二十一世纪崭新的前沿科学—纳米药学

纳米技术是20世纪90年代出现的一门崭新技术,是近几年迅速发展起来的一个全新的科学领域,在材料、生命信息、环境、能源和国家安全等方面具有广泛的应用,被认为是21世纪最重要的科技领域.

纳米药学的市场发展和障碍

在生命科学领域中纳米技术最重要和直接的应用之一是纳米药学。例如，纳米配方似乎能提供一种手段，以使多种治疗药物包括DNA、蛋白质、肽和常规小分子量药物的输送和药代动力学最适化。一家研究公司Freedonia预测，2016年所有纳米技术医学产品和纳米医药的总销售额将分别达到1，105亿和820亿美元。一家咨询公司Cientifica估计，今后几年采用纳米技术的药物输送系统市场其年度增长率将达到37％。

现代给药技术的研究进展

药物治疗在临床上是一个不可或缺的重要环节,在疾病防治过程中起着举足轻重的作用。但药物在体内的作用效果在很大程度上,受制于药物剂型、释药系统和给药途径。因此,拓宽给药途径、发展释药系统已成为近几年来较受关注的研究课题。随着研究的不断深入和现代技术的发展,人们发现采用不同的药剂学手段可以广泛提高药物的生物利用度和作用效果。现就有关方面的进展综述如下:

Fluid-Solid Interaction Analysis of Drug Delivery Mechanism to Damaged Cancer Cellules in the Shape of Single-Walled Carbon Nanocone by Molecular Mechanics Approach

Drug delivery systems able to deliver the required dose of the drug to the target level use active or passive nano metric designed systems. In the earlier researches, carbon nanocones are used for transferring the serum to damaged proteins and damaged cancer cellules. In this lecture, stability analysis of drug delivery to damaged cancer cellutes is studied in the shape of single-walled carbon nanocone. In this method, each atom is considered as node and interactions between them are supposed as 3D-beam elements. By supposing that potential energy in macro relations is equal to the nano relations, nano-drug characteristics can be calculated. Then shape functions can be extracted to use in blood＇s FEM model and using reduced-order method, divergence velocities of carbon nanocone can be found. In this lecture, carbon nanocones are modeled with different dimensions and boundary conditions and stability of them in blood flow is studied and optimized carbon nanocone is selected in blood flow. Results show that conical nano-drug structures have more efficiency in blood flow rather than tube nano-drug structures and by increasing length of carbon nanocones, dimensionless stability parameter decreased and by increasing declination angle of carbon nanocones, dimensionless stability parameter increased.

Preparation and evaluation of docetaxel-loaded albumin nanoparticles for intravenous administration

Docetaxel （DTX） was incorporated into albumin nanoparticles to form the docetaxel loaded nanoparticles （DTX-NPs） with a high-pressure homogenization method. The purpose of this procedure was to improve the solubility, stability and biocompatibility of DTX. In our study, particle size, zeta potential, size distribution, and encapsulation efficiency were investigated. The crystalloid state of DTX in nanoparticles was further determined by the X-ray diffraction technique. The hemolysis rate, pharmacokinetics and pharmacodynamics of the DTX-NPs were analyzed and compared with the injectable docetaxel solution （DTX-Sol）, which was fabricated according to the formulation of the commercial Taxotere. It demonstrated that the DTX-NPs were prepared successfully with these properties, including the （193±4） nm size, （-30±1） mV zeta potential and 69%±2% encapsulation efficiency. Higher stability was achieved in the lyophilized nanoparticles compared to that in the nanoparticle suspension. Furthermore, less hemolysis effect was observed in the DTX-NPs than that in the DTX-Sol. The pharmacokinetic and pharmacodynamic behaviors of the DTX-NPs were similar as that of DTX-Sol based on the in vivo experiments. In conclusion, albumin nanoparticles may act as a useful and safe carder for DTX.

Preparation of the nanostructured lipid carriers of artemisinin and its pharmacokinetic evaluation

Artemisinin（ART） is a widely used active drug for malaria, including severe and cerebral malaria. However, its therapeutic efficacy is affected by its lower bioavailability. In the present study, nanostructured lipid carriers（NLCs） were proposed as carrier of ART to improve pharmacokinetic properties of the drug. ART-NLC was prepared by high-pressure homogenization based on orthogonal design. The particle size, zeta potential, encapsulation efficiency（EE） and percentage of drug loading（DL） of ART-NLC were（53.06±2.11） nm,（–28.7±3.59） m V, 73.9%±0.5% and 11.23%±0.37%, respectively. ART-NLC showed the sustained release characteristics and scarcely the hemolysis effect on human red blood cells. The pharmacokinetics of ART-NLC for rats after tail intravenous injection（i.v） or intraperitoneal injection（i.p） were investigated by liquid chromatography-tandem mass spectroscopy（LC-MS/MS）. And ART solution was designed as control preparation. For rats of i.v groups, the AUC0–∞（（707.45±145.65） ng·h/m L） of ART-NLC were significantly bigger than that of ART（（368.98±139.58） ng·h/m L）. The MRT（（3.38±0.46） h） of ART-NLC was longer than that of ART（（1.39±0.61） h）. And similar results were observed for rats of i.p groups. The AUC0–∞（（1233.06±235.57） ng·h/m L） and MRT（（4.97±0.69） h） of ART-NLC were both bigger than those of ART, which were（871.17±234.03） ng·h/m L） and（1.75±0.31） h）, respectively. Compared with ART, ART-NLC showed a significant increase in AUC0–∞（P〈0.05） and MRT（P〈0.001） for both i.p and tail i.v administrations.

