Multifunctional Polymer Vesicles for Synergistic Antibiotic-Antioxidant Treatment of Bacterial Keratitis.

As an acute ophthalmic infection, bacterial keratitis (BK) can lead to severe visual morbidity, such as corneal perforation, intraocular infection, and permanent corneal opacity, if rapid and effective treatments are not available. In addition to eradicating pathogenic bacteria, protecting corneal tissue from oxidative damage and promoting wound healing by relieving inflammation are equally critical for the efficient treatment of BK. Besides, it is very necessary to improve the bioavailability of drugs by enhancing the ocular surface adhesion and corneal permeability. In this investigation, therefore, a synergistic antibiotic-antioxidant treatment of BK was achieved based on multifunctional block copolymer vesicles, within which ciprofloxacin (CIP) was simultaneously encapsulated during the self-assembly. Due to the phenylboronic acid residues in the corona layer, these vesicles exhibited enhanced muco-adhesion, deep corneal epithelial penetration, and bacteria-targeting, which facilitated the drug delivery to corneal bacterial infection sites. Additionally, the abundant thioether moieties in the hydrophobic membrane enabled the vesicles to both have ROS-scavenging capacity and accelerated CIP release at the inflammatory corneal tissue. In vivo experiments on a mice model demonstrated that the multifunctional polymer vesicles achieved efficient treatment of BK, owing to the enhanced corneal adhesion and penetration, bacteria targeting, ROS-triggered CIP release, and the combined antioxidant-antibiotic therapy. This synergistic strategy holds great potential in the treatment of BK and other diseases associated with bacterial infections.

Desirable PEGylation for improving tumor selectivity of hyaluronic acid-based nanoparticles via low hepatic captured, long circulation times and CD44 receptor-mediated tumor targeting.

PEG coating was regarded as one effective method to improve the tumor-targeting efficiency of hyaluronic acid-based nanoparticles (HBN). However, the research of interaction between PEG coating and different receptors such as stabilin-2 and CD44 was limited. Herein, we synthesized a series of PEGylated hyaluronic acid with Curcumin (PHCs) to evaluate the role of PEG coating density in the interaction between HA and its receptors, which influenced tissues targeting activity, pharmacokinetic profiles and therapeutic efficacy of HBN. Compared with other counterparts, PHC HBN with about 5% PEG coating density preferably accumulated in the tumor mass, rather than in the liver, and hold desirable anti-cancer effect. These results indicated that to obtain optimized anticancer effect of HBN, the cellular uptake efficiency between different types of the cells should be carefully balanced by different PEG densities.

Improved oral absorption of doxorubicin by amphiphilic copolymer of lysine-linked ditocopherol polyethylene glycol 2000 succinate: in vitro characterization and in vivo evaluation.

In the previous study, we have synthesized an amphiphilic copolymer of nanostructure-forming material and P-glycoprotein (P-gp) inhibitor, lysine-linked ditocopherol polyethylene glycol 2000 succinate (PLV2K). The cytotoxicty in vitro and anticancer efficacy in vivo after intravenous administration of DOX-loaded PLV2K micelles (PLV2K-DOX) was found more effective than DOX solution (DOX-Sol). However, its performance and mechanism on oral absorption of doxorubicin are not well understood yet. PLV2K-DOX are spherical micelles with a narrow size distribution of 20.53 ± 2.44 nm. With an in situ intestinal perfusion model, the intestinal absorption potential of PLV2K-DOX was evaluated in comparison with DOX-Sol. PLV2K-DOX was specifically absorbed in duodenum and ileum sites of rats after oral administration. The intestinal absorption rate (Ka) of PLV2K-DOX is 3.19-, 1.61-, and 1.80-fold higher than that of DOX-Sol in duodenum, jejunum, and ileum, respectively. In Caco-2 uptake studies, PLV2K-DOX micelles significantly improve the internalized amount of DOX by P-gp inhibition of free PLV2K copolymer and endocytosis of DOX-loaded nanoparticles. Moreover, PLV2K-DOX micelles improve the membrane permeability of DOX by multiple transcytosis mechanisms, including caveolin-, clathrin-dependent, and caveolin-/clathrin-independent transcytosis in Caco-2 transport studies. However, the transepithelia electrical resistance (TEER) of Caco-2 cellular monolayer is not changed, suggesting no involvement of paracellular transport of PLV2K-DOX. In vivo pharmacokinetics in rats following oral administration demonstrated that PLV2K-DOX demonstrates higher AUC (5.6-fold) and longer t1/2 (1.2-fold) than DOX-Sol. The findings suggest the new PLV2K micelles might provide an effective nanoplatform for oral delivery of anticancer drugs with poor membrane permeability and low oral bioavailability.

Multi-stage 3D-printed guide for precise restoration of severely inclined teeth based on target restorative space guidance: a case report.

