David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Department of Chemistry, Materials and Chemical Engineering, Politecnico di Milano, Via Mancinelli 7, 20131, Milano, Italy.
Adv Healthc Mater. 2018 Jul;7(14):e1800249. doi: 10.1002/adhm.201800249. Epub 2018 May 14.
The production of new proteins with messenger RNA (mRNA) has gained a broad interest due to its potential for addressing a wide range of diseases. Here, the design and characterization of novel ionizable poly(β-amino ester)-co-poly(caprolactone) terpolymers, synthesized via the combination of the ring opening polymerization and the Michael step-growth polymerization, are reported. The versatility of this method is demonstrated by varying the number of caprolactone units attached to each poly(β-amino ester) (PBAE) terpolymer. The ability of the novel poly-caprolactone (PCL)-based PBAE materials to deliver mRNA is shown to depend on the physiochemical characteristics of the material, such as lipophilicity, as well as the formulation method used to complex the polymer with the oligonucleotide. This latter variable represents a previously unstudied aspect of PBAE library screens that can play an important role in identifying true top candidates for nucleic acid delivery. The most stable terpolymer is injected intravenously (IV) in mice and shows a transfection efficacy several times higher than the polyethylenimine (PEI) which is focused in the spleen, opening the possibility to use these biodegradable carriers in the intravenous delivery of antigen-encoding mRNA for cancer immunotherapy and vaccination.
信使 RNA（mRNA）生产新蛋白因其在治疗多种疾病方面的潜力而引起了广泛关注。在此，我们报道了新型可离子化聚（β-氨基酸酯）-共-聚（己内酯）三嵌段共聚物的设计和特性，这些共聚物是通过开环聚合和迈克尔加成聚合相结合合成的。该方法的多功能性通过改变每个聚（β-氨基酸酯）（PBAE）三嵌段共聚物上连接的己内酯单元的数量来证明。新型基于聚己内酯（PCL）的 PBAE 材料递送 mRNA 的能力取决于材料的物理化学特性，如亲脂性，以及用于将聚合物与寡核苷酸复合的制剂方法。后者是 PBAE 文库筛选中以前未研究的方面，它在确定核酸递送的真正最佳候选物方面起着重要作用。最稳定的三嵌段共聚物通过静脉内（IV）注射到小鼠体内，其转染效率比聚醚酰亚胺（PEI）高几倍，聚醚酰亚胺主要集中在脾脏中，这为在癌症免疫治疗和疫苗接种中使用这些可生物降解载体进行静脉内递送抗原编码 mRNA 开辟了可能性。
