[Preparation and characterization of near-infrared responsive sinomenine hydrochloride reservoir microneedles].

The present study designed and prepared near-infrared responsive sinomenine hydrochloride(SIN) reservoir microneedles and evaluated the feasibility of this type of microneedles in increasing the drug loading and transdermal absorption by characterizing their mechanical properties and in vitro release characteristics.SIN was selected as the model drug, and methoxy poly(ethylene glycol) poly(caprolactone)(mPEG-PCL) copolymers and indocyanine green(ICG) were employed as amphiphilic block copolymers and light inductor to prepare near-infrared responsive nanoparticles.Based on the preparation principle of bubble microneedles, near-infrared responsive SIN reservoir microneedles were designed and prepared.The features of the near-infrared responsive SIN reservoir microneedles were characterized by measuring the morphology, length, mechanical properties, and skin penetration of microneedles.Meanwhile, the drug release performance of reservoir microneedles was evaluated by in vitro release assay.The results showed that the prepared SIN microneedles were conical, with an exposed tip height of about 650 µm.Each needle could load about 0.5 mg of drugs per square centi-meter, and this type of microneedle showed good mechanical properties and performance in skin penetration.The results of the in vitro release assay showed that the 24 h cumulative release per unit area and release rate of the microneedle were 825.61 µg·cm~(-2) and 74.3%, respectively, which indicated that its release kinetics was in line with the first-order kinetic model.This study preliminarily proved that the reservoir microneedle could effectively increase the drug loading with good mechanical properties and release perfor-mance.

The efficacy of dental floss and a hemoclip as a traction method for the endoscopic full-thickness resection of submucosal tumors in the gastric fundus.

BACKGROUND: Endoscopic full-thickness resection (EFTR) provides a significant advancement to the treatment of gastrointestinal submucosal tumors (SMTs). However, technological challenges, particularly in the gastric fundus, hinder its wider application. Here, we investigated the efficacy of a simple traction method that used dental floss and a hemoclip (DFC) to facilitate EFTR. METHODS: Between July 2014 and December 2016, we retrospectively reviewed data from all patients with SMTs in the gastric fundus originating from the muscularis propria layer that were treated by EFTR at Zhongshan Hospital of Fudan University. Baseline characteristics and clinical outcomes, including procedure time and complications rate, were compared between groups of patients receiving DFC-EFTR and conventional EFTR. RESULTS: A total of 192 patients were included in our analysis (64 in the DFC-EFTR group and 128 in the conventional EFTR group). Baseline characteristics for the two groups were similar. The mean time for DFC-EFTR and conventional EFTR was 44.2 ± 24.4 and 54.2 ± 33.2 min, respectively (P = 0.034). Although no serious adverse events presented in any of our cases, post-EFTR electrocoagulation syndrome (PEECS), as a minor complication, was less frequent in the DFC-EFTR group (3.1% vs. 12.5%, P = 0.036). Univariate and multivariate analysis identified that DFC, when used in EFTR, played a significant role in reducing procedure time and the rate of PEECS. The mean procedure time was significantly shorter in the DFC-EFTR group for lesions over 1.0 cm (P = 0.005), when the lesions were located in the greater curvature of the gastric fundus (P = 0.025) or when the lesions presented with intraluminal growth (P = 0.032). Moreover, when EFTR was carried out by experts, the mean procedure time was 20.4% shorter in the DFC-EFTR group (P = 0.038). CONCLUSIONS: This study indicated that DFC-EFTR for SMTs in the gastric fundus resulted in a shorter procedure time and reduced the risk of PEECS, a minor complication.

A cremophor-free self-microemulsified delivery system for intravenous injection of teniposide: evaluation in vitro and in vivo.

