Proton beam spot size and position measurements using a multi-strip ionization chamber.

PURPOSE: To develop and characterize a large-area multi-strip ionization chamber (MSIC) for efficient measurement of proton beam spot size and position at a synchrotron-based proton therapy facility. METHODS AND MATERIALS: A 420 mm x 320 mm MSIC was designed with 240 vertical strips and 180 horizontal strips at 1.75 mm pitch. The MSIC was characterized by irradiating a grid of proton spots across 17 energies from 73.5 MeV to 235 MeV and comparing to simultaneous measurements made with a reference Gafchromic EBT3 film. Beam profiles, spot sizes, and positions were analyzed. Short term measurement stability and sensitivity were evaluated. RESULTS: Excellent agreement was demonstrated between the MSIC and EBT3 film for both spot size and position measurements. Spot sizes agreed within ± 0.18 mm for all energies tested. Measured beam spot positions agreed within ± 0.17 mm. The detector showed good short term measurement stability and low noise performance. CONCLUSION: The large-area MSIC enables efficient and accurate proton beam spot characterization across the clinical energy range. The results indicate the MSIC is suitable for pencil beam scanning proton therapy commissioning and quality assurance applications requiring fast spot size and position quantification.

Discovery of mitochondrion-targeting copper(II)-plumbagin and -bipyridine complexes as chemodynamic therapy agents with enhanced antitumor activity.

Four copper(II)-plumbagin and -bipyridine complexes (Cu1-Cu4) were synthesized as chemodynamic therapy agents with enhanced antitumor activity. As lipophilic and positively charged compounds, Cu1-Cu4 were preferentially accumulated in mitochondria and activated the mitochondrial apoptosis pathway. Mechanistic studies showed that Cu1-Cu4 reacted with GSH to reduce Cu2+ ions to Cu+ ions, catalyzed the formation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H2O2) through a Fenton-like reaction, induced mitochondrial dysfunction, and activated caspase-9/3, which eventually led to apoptosis. Cu1-Cu4 arrested HeLa cells in the S phase and eventually killed cancer cells. Cu2 showed a favorable pharmacokinetic profile in mice. Moreover, Cu2 effectively inhibited the growth of HeLa xenografts in nude mice and showed low toxicity in vivo.

Copper(II) complexes with plumbagin and bipyridines target mitochondria for enhanced chemodynamic cancer therapy.

The combination of mitochondrial targeting and chemodynamic therapy is a promising anti-cancer strategy. Three mitochondria targeting copper(II) complexes (Cu1-Cu3) with plumbagin and bipyridine ligands for enhanced chemodynamic therapy were synthesized and characterized. Their anti-proliferative activity to HeLa cells was higher than that of cisplatin, and their toxicity to normal cells was low. Cellular uptake and distribution studies indicated that Cu1 and Cu3 were mainly accumulated in mitochondria. The mechanism studies showed that Cu1 and Cu3 converted intracellular H2O2 into toxic hydroxyl radicals by consuming glutathione, leading to mitochondrial dysfunction. Treatment with the copper complex caused ER stress and cell arrest in the S phase which resulted in apoptosis. In vivo, Cu1 and Cu3 effectively inhibited the growth of HeLa xenograft tumors without obvious toxic and side effects.

Platinum-Based Mcl-1 Inhibitor Targeting Mitochondria Achieves Enhanced Antitumor Activity as a Single Agent or in Combination with ABT-199.

Discovery of small molecule inhibitors targeting Mcl-1 (Myeloid cell leukemia 1) confronts many challenges. Based on the fact that Mcl-1 is mainly localized in mitochondria, we propose a new strategy of targeting mitochondria to improve the binding efficiency of Mcl-1 inhibitors. We report the discovery of complex 9, the first mitochondrial targeting platinum-based inhibitor of Mcl-1, which selectively binds to Mcl-1 with high binding affinity. Complex 9 was mainly concentrated in the mitochondria of tumor cells which led to an enhanced antitumor efficacy. Complex 9 induced Bax/Bak-dependent apoptosis in LP-1 cells and synergized with ABT-199 to kill ABT-199 resistant cells in multiple cancer models. Complex 9 was effective and tolerable as a single agent or in combination with ABT-199 in mouse models. This research work demonstrated that developing mitochondria-targeting Mcl-1 inhibitors is a new potentially efficient strategy for tumor therapy.

[Minimally invasive osteotomy and manual reduction for hallux valgus].