In clinical dentistry, addressing unique conditions such as tilted, elongated, and torsion teeth during preparation can be effectively managed through digital tooth morphology design. The production of a multi-stage 3D-printed guide offered a more efficient and accurate solution. This article presented a case of significant inclination, elongation, and torsion in the maxillary and mandibular canines that were successfully treated using crown restoration modification. A crown preparation guide was fabricated based on the final form design of the restoration using the target restorative space analysis technique to ensure precise tooth preparation. A tooth preparation guide was also designed and utilized further to enhance accuracy and efficiency during complex tooth preparation. The combined application of these multi-stage guides demonstrated promising clinical prospects.

A case of precise prosthesis under the direction of target restoration space analysis after multidisciplinary combination therapy.

Quantitative grinding of abutment teeth is needed in crown and bridge restoration. Accurate quantitative preparation of teeth is one of the goals of minimally invasive restoration. In this paper, a case of congenital loss of upper and lower incisors was reported. Guided by the target restoration space (TRS), a personalized digital guide plate for tooth preparation was built to assist precise tooth preparation after the multidisciplinary combination therapy of orthodontic and periodontal teeth. Finally, the fixed bridge was prepared to meet the integrity, beauty, and function of the maxillary for the patient. In this case, the results suggest that the digital guide plate built under the guidance of TRS can be used to improve the accuracy of dental preparation.

Strategies to improve dissolution and oral absorption of glimepiride tablets: solid dispersion versus micronization techniques.

The objective of this study is to compare two different dissolution-enhancing strategies, solid dispersion (SD) and micronized techniques, for improving oral absorption of poorly soluble glimepiride, and to decide which strategy is suitable for its solubilization. The formulation of glimepiride SD was prepared by a solvent-evaporation process with povidone k-30 (PVPk30) at a weight ratio of 1:9 (drug:carrier). The other was prepared via a modified micronization technique, where glimepiride was premilled together with lactose and Lutrol F68 until the milled material passes through a 500 mesh ASTM sieve (30 µm). The dissolution results indicated that the two techniques were both capable of enhancing the dissolution rate and extent of glimepiride. The release profiles of the two prepared products were similar to the marketed product (Amaryl®) in various types of dissolution media. Furthermore, the oral bioavailability was evaluated for the three formulations in fasted beagle dogs. Statistical analysis indicated that there were no significant differences in pharmacokinetic parameters among the two prepared formulations and a marketed product, especially for AUC0₋36, C(max), and T(max). The dissolution parameters (D10 and AUC0₋20) in Tris buffer demonstrated the good in vitro/in vivo relationship with T(max) values for the three formulations. In conclusion, our studies confirmed that both SD and micronization techniques were capable of improving dissolution and oral absorption of glimepiride tablets to a similar extent as the marketed product, and the three glimepiride tablets were bioequivalent in the case of the rate and extent of absorption in dogs.

Nanoplatform Assembled from a CD44-Targeted Prodrug and Smart Liposomes for Dual Targeting of Tumor Microenvironment and Cancer Cells.

The tumor microenvironment (TME) plays a critical role in tumor initiation, progression, invasion, and metastasis. Therefore, a therapy that combines chemotherapeutic drugs with a TME modulator could be a promising route for cancer treatment. This paper reports a nanoplatform self-assembled from a hyaluronic acid (HA)-paclitaxel (PTX) (HA-PTX) prodrug and marimastat (MATT)-loaded thermosensitive liposomes (LTSLs) (MATT-LTSLs) for the dual targeting of the TME and cancer cells. Interestingly, the prodrug HA-PTX can self-assemble on both positively and negatively charged liposomes, forming hybrid nanoparticles (HNPs, 100 nm). Triggered by mild hyperthermia, HA-PTX/MATT-LTSLs HNPs rapidly release their payloads into the extracellular environment, and the released HA-PTX quickly enters 4T1 cells through a CD44-HA affinity. The HNPs possess promoted tumor accumulation (1.6-fold), exhibit deep tumor penetration, and significantly inhibit the tumor growth (10-fold), metastasis (100%), and angiogenesis (10-fold). Importantly, by targeting the TME and maintaining its integrity via inhibiting the expression and activity of matrix metalloproteinases (>5-fold), blocking the fibroblast activation by downregulating the TGF-ß1 expression (5-fold) and suppressing the degradation of extracellular matrix, the HNPs allow for significant metastasis inhibition. Overall, these findings indicate that a prodrug of an HA-hydrophobic-active compound and liposomes can be self-assembled into a smart nanoplatform for the dual targeting of the TME and tumor cells and efficient combined treatment; additionally, the co-delivery of MATT and HA-PTX with the HNPs is a promising approach for the treatment of metastatic cancer. This study creates opportunities for fabricating multifunctional nanodevices and offers an efficient strategy for disease therapy.