In order to tackle the problems on low water solubility of teniposide, involvement of toxic surfactant in its injection, and the poor stability during infusion, a Cremophor-free teniposide self-microemulsified drug delivery system (TEN-SMEDDS) was prepared for the first time, characterized, and evaluated in comparison with teniposide injection (VUMON) in vitro and in vivo. The optimized formulation contained N, N-dimethylacetamide, medium-chain triglyceride, lecithin, and dehydrated alcohol besides teniposide. The TEN-SMEDDS could form fine droplets with mean diameter of 282 ± 21 nm and zeta potential of -7.5 ± 1.7 mV after dilution with 5% glucose, which were stable within 4 h. The release of teniposide from TEN-SMEDDS and VUMON was similar. However, the pharmacokinetic behavior of TEN-SMEDDS in rats was different from that of VUMON, evidenced by the lower area under the concentration-time curve and larger volume of distribution in emulsion group. Finally, TEN-SMEDDS was found to distribute more teniposide in most tissues, especially in reticuloendothelial system, after intravenous administration to rats. Importantly, brain drug level in TEN-SMEDDS group was higher than or similar to that in control group, although the emulsion system had a lower plasma drug concentration. In conclusion, the novel SMEDDS prepared here, without toxic surfactant and as an oil solution before use, may be potential for clinical use due to its low toxicity and high store stability. It may be favorable for the treatment of some tumors like cerebroma, since it may achieve the relatively higher drug level in brain but lower blood concentration.

Biological Hair-Inspired AgNWs@Au-Embedded Nafion Electrodes with High Stability for Self-Powered Ionic Flexible Sensors.

Ionic flexible sensors (IFS) usually consist of an ionomer matrix and two conductive electrodes, the failure of which mostly originates from interfacial debonding between matrix and electrode layers. To improve electrode's adhesion and impedance matching with matrix, polymer binder or plasmonic heating technology is used to enhance the adhesion of electrodes, but there are technical challenges such as high resistance and harsh conditions. Herein, inspired by biological hair, we proposed a reliable and facile method to form AgNWs@Au-embedded Nafion flexible electrodes (AN FEs) for IFS without rigorous temperature and harsh conditions. Through integrating the spraying and electrodepositing Au method, we achieved that the AgNWs are partly embedded in the matrix layer for forming the embedded layer, similar to the root of biological hair, which is used to fix the FEs and collect the ion charges. The other parts of AgNWs exposed on the surface form the conductive mesh layer for transmitting the signal, analogous to the tip of biological hair. Compared with other AgNWs FEs, AN FEs exhibit high adhesion (∼358 kPa) and low sheet resistance (∼ 3.7 Ω/□), and high stabilities after 100 washing cycles, 200 s H2O2 corrosion or 1500s HCl corrosion. A self-powered IFS prepared by AN FEs can achieve dual sensing of mechanical strain and ambient humidity and still has promising sensing performance after being exposed to air for 2 months, which further indicates potential applications of the prepared FEs in next-generation multifunctional flexible electronic devices.

[The crystalline polymorph control and selection of gabapentin with polymer heteronuclei].

The pharmaceutical properties, including the physical and chemical properties, and the bioavailability are greatly influenced by their polymorphism. In this paper the polymer heteronuclei were used to produce the gabapentin polymorphs that were characterized by X-ray powder diffraction, FT-IR and DSC. The results indicated that the polymer heteronuclei are an effective method to control and select the gabapentin polymorphism. One new polymorph of gabapentin was found besides all known gabapentin polymorphs.

Platelet membrane-cloaked paclitaxel-nanocrystals augment postoperative chemotherapeutical efficacy.

Chemotherapy post cancer surgery has important clinical significance for reducing the chance of recurrent-metastasis. However, postoperative chemotherapy efficacy is hampered by poor targeting capability and dose-limiting toxicity of chemo-drugs. Herein, we report a bio-mimetic platelet membrane-cloaked paclitaxel nanocrystal system (PPNCs), which consists of spherical paclitaxel nanocrystals (PNCs) as a high-dose drug core, polyethylene glycol-conjugated paclitaxel (PEG-PTX) as an amphiphilic molecule to adjust the surface hydrophilicity of PNCs and the shell of platelet membrane that can target surgical coagulation site. The in vitro characterization of PPNCs exhibited uniform particle size distribution, high drug loading, and good stability, which are crucial for effective drug delivery. At cell levels, PPNCs showed greater cellular uptake and higher cytotoxicity in 4T1 breast cancer cells than bare PNCs. In vivo, the nanoparticles could deliver high-dose chemo-drugs and target the coagulation site caused by surgery or vascular disrupting agents, resulting in enhanced anti-tumor efficacy and reduced systemic toxicities. In general, the PPNCs system can be served as a promising and efficient drug delivery system for postoperative chemotherapy.

