Fractionated FLASH radiation in xenografted lung tumors induced FLASH effect at a split dose of 2 Gy.

PURPOSE: To explore the minimum split dose of FLASH radiotherapy (FLASH). MATERIAL AND METHODS: Lungs of nude mice were used to verify the capacity of normal tissue sparing of FLASH, while tumor-bearing nude mice were used to evaluate the curative power. Xenografted tumor models were established in Balb/c-nu mice using A549 cells at a concentration of 5×106/100 µL. With the same total dose (20 Gy), the dose rate of FLASH was 200 Gy/s when conventional radiotherapy(CONV) was 0.033 Gy/s. Two schemes of FLASH irradiations were applied: single pulse (FLASH1) and ten pulses (FLASH10). Then, according to the different tissue types and irradiation schemes, mice were divided into eight groups: Control-T, CONV-T, FLASH1-T, FLASH10-T (T for tumor) and Control-L, CONV-L, FLASH1-L, FLASH10-L (L for lung). Evaluation of FLASH effect was based on the changes in tumor volume and pathological analysis of tumor and lung tissues before and after irradiation. RESULTS: Compared to control group, the mean volume of tumors in nude mice increased slowly or decreased after irradiation with both FLASH and CONV (Control-T: 233.6±55.19 mm3, CONV-T: 146.1±50.62 mm3, FLASH1-T: 148±18.83 mm3, FLASH10-T: 119.1±50.62 mm3, p ≤ .05) . Tumor cells of irradiated groups had similar degrees of dissolution damage and inflammation, while the acute radiation pneumonia induced by FLASH was less severe. The pulmonary pathology of FLASH1-L and FLASH10-L were similar, and only a few neutrophils were observed. In addition to inflammatory cells, slight thickening of alveolar septum and obvious interstitial hemorrhage were also observed in the CONV-L group. CONCLUSION: The FLASH effect was successfully reproduced in both single and fractionated irradiation, with 2 Gy being the minimum split dose to achieve the FLASH effect in existing experiments. It is suggested that the transient oxygen depletion might not be the only mechanism behind the FLASH effect.

Synthesis and characterization of amphiphilic star-shaped copolymers based on ß-cyclodextrin for micelles drug delivery.

PURPOSE: A series of ß-CD amphiphilic star-shaped copolymers with exceptional characteristics were synthesized and their potential as carriers for micelles drug delivery was investigated. METHODS: A series of amphiphilic copolymers based on ß-CD were synthesized by introducing poly (acrylic acid)-co-poly(methyl methacrylate)-poly (vinyl pyrrolidone) or poly (acrylic acid)-co-poly(methyl methacrylate)-co-poly(monoacylated-ß-CD)-poly (vinyl pyrrolidone) blocks to the primary hydroxyl group positions of ß-CD. The micellization behavior of the copolymers, the synthesis conditions, characteristics, drug release in vitro and tissue distribution of vinpocetine (VP) micelles in vivo were investigated. RESULTS: Around 60 types of ß-CD amphiphilic star-shaped copolymers were successfully synthesized and the critical micelle concentration ranged from 9.80 × 10-4 to 5.24 × 10-2g/L. The particle size, drug loading and entrapment efficiency of VP-loaded ß-CD-P4 micelles prepared with optimal formulation were about 65 nm, 21.44 ± 0.14%, and 49.05 ± 0.36%, respectively. The particles had good sphericity. The cumulative release rates at 72 h of VP-loaded ß-CD-P4 micelles in pH 1.0, pH 4.5, pH 6.5, or pH 7.4 media were 93%, 69%, 49%, and 43%, respectively. And, the lung targeting efficiency of VP-loaded ß-CD-P4 micelles was 8.98 times higher than that of VP injection. CONCLUSION: The VP-loaded ß-CD-P4 micelles exhibited controlled-release property, pH-induced feature and lung targeting capacity compared with VP injection, suggesting that the ß-CD-P4 copolymers are an excellent candidate for micelles drug delivery.

Pharmacokinetics and efficiency of brain targeting of ginsenosides Rg1 and Rb1 given as Nao-Qing microemulsion.

Nao-Qing solution has been shown to be clinically effective in the treatment of acute ischemic stroke (AIS). The purpose of this study was to improve the pharmacokinetics and brain uptake of Nao-Qing, administered as an oil-in-water microemulsion. Sprague-Dawley (SD) rats were given Nao-Qing microemulsion by intranasal or intragastric routes. Samples of blood, brain, heart, liver, lung and kidney were collected at pre-determined time intervals, and the contents of ginsenosides Rg1 and Rb1 (active ingredients of the Nao-Qing microemulsion) were analyzed by high-performance liquid chromatography (HPLC). The results showed that contents of ginsenosides Rg1 and Rb1 in Nao-Qing microemulsion was 8475.13 ± 54.61 µg/ml and 6633.42 ± 527.27 µg/ml, respectively, and that the particle size, pH and viscosity of the microemulsion were 19.9 ± 5.07 nm, 6.1 and 3.056 × 10(-3 )Pas, respectively. Absorption of ginsenoside Rg1 was higher than that of ginsenoside Rb1, which was barely detectable after intragastric administration; furthermore, the concentration of ginsenoside Rg1 in blood and other tissues at each time point was lower for intragastric than for intranasal administration. Compared with intragastric administration, intranasal administration resulted in a shorter tmax (0.08 versus 1 h), a higher Cmax (16.65 versus 11.29 µg/ml), and a higher area under the concentration-time curve (AUC) (592.91 versus 101.70 µgch/ml) in the brain. The relative rates of uptake (Re) and the ratio of peak concentration (Ce) in the brain were 126.31% and 147.48% for ginsenoside Rg1, respectively. These data illustrate that intranasal administration can promote the absorption of drugs in Nao-Qing microemulsion and achieve fast effect.