Design and optimization of gastro-floating sustained-release tablet of pregabalin: In vitro and in vivo evaluation.

Pregabalin is a promising drug for the treatment of neuropathic pain, a chronic disease affecting a large population needing long-term treatment. However, due to its short half-life, the commercial tablet has to be administered 2-3 times per day, with inconvenience for patient and fluctuations of plasma concentration. In this study, a gastro-floating drug delivery system of pregabalin was developed to prolong the gastric retention of drugs absorbed or act in stomach or upper gastrointestinal tract. First of all, it was proved that the drug was mainly absorbed in stomach and upper gastrointestinal tract. The final formulation was optimized in consideration of buoyancy and drug release profile. The gastro-floating tablet was prepared with hydroxypropyl methylcellulose (HPMC) as sustained-release matrix, lipophilic cetyl alcohol as floating-assistance agent and other excipients to achieve satisfying buoyancy and sustained release performance with mechanisms of diffusion and matrix erosion. Food exhibited significant effect on the pharmacokinetics of gastro-floating tablet and conventional capsule. Compared with conventional capsules, the relative bioavailability of gastro-floating tablet in fasted conditions or in fed conditions was only 62.47 ±â€¯10.80% and 100.98 ±â€¯17.25% respectively, even though the gastro-floating tablet obtained decreased Cmax and prolonged Tmax in fasted and fed conditions. Besides, good in vivo-in vitro correlation of the gastro-floating tablet was established. In summary, a gastro-floating tablet of pregabalin exhibiting desired buoyancy and release profiles was designed, and the tablet expressed significantly sustained-release behavior in fed conditions with good in vivo-in vitro correlation. The designed gastro-floating system is a promising choice for the patients to relieve neuropathic pain.

[The changes of maxillary sinus membrane thickeness after maxillary sinus floor elevation surgery].

OBJECTIVE: To evaluate the success rate of dental implants and the changes of sinus membrane thickness after sinus lift in cases of thickened sinus membrane. METHODS: Sixteen patients without maxillary sinusitis and with 5-8 mm residual alveolar bone heights were included in this study. The sinus membrane thickeness of these patients were more than 2 mm. All patients received sinus lift surgery and dental implants insertion. The changes of sinus membrane was evaluated by cone-beam CT (CBCT) pre-surgery and 6 months after sinus lift surgery, and the short term success rate of dental implants was also evaluated. RESULTS: A total of 18 implants from 16 subjects were inserted. The thickness of membrane was decreased in 14 cases after sinus lift and increased in 2 cases. All the orifice of maxillary sinus was unobstructed before surgery, one case was obstructed after surgery without inflammation. All the dental implants succeeded. CONCLUSIONS: Sinus augmentation with thickened sinus membrane is not contraindication of sinus lift.

Stealth CD44-targeted hyaluronic acid supramolecular nanoassemblies for doxorubicin delivery: probing the effect of uncovalent pegylation degree on cellular uptake and blood long circulation.

Stealth active targeting nanoparticles (NPs) usually include two types of ligand sites: ligand anchored on distal ends of the polyethylene glycol (PEG) and ligand buried under pegylated layer. The latter typical case is hyaluronic acid (HA)-based NPs; however, there is little information available for the latter NPs about effect of the optimal density of surface PEG coating on the blood circulation time, cellular uptake and in vivo anticancer activity. Thus, in this study, in order to optimize the anticancer effects of HA-based NPs, we focus on how uncovalent pegylation degree modulates blood circulation time and cellular uptake of HA-based NPs. We firstly designed a new double-hydrophilic copolymer by conjugating HP-ß-cyclodextrin with HA, and this carrier was further pegylated with adamantyl-peg (ADA-PEG) to form inclusion complex HA-HPCD/ADA-PEG, termed as HCPs. The supramolecular nanoassemblies were fabricated by host-guest and polar interactions between HCPs and doxorubicin (Dox), with vitamin E succinate (VES) being a nanobridge. Despite the active recognition between HA and CD44 receptor, the cellular uptake and targeting efficiency of HA-NPs decreased with the increasing peg density, demonstrating HA was partly buried by high density peg coating. However, the high density of peg coating was beneficial to long circulation time, tumor biodistribution and anticancer activity in vivo. NPs with 5% peg coating had the optimal cellular targeting efficiency in vitro and anticancer effects in vivo. The findings suggest that balancing long circulation property and cellular uptake is important to achieve the optimal antitumor efficacy for pegylated HA-based NPs, and that PEG coating densities cannot be extended beyond a certain density for shielding effect without compromising the efficacy of hyaluronic acid targeted delivery.

