Yankovsky Igor, Bastien Estelle, Yakavets Ilya, Khludeyev Ivan, Lassalle Henri-Pierre, Gräfe Susanna, Bezdetnaya Lina, Zorin Vladimir
Laboratory of Biophysics and Biotechnology, Physics Faculty, Belarusian State University, 4 Nezavisimosti Ave, 220030 Minsk, Belarus; Centre de Recherche en Automatique de Nancy (CRAN), CNRS UMR 7039 (Centre National de la Recherche Scientifique), Université de Lorraine, Campus Sciences, Vandœuvre-lès-Nancy, France; Institut de Cancérologie de Lorraine, Research Department, Avenue de Bourgogne, 54519 Vandœuvre-lès-Nancy, France.
Centre de Recherche en Automatique de Nancy (CRAN), CNRS UMR 7039 (Centre National de la Recherche Scientifique), Université de Lorraine, Campus Sciences, Vandœuvre-lès-Nancy, France; Institut de Cancérologie de Lorraine, Research Department, Avenue de Bourgogne, 54519 Vandœuvre-lès-Nancy, France.
Eur J Pharm Sci. 2016 Aug 25;91:172-82. doi: 10.1016/j.ejps.2016.06.012. Epub 2016 Jun 16.
Application of meta-tetra(hydroxyphenyl)chorin (mTHPC) one of the most effective photosensitizer (PS) in photodynamic therapy of solid tumors encounters several complications resulting from its insolubility in aqueous medium. To improve its solubility and pharmacokinetic properties, two modified β-cyclodextrins (β-CDs) methyl-β-cyclodextrin (M-β-CD) and 2-hydroxypropyl-β-cyclodextrin (Hp-β-CD) were proposed. The aim of this work was to evaluate the effect of β-CDs on mTHPC behavior at various stages of its distribution in vitro and in vivo. For this purpose, we have studied the influence of the β-CDs on mTHPC binding to the serum proteins, its accumulation, distribution and photodynamic efficiency in HT29 cells. In addition, the processes of mTHPC biodistribution in HT29 tumor bearing mice after intravenous injection of PS alone or with the β-CDs were compared. Interaction of mTHPC with studied β-CDs leads to the formation of inclusion complexes that completely abolishes its aggregation after introduction into serum. It was demonstrated that the β-CDs have a concentration-dependent effect on the process of mTHPC distribution in blood serum. At high concentrations, β-CDs can form inclusion complexes with mTHPC in the blood that can have a significant impact on PS distribution out of the vascular system in solid tissues. Besides, the β-CDs increase diffusion movement of mTHPC molecules that can significantly accelerate the delivery of PS to the targets cells and tissues. In vivo study confirms the fact that the use of β-CDs allows to modify mTHPC distribution processes in tumor bearing animals that is reflected in the decreased level of PS accumulation in skin and muscles, as well as in the increased PS accumulation in tumor. Further studies are underway to verify the optimal protocols of mTHPC/β-CD formulation for photodynamic therapy.
间-四(羟苯基)氯卟啉(mTHPC)作为实体瘤光动力疗法中最有效的光敏剂(PS)之一，由于其在水性介质中不溶，应用时会遇到一些并发症。为了改善其溶解性和药代动力学性质，提出了两种改性β-环糊精(β-CDs)，即甲基-β-环糊精(M-β-CD)和2-羟丙基-β-环糊精(Hp-β-CD)。这项工作的目的是评估β-CDs在mTHPC体外和体内分布的各个阶段对其行为的影响。为此，我们研究了β-CDs对mTHPC与血清蛋白结合、在HT29细胞中的积累、分布及光动力效率的影响。此外，还比较了单独静脉注射PS或与β-CDs联合注射后mTHPC在荷HT29肿瘤小鼠体内的生物分布过程。mTHPC与所研究的β-CDs相互作用会形成包合物，在引入血清后完全消除其聚集。结果表明，β-CDs对血清中mTHPC的分布过程具有浓度依赖性影响。在高浓度下，β-CDs可与血液中的mTHPC形成包合物，这可能对实体组织中血管系统外的PS分布产生重大影响。此外，β-CDs增加了mTHPC分子的扩散运动，可显著加速PS向靶细胞和组织的递送。体内研究证实，使用β-CDs可以改变荷瘤动物体内mTHPC的分布过程，这表现为皮肤和肌肉中PS积累水平降低，以及肿瘤中PS积累增加。目前正在进行进一步研究，以验证用于光动力疗法的mTHPC/β-CD制剂的最佳方案。