OBJECTIVE: To explore clinical effects of minimally invasive osteotomy and manual reduction in treating hallux valgus. METHODS: From January 2018 to May 2019, 31 patients (42 feet) with hallux valgus were treated with minimally invasive osteotomy and manual reduction, including 3 males and 28 females aged from 18 to 76 years old with an average of (50.1± 4.9) years old. Preoperative and postoperative hallux valgus (HVA), intermetatarsal angles(IMA), length difference between 1 and 2 metatarsals were recorded and compared, and American Orthopedic Foot and Ankle Society (AOFAS)score were observed and measured. RESULTS: Thirty-one patients (42 feet) were followed up from 14 to 18 months with an average of (15.1± 1.2) months. HVA, IM before operation were (38.5±5.4)°, (13.0± 1.1)°, and improved to (14.3±4.7)°and (9.1±1.5)°after operation respectively(P<0.05). Preopertaive length difference between 1 and 2 metatarsals was 2-4(-0.59±1.80) mm, and 0 to -6(-3.53±1.60) mm after operation, the average shortening of the first metatarsal was 2.94 mm. There were significant difference between preoperative and postoperative. Preoperative AOFAS score was 57.8±9.7, increased to 92.1±9.3 at the final follow-up, there was significant differences (P<0.05). According to standard of AOFAS score, 32 feet obtain excellent results, 16 good and 3 moderate. CONCLUSION: Minimally invasive osteotomy and manual reduction in treating hallux valgus have advantages of shorter operation time, less length of incision, and could correct hallux valgus deformity, improve front feet and receive good clinical effect in further.

In vitro and in vivo study of Baicalin-loaded mixed micelles for oral delivery.

The aim of this work was to research the potential functions and the mechanism of absorption of the baicalin (BC)-loaded micelle system that contained Pluronic P123 copolymer (P123) and sodium taurocholate (ST) as carrier materials via oral delivery. Based on the numerous advantages of oral administration, such as cost-effectiveness, flexible and accommodated dosing regimen, and improved compliance for patients, the ST-P123-MMs system would be evaluated as oral delivery vehicle of BC. In this study, X-ray powder diffractometer analysis confirmed the phase change of BC after being incorporated in mixed micelles. The release study in simulated gastric fluid/simulated intestinal fluid exhibited that BC-loaded ST-P123-MMs presented a sustained drug release behavior. Compared with coumarin-6 solution, higher cellar uptake efficiency was achieved for coumarin-6 loaded ST-P123-MMs towards Caco-2 cell lines. The in situ perfusion test in rat indicated that the absorption of BC-loaded ST-P123-MMs in intestinal tract was stronger than BC solution. After oral administration, the Cmax and AUC of BC-loaded ST-P123-MMs were 1.77 times and 1.54 times as high as those of BC suspension in rat, respectively. Promisingly, the formulated BC exhibited a prolonged circulation time with the oral bioavailability increased to 1.54-fold compared with the control group. These results all suggested that P123 and ST mixed micelles could serve as a promising approach to oral administration of BC.

Current research on hyaluronic acid-drug bioconjugates.

Hyaluronic acid (HA) is a mucopolysaccharide acid composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine. Based on numerous characteristics such as viscoelastic properties, water-binding ability, biocompatibility and non-immunogenicity, HA has been approved by FDA for biological and medical applications. In addition, multifarious receptors of HA like CD44, RHAMM and TSG6 are over-expressed on the surface of malignant cells, which play important roles in targeting ability. Bioconjugates linking drugs to HA could improve solubility, prolong half-life, provide active targeting capability and then increase the bioavailability of these coupled drugs by pro-drug strategy. Therefore, a large number of HA-drug bioconjugates have been studied. The purpose of this review was to summarize these HA-drug bioconjugates and further discuss synthetic methods and the relevant application in pharmaceuticals.

Preparation, optimization, characterization and cytotoxicity in vitro of Baicalin-loaded mixed micelles.