Critical determinant of intestinal permeability and oral bioavailability of pegylated all trans-retinoic acid prodrug-based nanomicelles: Chain length of poly (ethylene glycol) corona.

Pegylation method is widely used to prolong the blood circulation time of proteins and nanoparticles after intravenous administration, but the effect of surface poly (ethylene glycol) (PEG) chain length on oral absorption of the pegylated nanoparticles is poorly reported. The aim of our study was to investigate the influence of PEG corona chain length on membrane permeability and oral bioavailability of the amphiphilic pegylated prodrug-based nanomicelles, taking all trans-retinoic acid (ATRA) as a model drug. The amphiphilic ATRA-PEG conjugates were synthesized by esterification reaction between all trans-retinoic acid and mPEGs (mPEG500, mPEG1000, mPEG2000, and mPEG5000). The conjugates could self-assemble in aqueous medium to form nanomicelles by emulsion-solvent evaporation method. The resultant nanomicelles were in spherical shape with an average diameter of 13-20 nm. The drug loading efficiency of ATRA-PEG500, ATRA-PEG1000, ATRA-PEG2000, and ATRA-PEG5000 was about 38.4, 26.6, 13.1, and 5.68 wt%, respectively. With PEG chain length ranging from 500 to 5000, ATRA-PEG nanomicelles exhibited a bell shape of chemical stability in different pH buffers, intestinal homogenate and plasma. More importantly, they were all rapidly hydrolyzed into the parent drug in hepatic homogenate, with the half-time values being 0.3-0.4h. In comparison to ATRA solution and ATRA prodrug-based nanomicelles, ATRA-PEG1000 showed the highest intestinal permeability. After oral administration, ATRA-PEG2000 and ATRA-PEG5000 nanomicelles were not nearly absorbed, while the oral bioavailability of ATRA-PEG500 and ATRA-PEG1000 demonstrated about 1.2- and 2.0-fold higher than ATRA solution. Our results indicated that PEG1000 chain length of ATRA-PEG prodrug nanomicelles has the optimal oral bioavailability probably due to improved stability and balanced mucus penetration capability and cell binding, and that the PEG chain length on a surface of nanoparticles cannot exceed a key threshold with the purpose of enhancement in oral bioavailability.

Star-shape redox-responsive PEG-sheddable copolymer of disulfide-linked polyethylene glycol-lysine-di-tocopherol succinate for tumor-triggering intracellular doxorubicin rapid release: head-to-head comparison.

A redox-responsive poly(ethylene glycol) (PEG)-sheddable copolymer of disulfide-linked PEG 5000-lysine-di-tocopherol succinate (P(5k)SSLV) is developed which can self-assemble into nanomicelles in aqueous condition and trigger the rapid release of encapsulated drugs within tumor cells. The reduction-insensitive doxorubicin (DOX)-loaded P(5k)LV (P(5k)LV-DOX) nanomicelles are further prepared. Then head-to-head comparison of P(5k)SSLV-DOX, P(5k)LV-DOX and DOX-Sol is performed concerning in vitro release, cytotoxicity, cellular uptake and apoptosis. Results show that P(5k)SSLV-DOX nanomicelles have a faster DOX release, a higher anti-tumor activity and more DOX concentrating in the nucleus than P(5k)LV-DOX nanomicelles. In conclusion, the redox-responsive P(5k)SSLV nanomicelles might hold a great potential to improve chemotherapy by tumor-triggering intracellular rapid release. The outcomes of this study also address the significance of such head-to-head comparison studies in translational research of nanomedicine.

[The effect of fluoride on dental alloys in different concentrations of fluoride artificial saliva].

OBJECTIVE: To study the changes in surface morphology of cobalt-chromium alloy, pure titanium and high-cobalt chromium molybdenum alloy immersed in artificial saliva with different concentrations of fluoride, and to analyze the corrosion resistance of these metals. METHODS: The three kinds of metal were polished and then were immersed in artificial saliva with different concentrations of fluoride (0%, 0.05%, 0.2%). All specimens were immersed for 3 weeks at (37.0 +/- 1.0) degrees C. Metal surface roughness before and after immersion were measured and analyzed by scanning electron microscope (SEM). RESULTS: Metal surface roughness was increased with the concentration of fluoride. The surface roughness of the Co-Cr group and Ti group had a statistically significant difference between before and after immersion at the fluoride concentration of 0.05% (P<0.01), and the difference between Co-Cr group and vitallium2000 group, Ti group and vitallium2000 group were statistically significant difference (P<0.01). The differences of three groups before and after immersion were statistically significant at the fluoride concentration of 0.2% (P<0.01), and the difference among three groups was statistically significant (P<0.01). CONCLUSION: Patients who frequently use fluoride products should not use pure titanium or cobalt-chromium alloy prosthesis. Patients with these three metal prostheses are not advised to use high concentration fluoride products.