Lucke Andrea, Fustella Elisabetta, Tessmar Jörg, Gazzaniga Andrea, Göpferich Achim
Department of Pharmaceutical Technology, University of Regensburg, 93040 Regensburg, Germany.
J Control Release. 2002 Apr 23;80(1-3):157-68. doi: 10.1016/s0168-3659(02)00020-2.
The combination of poly(ethylene glycol) (PEG) with a biodegradable poly(ester), such as poly(D,L-lactic acid) (PLA), is an approach that has been successfully used for the stabilization of proteins and peptides in several biodegradable delivery devices. The acylation of peptides inside degrading PLA microspheres has been described only recently as another instability mechanism related to the accumulation of polymer degradation products inside eroding PLA. We investigated whether the block copolymerization of PLA with PEG reduces peptide acylation inside degrading microspheres. Diblock copolymers consisting of poly(D,L-lactic acid) covalently bound to poly(ethylene glycol)-monomethyl ether (Me.PEG-PLA) were used for these investigations. Human atrial natriuretic peptide (ANP) was incorporated into microspheres manufactured from Me.PEG5-PLA45, a diblock copolymer with an overall PEG content of 10%. Peptide integrity inside the microspheres was monitored by HPLC-MS analysis during 4 weeks of microsphere degradation in isotonic phosphate buffer (pH 7.4) at 37 degrees C. Inside the degrading Me.PEG5-PLA45 microspheres, acylation products as well as an oxidation product of ANP were formed. The results demonstrate that the combination of PEG with PLA does not necessarily display a favorable effect concerning peptide acylation inside degrading polymer microspheres. However, they also suggested that the acylation reaction is mainly driven by the formation and accumulation of polymer degradation products inside the degrading microspheres.
聚乙二醇（PEG）与可生物降解的聚酯（如聚（D，L-乳酸）（PLA））相结合，是一种已成功用于在多种可生物降解递送装置中稳定蛋白质和肽的方法。直到最近，才有人描述了在降解的PLA微球内肽的酰化作用，这是另一种与侵蚀性PLA内聚合物降解产物积累相关的不稳定性机制。我们研究了PLA与PEG的嵌段共聚是否能减少降解微球内肽的酰化作用。由共价结合到聚（乙二醇）-单甲醚上的聚（D，L-乳酸）组成的二嵌段共聚物（Me.PEG-PLA）用于这些研究。将人心房利钠肽（ANP）掺入由Me.PEG5-PLA45制成的微球中，Me.PEG5-PLA45是一种总PEG含量为10%的二嵌段共聚物。在37℃的等渗磷酸盐缓冲液（pH 7.4）中，在微球降解4周的过程中，通过HPLC-MS分析监测微球内肽的完整性。在降解的Me.PEG5-PLA45微球内，形成了酰化产物以及ANP的氧化产物。结果表明，PEG与PLA的组合在降解的聚合物微球内肽的酰化方面不一定显示出有利的效果。然而，它们也表明酰化反应主要是由降解微球内聚合物降解产物的形成和积累驱动的。
