Thermosensitive liposomes (TSL) in combination with regional hyperthermia represent a powerful tool for tumor specific drug delivery. The objective of this study was to investigate the influence of vesicle size on the biophysical properties of TSL. TSL were composed of DPPC/DSPC/1,2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPG(2)) 50:20:30 (mol/mol) (DPPG(2)-TSL) and DPPC/P-Lyso-PC/DSPE-PEG2000 90:10:4 (mol/mol) (PEG/Lyso-TSL) with encapsulated fluorescent dye carboxyfluorescein, anticancer drug doxorubicin or magnetic resonance contrast agent gadodiamide. Extrusion was performed with polycarbonate filters of distinct pore size to obtain TSL with different diameters (50 to 200nm). Phase transition temperature (T(m)) of the bilayer forming phospholipids was not influenced by vesicle size in the tested range. However, vesicle size had a major impact on in vitro content release properties of TSL in the investigated temperature range between 30 and 45°C. Generally, vesicle size was inversely related to content release properties with increased content release rates for decreased vesicle sizes. Size dependency of content release properties varied between all tested formulations and DPPG(2)-TSL were generally less affected by size changes in the range of 100 to 150nm as compared to PEG/Lyso-TSL. Independent from gadodiamide release, vesicle size influenced the signal intensity of DPPG(2)-TSL also at temperatures below T(m) due to improved water exchange for smaller vesicles. Liposomes around 100nm in size are routinely used in vivo, hence a quality control for TSL preparations is required prior to use. Even small changes in size or a wider size distribution might affect stability and release properties and thus yield in decreased efficacy or unwanted side effects of drug loaded TSL during in vivo applications.

译文

热敏脂质体 (TSL) 与局部热疗相结合是肿瘤特异性药物递送的强大工具。这项研究的目的是研究囊泡大小对TSL生物物理性质的影响。TSL由DPPC/DSPC/1,2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPG(2)) 50:20:30 (mol/mol) (DPPG(2)-TSL) 和DPPC/P-lyso-pc/DSPE-PEG2000 90:10组成: 4 (mol/mol) (PEG/lyso-tsl) 用包封荧光染料羧基荧光素、抗癌药物阿霉素或磁共振对比剂加多二胺。用不同孔径的聚碳酸酯过滤器进行挤出,以获得不同直径 (50至200nm) 的TSL。在测试范围内,形成双层的磷脂的相变温度 (T(m)) 不受囊泡大小的影响。然而,在30至45 °C的研究温度范围内,囊泡大小对TSL的体外含量释放特性有重大影响。通常,囊泡大小与内容物释放特性成反比,随着囊泡大小减小,内容物释放速率增加。在所有测试的制剂之间变化的内容物释放性质的尺寸依赖性,与PEG/lyso-tsl相比,DPPG(2)-TSL通常受100至150nm范围内的尺寸变化的影响较小。与gadodiamide的释放无关,囊泡的大小在低于T(m) 的温度下也影响了DPPG(2)-TSL的信号强度,这是因为较小的囊泡的水交换得到了改善。体内常规使用大小约100nm的脂质体,因此在使用前需要对TSL制剂进行质量控制。即使尺寸的微小变化或较宽的尺寸分布也可能影响稳定性和释放特性,从而在体内应用过程中降低了载药TSL的功效或不想要的副作用。

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