cRGDfK-Grafted Small-Size Quercetin Micelles For Enhancing Therapy Efficacy Of Active Ingredient From The Chinese Medicinal Herb.

BACKGROUND: As an active ingredient of Chinese herbal medicine, quercetin (QU) can significantly induce apoptosis of tumor cells and give play to other effect such as decreasing both fibroblast population and collagen in cancer cell nest. However, the antitumor efficacy of quercetin was mostly evaluated at cellular level and rarely developed in vivo by intravenous injection, which may be ascribed to its inferior physicochemical properties including water insolubility, short plasma half-time, and insufficient enrichment in the tumor tissues. METHODS: The DSPE-PEG was used to construct quercetin-loaded micelles, and the integrin ligand cRGDfK was grafted to modify the nanocarrier for enhancing its cancer-specific homing. The MALDI-TOF-MS, DLS, TEM, and UV were orderly operated to characterize guidance molecules and micelles by morphology, size distribution, Zeta potential, and drug encapsulation efficiency. In addition, the surface plasmon resonance study and real-time confocal analysis were employed to demonstrate αvß3 integrin-overexpressing B16 cells-specific binding and uptake. After further pharmacodynamics studies in vitro and in vivo, we also evaluate systemic toxicity about cRGDfK-PM-QU. RESULTS: The cRGDfK was successfully stitched with DSPE-PEG and modified on the surface of micelles. The ligand modification enhanced the negative charges of the micelles, but it did not induce significant changes in particle size. The quercetin micelles were about 15 nm in size and negatively charged, and had spherical morphology and high drug encapsulation efficiency. In vitro, the cRGDfK-modified micelles (cRGDfK-PM) showed αvß3 integrin-overexpressing B16 cells-specific binding and uptake, and cRGDfK-PM-QU (QU loaded in cRGDfK-PM) induced more significant cell apoptosis and cytotoxic effects against B16 tumor cells than counterpart micelles (PM-QU). In vivo, the cRDGfK modification enhanced enrichment in B16 tumor tissue, improved the therapeutic efficacy of the quercetin-loaded micelles against B16 tumor, and exhibited lower systemic and pulmonary toxicity compared with counterpart micelles in the mouse mode. CONCLUSION: Quercetin as a natural product has triggered increasing interest in the antitumor field. In this study, cRGDfK-modified DSPE-PEG micelles significantly optimized quercetin therapeutic efficacy and pulmonary toxicity as well as lowered systemic toxicity.

α-Conotoxin ImI-modified polymeric micelles as potential nanocarriers for targeted docetaxel delivery to α7-nAChR overexpressed non-small cell lung cancer.

A micelle system modified with α-Conotoxin ImI (ImI), a potently antagonist for alpha7 nicotinic acetylcholine receptor (α7-nAChR) previously utilized for targeting breast cancer, was constructed. Its targeting efficiency and cytotoxicity against non-small cell lung cancer (NSCLC) highly expressing α7-nAChR was investigated. A549, a non-small cell lung cancer cell line, was selected as the cell model. The cellular uptake study showed that the optimal modification ratio of ImI on micelle surface was 5% and ImI-modification increased intracellular delivery efficiency to A549 cells via receptor-mediated endocytosis. Intracellular Ca2+ transient assay demonstrated that ImI modification led to enhanced molecular interaction between nanocarriers and A549 cells. The in vivo near-infrared fluorescence imaging further revealed that ImI-modified micelles could facilitate the drug accumulation in tumor sites compared with non-modified micelles via α7-nAChR mediation. Moreover, docetaxel (DTX) was loaded in ImI-modified nanomedicines to evaluate its in vitro cytotoxicity. As a result, DTX-loaded ImI-PMs exhibited greater anti-proliferation effect on A549 cells compared with non-modified micelles. Generally, our study proved that ImI-modified micelles had targeting ability to NSCLC in addition to breast cancer and it may provide a promising strategy to deliver drugs to NSCLC overexpressing α7-nAChR.

