Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
J Am Chem Soc. 2012 Sep 12;134(36):14945-57. doi: 10.1021/ja305080f. Epub 2012 Aug 30.
Multifunctional biocompatible and biodegradable nanomaterials incorporating specific degradable linkages that respond to various stimuli and with defined degradation profiles are critical to the advancement of targeted nanomedicine. Herein we report, for the first time, a new class of multifunctional dendritic polyether polyketals containing different ketal linkages in their backbone that exhibit unprecedented control over degradation in solution and within the cells. High-molecular-weight and highly compact poly(ketal hydroxyethers) (PKHEs) were synthesized from newly designed α-epoxy-ω-hydroxyl-functionalized AB(2)-type ketal monomers carrying structurally different ketal groups (both cyclic and acyclic) with good control over polymer properties by anionic ring-opening multibranching polymerization. Polymer functionalization with multiple azide and amine groups was achieved without degradation of the ketal group. The polymer degradation was controlled primarily by the differences in the structure and torsional strain of the substituted ketal groups in the main chain, while for polymers with linear (acyclic) ketal groups, the hydrophobicity of the polymer may play an additional role. This was supported by the log P values of the monomers and the hydrophobicity of the polymers determined by fluorescence spectroscopy using pyrene as the probe. A range of hydrolysis half-lives of the polymers at mild acidic pH values was achieved, from a few minutes to a few hundred days, directly correlating with the differences in ketal group structures. Confocal microscopy analyses demonstrated similar degradation profiles for PKHEs within live cells, as seen in solution and the delivery of fluorescent marker to the cytosol. The cell viability measured by MTS assay and blood compatibility determined by complement activation, platelet activation, and coagulation assays demonstrate that PKHEs and their degradation products are highly biocompatible. Taken together, these data demonstrate the utility this new class of biodegradable polymer as a highly promising candidate in the development of multifunctional nanomedicine.
多功能生物相容性和可生物降解的纳米材料，其包含对各种刺激做出响应的特定可降解键，并具有定义明确的降解曲线，对于靶向纳米医学的发展至关重要。在此，我们首次报道了一类新型多功能树枝状聚醚聚缩醛，其主链中含有不同的缩醛键，在溶液中和细胞内具有前所未有的降解控制能力。通过阴离子开环多支化聚合，从新型设计的带有结构不同缩醛基团（环状和非环状）的α-环氧-ω-羟基官能化 AB(2)型缩醛单体合成了高分子量和高紧凑的聚（缩醛羟醚）（PKHEs），可以很好地控制聚合物性能。通过与多个叠氮化物和胺基的聚合物功能化而不降解缩醛基团。聚合物的降解主要受主链中取代缩醛基团的结构和扭转应变的差异控制，而对于具有线性（非环状）缩醛基团的聚合物，聚合物的疏水性可能起额外的作用。这得到单体的 log P 值和荧光光谱法使用芘作为探针测定的聚合物疏水性的支持。在温和的酸性 pH 值下，实现了一系列聚合物的水解半衰期，从几分钟到几百天不等，这与缩醛基团结构的差异直接相关。共聚焦显微镜分析表明，PKHEs 在活细胞内的降解曲线与在溶液中和将荧光标记物递送到细胞质中的降解曲线相似。通过 MTS 测定法测量的细胞活力和通过补体激活、血小板激活和凝血测定法确定的血液相容性表明，PKHEs 及其降解产物具有高度的生物相容性。总的来说，这些数据表明这种新型可生物降解聚合物作为多功能纳米医学发展的极具前途的候选物的实用性。
