Tzannis S T, Hrushesky W J, Wood P A, Przybycien T M
The Howard P. Isermann Department of Chemical Engineering, Applied Protein Biophysics Laboratory, Rensselaer Polytechnic Institute, Troy, NY 12180-3590, USA.
Proc Natl Acad Sci U S A. 1996 May 28;93(11):5460-5. doi: 10.1073/pnas.93.11.5460.
The physical stability of pharmaceutical proteins in delivery environments is a critical determinant of biological potency and treatment efficacy, and yet it is often taken for granted. We studied both the bioactivity and physical stability of interleukin 2 upon delivery via continuous infusion. We found that the biological activity of the delivered protein was dramatically reduced by approximately 90% after a 24-hr infusion program. Only a portion of these losses could be attributed to direct protein deposition on the delivery surfaces. Analysis of delivered protein by size exclusion chromatography gave no indication of insulin-like, surface-induced aggregation phenomena. Examination of the secondary and tertiary structure of both adsorbed and delivered protein via Fourier-transform infrared spectroscopy, circular dichroism, and fluorescence spectroscopy indicated that transient surface association of interleukin 2 with the catheter tubing resulted in profound, irreversible structural changes that were responsible for the majority of the biological activity losses.
药物蛋白在给药环境中的物理稳定性是生物活性和治疗效果的关键决定因素，但人们常常对此习以为常。我们研究了通过持续输注给药时白细胞介素2的生物活性和物理稳定性。我们发现，在进行24小时输注方案后，所输送蛋白的生物活性显著降低了约90%。这些损失中只有一部分可归因于蛋白直接沉积在给药表面。通过尺寸排阻色谱法对所输送蛋白进行分析，未发现胰岛素样的、表面诱导的聚集现象。通过傅里叶变换红外光谱、圆二色性和荧光光谱对吸附和输送的蛋白的二级和三级结构进行检测，结果表明白细胞介素2与导管短暂的表面结合导致了深刻的、不可逆的结构变化，这是造成大部分生物活性损失的原因。