Clinical Values of Dental Floss Traction Assistance in Endoscopic Full-Thickness Resection for Submucosal Tumors Originating from the Muscularis Propria Layer in the Gastric Fundus.

BACKGROUND: Endoscopic full-thickness resection (EFTR) derived from endoscopic submucosal dissection has gradually been accepted and even promoted for the treatment of submucosal tumors (SMTs) originating from the muscularis propria (MP) layer. However, there are some difficulties when EFTR is used to treat MP lesions in the gastric fundus. This study intends to explore whether EFTR can be made simpler, safer, and more effective with the traction assistance of dental floss. METHODS: The clinical data of patients (trial group) with lesions in the MP layer in the gastric fundus undergoing EFTR with traction assistance of dental floss at Zhongshan Hospital, in 2016, were reviewed retrospectively. The control group was matched with the trial group according to tumor size. The differences in tumor resection time, patient hospitalization time, and complication rate were evaluated. RESULTS: There was no significant difference in the average age of the two groups, each of which comprised 24 cases (58.7 ± 11.8 years versus 56.6 ± 7.9 years, t = 0.663, P = .511). However, there was a statistically significant difference in the operative time between the two groups (10.8 ± 2.8 minutes versus 19.0 ± 4.7 minutes, t = 7.298, P < .05). There was no statistically significant difference in the length of the postoperative hospital stay (3.2 ± 0.5 days versus 3.2 ± 0.5 days, t = 0.291, P = .772). In the trial group, there were 19 cases of gastrointestinal stromal tumors (group 1) and 5 cases of leiomyoma. The control group had similar results. Neither group experienced postoperative delayed bleeding, perforation, or other complications. CONCLUSIONS: When EFTR is used to treat SMTs originating from the MP in the gastric fundus, dental floss traction assistance can relieve the tumor boundary to simplify the surgical procedure and save the operation time.

Radiographic and clinical outcomes of rooted, platform-switched, microthreaded implants with a sandblasted, large-grid, and acid-etched surface: A 5-year prospective study.

BACKGROUND: There is no data available on the long-term outcomes of a rooted, platform-switched, microthreaded implant with a sandblasted, large-grid, and acid-etched surface. PURPOSE: This prospective, longitudinal study evaluated the clinical and radiographic outcomes of rooted, platform-switched, microthreaded and sandblasted, large-grid, and acid-etched (SLA) surface implants for 5 years. MATERIALS AND METHODS: Sixty implants were placed in sixty patients with partially edentulous maxillae or mandibles. The permanent prostheses were inserted 2-4 months after implant placement. Clinical and radiographic examinations were performed at follow-up visits scheduled postoperation, prosthesis installation, 1 year, and 5 years after surgery, to assess implant survival and success rates, biological and mechanical complications, and marginal bone loss. RESULTS: After 5 years' follow-up, four patients withdrawn from the study, and 56 implants achieved a 100% survival rate and 98.2% success rate. Three prosthetic complications occurred, resulting in a success rate for prostheses of 94.6%. The incidence of peri-implant mucositis was 9.1% and no peri-implantitis was diagnosed. The average marginal bone loss at the mesial aspect was 0.46 ± 0.27 mm after 1 year and 0.48 ± 0.27 mm after 5 years. The average marginal bone loss at the distal aspect was 0.46 ± 0.32 mm after 1 year and 0.50 ± 0.35 mm after 5 years. CONCLUSION: After 5 years of loading, the rooted, platform-switched, microthreaded, and SLA surface implants showed high survival and success rates, steady crestal bone levels, and excellent long-term clinical outcomes in the soft tissue. Overloading may be related to the marginal bone loss around implants, but the surgical protocol, different sites, and jaw position did not correlate with crestal bone loss.

