Shinde Usha Pramod, Moon Hyo Jung, Ko Du Young, Jung Bo Kyong, Jeong Byeongmoon
Department of Chemistry and Nano Science, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 120-750, Korea.
Biomacromolecules. 2015 May 11;16(5):1461-9. doi: 10.1021/acs.biomac.5b00325. Epub 2015 Apr 15.
Poly(ethylene glycol)-poly(l-alanine-co-l-phenyl alanine) diblock copolymers (PEG-PAF) of 2000-990 Da (P2K) and 5000-2530 Da (P5K) with the different molecular weights of PEGs, but having a similar molecular weight ratio of hydrophobic block to hydrophilic block were synthesized to compare their solution behavior and corresponding protein drug release profiles from their in situ formed thermogels. The PEG-PAF aqueous solutions underwent heat-induced sol-to-gel transition in a concentration range of 18.0-24.0 wt % and 8.0-12.0 wt % for P2K and P5K, respectively. P5K formed bigger micelles than P2K, of a broad distribution, whereas the PAF blocks of P5K developed richer in α-helix than those of P2K in the core of the micelles. As the temperature increased, the micelles underwent dehydration of the PEG, which led to the aggregation of micelles, while the secondary structure of PAF was slightly affected during the sol-to-gel transition. The P5K exhibited higher tendency to aggregate and formed a tighter gel than P2K. Upon injection into the subcutaneous layer of rats, both polymer aqueous solutions formed a biocompatible gel with typical mild inflammatory tissue responses. Recombinant human growth hormone (rhGH) maintained its stability without forming any aggregates in both sol (4 °C) and gel (37 °C) states of the PEG-PAFs. Even though P2K and P5K have a similar molecular weight ratio of hydrophobic block to hydrophilic block, the P5K system exhibited a reduced initial burst release, improved bioavailability, and prolonged therapeutic duration of the rhGH, compared to the P2K system. The current research suggests that a drug release profile is a complex function of self-assembling carriers and incorporated drugs, and thus, a promising protein delivery system could be designed by adjusting the molecular parameters of a thermogel.
合成了分子量为2000 - 990 Da（P2K）和5000 - 2530 Da（P5K）的聚（乙二醇）-聚（L-丙氨酸-co-L-苯丙氨酸）二嵌段共聚物（PEG-PAF），其聚乙二醇分子量不同，但疏水嵌段与亲水嵌段的分子量比相似，以比较它们的溶液行为以及从其原位形成的热凝胶中相应的蛋白质药物释放曲线。PEG-PAF水溶液在浓度范围分别为18.0 - 24.0 wt%（P2K）和8.0 - 12.0 wt%（P5K）时经历热诱导的溶胶-凝胶转变。P5K形成的胶束比P2K大，分布较宽，而P5K的PAF嵌段在胶束核心中比P2K的PAF嵌段形成更丰富的α-螺旋。随着温度升高，胶束的聚乙二醇发生脱水，导致胶束聚集，而PAF的二级结构在溶胶-凝胶转变过程中受到轻微影响。P5K比P2K表现出更高的聚集倾向并形成更紧密的凝胶。注入大鼠皮下层后，两种聚合物水溶液均形成具有典型轻度炎症组织反应的生物相容性凝胶。重组人生长激素（rhGH）在PEG-PAF的溶胶（4℃）和凝胶（37℃）状态下均保持其稳定性，未形成任何聚集体。尽管P2K和P5K的疏水嵌段与亲水嵌段的分子量比相似，但与P2K系统相比，P5K系统表现出初始突释减少、生物利用度提高以及rhGH治疗持续时间延长。当前研究表明，药物释放曲线是自组装载体和包封药物的复杂函数，因此，通过调节热凝胶的分子参数可以设计出有前景的蛋白质递送系统。