Au nanostructures:an emerging prospect in cancer theranostics

Au nanoparticles have been used in biomedical applications since ancient times. However, the rapid development of nanotechnology over the past century has led to recognition of the great potential of Au nanoparticles in a wide range of applications. Advanced fabrication techniques allow us to synthesize a variety of Au nanostructures possessing physiochemical properties that can be exploited for different purposes. Functionalization of the surface of Au nanoparticles further eases their application in various roles. These advantages of Au nanoparticles make them particularly suited for cancer treatment and diagnosis. The small size of Au particles enables them to preferentially accumulate at tumor sites to achieve in vivo targeting after systemic administration. Efficient light absorption followed by rapid heat conversion makes them very promising in photothermal therapy. The facile surface chemistry of Au nanoparticles eases delivery of drugs, ligands or imaging contrast agents in vivo. In this review, we summarize recent development of Au nanoparticles in cancer theranostics including imaging-based detection, photothermal therapy, chemical therapy and drug delivery. The multifunctional nature of Au nanoparticles means they hold great promise as novel anti-cancer therapeutics.

Preparation,characterization and pharmacokinetics of 10-hydroxycamptothecin nanosuspension

10-Hydroxycamptothecin （HCPT） is a broad-spectrum anticancer drug, while its low solubility and instability severely limit its application. In this study, HCPT nanosuspension （HCPT-NSP）, also known as nanocrystal, was prepared by micro-precipitation combined with high-pressure homogenization method. This nanosuspension was characterized by size, shape, zeta potential, drug loading efficiency and in vitro drug release behavior. Preferred formulation and process showed that particle size was （129.8±13.9） nm, PDI was 0.20±0.07, and drug loading efficiency was 36.5%±9.5%. Moreover, HCPT nanocrystal concentration reached （1.35±0.2） mg/mL in HCPT-NSP, which was more than 1000-fold higher than that of HCPT. Transmission electron microscopy （TEM） results showed that the nanosuspension was short rod in shape. X-ray powder diffraction （XRD）, thermogravimetric analysis （TGA）, derivative thermogravimetric analysis （DTA） and differential scanning calorimetry （DSC） further elaborated the crystal state of the HCPT. The drug concentration-time curve of HCPT-NSP in rats was in accordance with the three-compartment model, showing prolonged half-life. Taken together, our data suggested that HCPT-NSP was a promising drug delivery system.

Preparation, characterization and pharmacokinetic studies of total paeony glycoside nanocrystals

Total paeony glycoside（TPG） is obtained from Radix Paeoniae Rubra with a variety of bioactivities. However, the low solubility and bioavailability limit its application. The present study aimed to develop TPG nanocrystals to increase the dissolution and then improve the oral bioavailability. TPG nanocrystals were prepared via precipitation and high-pressure homogenization method. The physical-chemical properties of the optimal TPG nanocrystals in terms of particle size, zeta potential, morphology and crystallinity were evaluated. The results showed that TPG nanocrystals had a mean particle size of（210.2±2.5） nm, a polydispersity index of 0.191±0.033 and a zeta potential of（–22.4±1.2） mV. The result of differential scanning calorimetry showed that the nanocrystals were still in crystalline state after the preparation procedure. Transmission electron microscopy（TEM） results showed that the nanosuspension was in spherical shape. The pharmacokinetics of TPG nanocrystals for rats was investigated by liquid chromatography-tandem mass spectroscopy（LC-MS/MS）. Compared with the TPG coarse suspension, TPG nanocrystals exhibited significant increase in AUC0–∞（approximately 1.85-fold）. Taken together, TPG nanocrystals could be used as a promising drug delivery system due to the enhanced oral bioavailability of TPG.

Determination of dabigatran in dog plasma by LC-MS/MS and its application to a pharmacokinetic study of dabigatran etexilate nanosuspension

In this study, a sensitive and rapid LC-MS/MS method was developed and validated to determine dabigatran in plasma of beagle dogs after oral administration of dabigatran etexilate nanosuspension （DABE-NS）. The analytes （dabigatran） and sertraline hydrochloride （internal standard, IS） were separated on a Kromasil C18 column using gradient elution consisting of methanol and formate buffer at a flow rate of 0.4 mL/min in 20 min. Detection and quantitation were carded out by multiple reaction monitoring following the transitions： m/z 472.17→289.07 and 305.98→275.00 for dabigatran and IS at positive ion mode, respectively. The calibration curves were linear from 1.0 to 500.0 ng/mL for dabigatran with r = 0.9995. The accuracy of each analyte ranged from 94.8% to 107.1%, and the precision was within 6%. Besides, this method was successfully applied in the investigation of the pharmacokinetic profile of dabigatran in beagle dogs after oral administration of DABE-NS. The maximum concentration and the areas under curves of dabigatran for DABE-NS were significantly higher than those of control formulation, indicating improved oral absorption.