Comprehensively priming the tumor microenvironment by cancer-associated fibroblast-targeted liposomes for combined therapy with cancer cell-targeted chemotherapeutic drug delivery system.

Cancer-associated fibroblasts (CAFs) not only support tumorigenesis and tumor metastasis by reciprocal cellular cross-talk with cancer cells, but also remodel the extracellular matrix (ECM) and architecture of tumor microenvironment. This leads to poor tumor penetration of traditional chemotherapeutic nanomedicines and resulting drug resistance. In this study, we use a novel tumor stroma-targeted nanovehicle (FH-SSL-Nav) to specifically eradicate CAFs, promote tumor penetration of nanomedicines and cut off the stroma's support to cancer cells. FH-SSL-Nav exhibited excellent and comprehensive tumor microenvironment modulation including downregulation ECM deposition, decreasing interstitial fluid pressure (IFP) and facilitating blood perfusion. As a result, more chemotherapeutic drug delivery systems penetrated deep into tumor spheroids in vitro and tumor tissues in vivo. Furthermore, chemotherapeutic drug resistance induced by microenvironment was partly reversed by FH-SSL-Nav. In a human Hep G2 xenograft nude mouse model, FH-SSL-Nav greatly improved the tumor suppression of cancer cell-targeted liposomal doxorubicin (7pep-SSL-DOX) with low dose and low toxicity. Since Nav and DOX exhibited no synergy against Hep G2 cells, it was clear that the improved antitumor efficacy was basically due to the comprehensive tumor microenvironment priming by FH-SSL-Nav.

A folate modified pH sensitive targeted polymeric micelle alleviated systemic toxicity of doxorubicin (DOX) in multi-drug resistant tumor bearing mice.

PURPOSE: The purpose of this work was to demonstrate the advantages of a folate modified pH sensitive micelle system (HPPF) on reducing the systemic toxicity of antitumor drug doxorubicin (DOX) as well as increasing the antitumor efficacy on multi-drug resistant tumor. METHODS: The micelle HPPF was fabricated by PHIS-PEG and Fol-PEG-PLA using dialysis method. Multi-drug resistant human breast-cancer cell (MCF-7Adr) was used to test the therapeutic effect of DOX loaded HPPF micelles (HPPF/DOX). Nude mice bearing MCF-7Adr tumor was used to evaluate the systemic toxicity of HPPF/DOX. RESULTS: The micelle HPPF was successfully prepared with good size uniformity and pH sensitivity. The in vitro experiments showed that HPPF significantly increased the intracellular level and cytotoxicity of DOX. The in vivo experiments demonstrated that HPPF had largely reduced the mortality and body weight loss, improved the animal status and decreased damages on heart and lung tissues comparing to free DOX. CONCLUSIONS: The HPPF/DOX could significantly increase the antitumor efficacy of DOX and largely alleviate the systemic side effects induced by high dose DOX in the treatment of multi-drug resistant tumor.

The use of α-conotoxin ImI to actualize the targeted delivery of paclitaxel micelles to α7 nAChR-overexpressing breast cancer.

