Impact of molecular weight on the intrinsic immunogenic activity of poly(beta amino esters)
Impact of molecular weight on the intrinsic immunogenic activity of poly(beta amino esters)
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DOI：
10.1002/jbm.a.35970
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发表时间：
2017-04-01
影响因子：
4.9
通讯作者：
Jewell, Christopher M.
中科院分区：
文献类型：
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作者：
Andorko, James I.;Pineault, Kevin G.;Jewell, Christopher M.
聚合物载体在疫苗和药物递送中被广泛研究以控制货物的封装、动力学和靶向。最近的研究表明，许多聚合物可以引起免疫刺激和炎症反应，即使在没有其他免疫信号的情况下。然而，这种内在免疫原性在降解过程中演变的程度尚未得到充分研究。在这里，我们合成了一个小的图书馆的聚（β氨基酯）（PBAE），表现出不同的起始分子量（MW），但具有相似的和快速的降解速率。原代树突状细胞（DC）处理游离PBAE，无论是完整的或降解形成低分子量片段，没有被激活。相反，由PBAE在不同程度的降解下形成的颗粒引起经典DC活化标志物（例如，CD 40、CD 80、CD 86、MHCII）的差异表达以及抗原呈递。在降解过程中，活化水平随着物理化学性质（例如，MW、浓度、尺寸、电荷）的变化而变化。值得注意的是，无论起始MW如何，当降解PBAE的MW降低到类似于1500-3000 Da的范围时，免疫原性达到峰值。这些发现可以帮助设计未来的载体，这些载体利用材料降解时与免疫系统的动态相互作用，导致载体递送货物，但也有助于引导对疫苗或免疫治疗货物的免疫应答。(C)2017 Wiley Periodicals，Inc.
Polymeric carriers are ubiquitously studied in vaccine and drug delivery to control the encapsulation, kinetics, and targeting of cargo. Recent research reveals many polymers can cause immunostimulatory and inflammatory responses, even in the absence of other immune signals. However, the extent to which this intrinsic immunogenicity evolves during degradation is understudied. Here we synthesized a small library of poly(beta amino esters) (PBAEs) that exhibit different starting molecular weights (MWs), but with similar and rapid degradation rates. Primary dendritic cells (DCs) treated with free PBAEs, either intact or degraded to form low MW fragments, were not activated. In contrast particles formed from PBAEs at different extents of degradation caused differential expression of classical DC activation markers (for example, CD40, CD80, CD86, MHCII), as well as antigen presentation. During degradation, activation levels changed with changing physicochemical properties (for example, MW, concentration, size, charge). Of note, irrespective of starting MW, immunogenicity peaked when the MW of degrading PBAEs decreased to a range of similar to 1500-3000 Da. These findings could help inform design of future carriers that exploit the dynamic interactions with the immune system as materials degrade, leading to carriers that deliver cargo but also help direct the immune responses to vaccine or immunotherapy cargo. (C) 2017 Wiley Periodicals, Inc.