The aim of this study was to develop a Baicalin (BC)-loaded mixed micelle delivery system (BC-ST-P123-MMs) with sodium taurocholate (ST) and pluronic P123 block copolymer (P123) as carrier materials to improve the solubility of BC, a poorly soluble drug. In this study, the mixed micelle system was prepared using the method of thin-film dispersion and then optimized by the homogeneous design-response surface methodology with the entrapment efficiency and drug loading as indexes. The average size and the zeta potential of the BC-ST-P123-MMs were 15.60 nm and -5.26 mV, respectively. Drug loading (DL, 16.94%) and entrapment efficiency (EE, 90.67%) contributed to high solubility (10.20 mg/mL) of BC in water. The optimized BC-ST-P123-MMs appeared spherical with obvious core-shell structure and well dispersed without aggregation and adhesion under TEM. In addition, DSC result indicated that BC had been wrapped in BC-ST-P123-MMs and crystalline state of BC was changed. The release result in vitro showed that BC-ST-P123-MMs presented sustained release behavior compared to control group. The IC50 value of BC-ST-P123-MMs (46.18 µg/mL) was lower than that of BC solution (67.14 µg/mL) on Hep G2 cell lines. Cellular uptake tests illustrated that the ST-P123-MMs system as carrier could significantly enhance the uptake of drugs by tumor cells. The results demonstrated that the BC-loaded mixed micelles could improve solubility of BC and exhibited great potential for delivering drug into cancer cells.

Advances in the formulations of non-injection administration of docetaxel.

Docetaxel is one of the most important anti-tumor drugs and has shown powerful therapeutic activity against breast cancer, non-small cell lung cancer, prostate cancer and so on. Owing to its poor water solubility and the efflux by P-glycoprotein (P-gp) and metabolism by CYP3A4 enzymes, it is generally administered as an injection form, the only manner for the current clinical application. However, the injection bearing polysorbate 80 and ethanol may cause adverse events such as severe hypersensitivity reactions, neutropenia, neurotoxicity, musculoskeletal toxicity and cumulative fluid retention, these adverse events limit clinical application and commercialization of docetaxel. Recently, various kinds of non-injection delivery systems for docetaxel have been developed to eliminate the polysorbate 80-based vehicle and increase the drug solubility. In this review, the non-injection delivery formulations of docetaxel for oral route, transdermal delivery, lung and rectal administration were discussed for future study and clinical application.

Preparation and evaluation in vitro and in vivo of docetaxel loaded mixed micelles for oral administration.

A mixed micelle that comprised of monomethylol poly(ethylene glycol)-poly(D,L-lactic acid) (MPP), D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and stearic acid grafted chitosan oligosaccharide(CSO-SA) copolymers was developed to enhance the oral absorption of docetaxel (DTX). DTX-loaded MPP/TPGS/CSO-SA mixed polymeric micelles (MPMs) were prepared with thin film hydration method and characterized in terms of morphology, size, zeta potential, encapsulation efficiency, critical micellization concentration, and in vitro stability in media modeling physiological conditions. The in vitro release of docetaxel from the mixed micelles was studied with dialysis method. The oral bioavailability studies were conducted in rats and the pharmacokinetic parameters were evaluated. The results showed that DTX-loaded MPP/TPGS/CSO-SA MPMs had a mean diameter of 34.96 nm and exhibited spherical shape under transmission electron microscopy. The drug loading of DTX in the mixed micelles was 19.15%. The critical micellization concentration of MPP/TPGS/CSO-SA copolymer was 2.11×10(-5) M, and the size of mixed micelles in gastric fluid (pH 1.6) for 2 h and simulated intestinal fluid (pH 6.5) for 6h showed no significant change. The in vitro release study showed that DTX-loaded MPP/TPGS/CSO-SA MPMs exhibited slower release characteristics compared to DTX solution. The oral bioavailability of the DTX-loaded MPP/TPGS/CSO-SA MPMs was increased by 2.52 times compared to that of DTX solution. The current results encourage further development of DTX mixed polymeric micelles as the oral drug delivery system.

Polymer-drug conjugates: present state of play and future perspectives.

Polymer conjugation is an efficient approach to improve therapeutic properties of drugs and biological agents. Since the first synthetic polymer-drug conjugate entered clinical trials in 1994, this technology has undergone notable development for the introduction and study of novel polymers and for the progress in the biological rationale for designing conjugates. Not surprisingly, new polymers, in addition to the best known polyethylene glycol, poly[N-(2-hydroxypropyl)methacrylamide], are continuously conjugated with drugs to achieve biodegradable, stimuli-sensitive and targeted systems in an attempt to prolong blood circulation times and enhance drug concentrations at the intended site of action. This overview focuses on bioconjugates of water-soluble polymers with low molecular weight drugs. Additionally, the most recent achievements in the polymer-drug conjugate field and several promising approaches for the future are discussed.