Biotherapeutics Division, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz (JGU), Obere Zahlbacher Straße 63, 55131 Mainz, Germany.
Biomacromolecules. 2024 Oct 14;25(10):6539-6554. doi: 10.1021/acs.biomac.4c00695. Epub 2024 Sep 18.
Miktoarm star polymers exhibit a captivating range of physicochemical properties, setting them apart from their linear counterparts. This study devised a synthetic pathway to synthesize cationic miktoarm stars utilizing polypept(o)ides (PeptoMiktoStars), comprising 3 or 6 polysarcosine (pSar) arms (AB, AB, overall 300) for shielding and a cross-linkable poly(-ethylsulfonyl-l-homocysteine) (pHcy(SOEt)) block and a poly(l-lysine) ((pLys)) block for nucleic acid complexation. Precise control over the DP and narrow molecular weight distributions ( ≈ 1.2) were achieved for both structures. Both PeptoMiktoStars efficiently complexed mRNA and pDNA into polyion complex micelles (PICMs). AB-PICMs provided modest (mRNA) to high (pDNA) stability against glutathione and heparin sulfate (HS), while even cross-linked AB-PICMs were susceptible to HS. All PICMs delivered pDNA and mRNA into D1 cells (over 80%) and Jurkat T cells (over 50%) in vitro. Despite payload- and cell-dependency, AB showed overall higher transfection efficiency, while AB demonstrated better shielding and enhanced stability.
星型嵌段聚合物表现出引人注目的物理化学性质，这使它们有别于其线性对应物。本研究设计了一种合成阳离子星型嵌段聚合物的途径，利用多肽（PeptoMiktoStars），包含 3 或 6 个聚肌氨酸（pSar）臂（AB，AB，总共 300）用于屏蔽和可交联的聚（乙基磺酰基-L-高半胱氨酸）（pHcy（SOEt））块和聚 L-赖氨酸（pLys）块用于核酸络合。两种结构均实现了对 DP 和窄分子量分布（≈1.2）的精确控制。两种 PeptoMiktoStars 均能将 mRNA 和 pDNA 高效地复合成聚离子复合物胶束（PICMs）。AB-PICMs 对谷胱甘肽和肝素硫酸盐（HS）具有中等（mRNA）到高（pDNA）稳定性，而即使交联的 AB-PICMs 也容易受到 HS 的影响。所有 PICMs 均能将 pDNA 和 mRNA 递送至 D1 细胞（超过 80%）和 Jurkat T 细胞（超过 50%）中。尽管与有效载荷和细胞依赖性有关，但 AB 显示出总体上更高的转染效率，而 AB 则表现出更好的屏蔽作用和增强的稳定性。
