (CMC) and positively charged chitosan oligosaccharide (CS), the pH-triggered charge-reversal CS/CMC bilayer was designed as a stimuli-responsive switch for MSNs via the protonation and deprotonation effect. The results showed that MSNs-CS/CMC were core-shell and mesoporous in structure. Surface charge conversion and pH dependence were clearly observed in the doxorubicin hydrochloride (DOX) delivery. The intracellular uptake indicated that DOX@MSNs-CS/CMC could be distributed in the cytoplasm of MCF-7 cells and exhibited lower toxicity, which would improve the stability and prolong the retention time compared to free DOX and unmodified DOX@MSNs at pH 7.4. Moreover, the cellular uptake and internalization of DOX@MSNs-CS/CMC were enhanced to promote drug delivery into the cell nucleus at pH 6.5. The biocompatible and surface-charge-reversible MSNs-CS/CMC have the potential to prolong the retention time in the bloodstream, facilitate the endosome escape, and enrich the targeted antitumor strategy, providing an alternative platform for efficient drug delivery in breast cancer therapy.

[Clinical features of hepatitis A in 1,629 children].

BACKGROUND: To investigate the clinical features of hepatitis A in 1 629 children under 14 years of age treated in our department at various periods of time. METHODS: The patients were divided into two groups: 1. Group A consisted of 883 patients treated from January 1984 to December 1990; 2. Group B consisted of 746 patients treated from January 1991 to December 2000. The clinical data of all the patients were retrospectively analyzed. RESULTS: 1. The average age was 7.17+/-3.27 and 8.78+/- 3.28 years (chi2=0.54, P>0.05) and the mean course of disease 26.25+/-16.96 and 25.65+/-12.58 days (chi2=0.29, P>0.05). 2. Double peak or multi-peak serum ALT was found in 89 patients. Four peaks of serum ALT was found in one patient. 3. HBsAg was found positive in 143 patients (8.80%). The mean course of disease was 34.40+/-25.86 and 25.20+/-15.43 days (chi2=146.5, P<0.001) in HBsAg positive and negative patients, respectively. 4. Liver puncture biopsy in 26 patients with hepatitis A showed that there was piecemeal necrosis in 2 patients. CONCLUSIONS: 1. There was no significant delay in age of children with HAV infection in 1990s. There was no marked difference in the course of disease between the patients simultaneously receiving various drugs and those receiving one or two drugs. 2. The double peak or multi-peak of serum ALT in patients with hepatitis A might be related to liver damage caused by HAV and immune mechanism. 3. The major type of virus for combined infection in patients with hepatitis A is HBV. The course of disease was prolonged with combined infection of HBV. 4. Piecemeal necrosis might be seen in the liver of a small proportion of patients with hepatitis A alone, which may not be enough to suggest chronicity.