Alpha7 nicotinic acetylcholine receptor (α7 nAChR), a ligand-gated ion channel, is increasingly emerging as a new tumor target owing to its expression specificity and significancy for cancer. In an attempt to increase the targeted drug delivery to the α7 nAChR-overexpressing tumors, herein, α-conotoxin ImI, a disulfide-rich toxin with highly affinity for α7 nAChR, was modified on the PEG-DSPE micelles (ImI-PMs) for the first time. The DLS, TEM and HPLC detections showed the spherical nanoparticle morphology about 20 nm with negative charge and high drug encapsulation. The ligand modification did not induce significant differences. The immunofluorescence assay confirmed the expression level of α7 nAChR in MCF-7 cells. In vitro and in vivo experiments demonstrated that the α7 nAChR-targeted nanomedicines could deliver more specifically and faster into α7 nAChR-overexpressing MCF-7 cells. Furthermore, fluo-3/AM fluorescence imaging technique indicated that the increased specificity was attributed to the ligand-receptor interaction, and the inducitivity for intracellular Ca(2+) transient by ImI was still remained after modification. Moreover, paclitaxel, a clinical frequently-used anti-tumor drug for breast cancer, was loaded in ImI-modified nanomedicines to evaluate the targeting efficacy. Besides of exhibiting greater cytotoxicity and inducing more cell apoptosis in vitro, paclitaxel-loaded ImI-PMs displayed stronger anti-tumor efficacy in MCF-7 tumor-bearing nu/nu mice. Finally, the active targeting system showed low systemic toxicity and myelosuppression evidenced by less changes in body weight, white blood cells, neutrophilic granulocyte and platelet counts. In conclusion, α7 nAChR is also a promising target for anti-tumor drug delivery and in this case, α-conotoxin ImI-modified nanocarrier is a potential delivery system for targeting α7 nAChR-overexpressing tumors.

An investigation of antitumor efficiency of novel sustained and targeted 5-fluorouracil nanoparticles.

Traditional chemotherapeutic drugs remain the major treatment for advanced colorectal cancer. However, due to the lack of tumor specificity these drug also destroy healthy tissue and organs, which has been the main reason for treatment failure and mortality. Folate-based drug delivery systems for improving nanoparticle endocytosis have been used to address these problems. Here, folic acid (FA) conjugated mPEG-b-P(CABCL-co-ACL) diblock copolymers were synthesized and characterized by TEM and NMR. Drug loaded nanoparticles were prepared using dialysis method and was obtained with a mean diameter of 45.2 nm with sustained in vitro release profile. In vitro cytotoxicity assay indicated that the cytotoxicity of folate modified nanoparticles were significantly increased compared to free drug and non-folate nanoparticles. In addition, results of hemolytic and histopathologic study suggested that the non-loaded nanoparticle (NL/NP) was non-toxic and biocompatible at the testing concentration. Moreover, in vivo results showed that FA/5-FU/NP effectively inhibited growth of HCT-8 cell-based xenograft tumors in BALB/c mice and revealed stronger antitumor efficacy than other treated groups. Thus, both in vitro and in vivo results exhibited that the folate conjugated mPEG-b-P(CABCL-co-ACL) copolymers have great potential to be used as sustainable and specific colon cancer targeting delivery system for anticancer agents.

Overcoming multidrug resistance in 2D and 3D culture models by controlled drug chitosan-graft poly(caprolactone)-based nanoparticles.

The principal limitations of chemotherapy are dose-limiting systemic toxicity and the development of multidrug-resistant phenotypes. The aim of this study was to investigate the efficiency of a new sustained drug delivery system based on chitosan and ε-caprolactone to overcome multidrug resistance in monolayer and drug resistance associated with the three-dimensional (3D) tumor microenvironment in our established 3D models. The 5-fluorouracil (5-FU)-loaded nanoparticles (NPs) were characterized by transmission electron microscope and dynamic light scattering, and its released property was determined at different pH values. 5-FU/NPs exhibited well-sustained release properties and markedly enhanced the cytotoxicity of 5-FU against HCT116/L-OHP or HCT8/VCR MDR cells in two-dimensional (2D) and its parental cells in 3D collagen gel culture with twofold to threefold decrease in the IC50 values, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Hoechst/propidium iodide staining and flow cytometry analysis. Furthermore, the possible mechanism was explored by high-performance liquid chromatography and rhodamine 123 accumulation experiment. Overall, the results demonstrated that 5-FU/NPs increase intracellular concentration of 5-FU and enhance its anticancer efficiency by inducing apoptosis. It was suggested that this novel NPs are a promising carrier to decrease toxic of 5-FU and has the potential to reverse the forms of both intrinsic and acquired drug resistance in 2D and 3D cultures.