Tong Rong, Cheng Jianjun
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
J Am Chem Soc. 2009 Apr 8;131(13):4744-54. doi: 10.1021/ja8084675.
We report here a unique method for formulating doxorubicin-polylactide (Doxo-PLA) conjugate nanoparticles, known as nanoconjugates (NCs), through Doxo/(BDI)ZnN(TMS)(2)-mediated [(BDI) = 2-((2,6-diisopropylphenyl)amido)-4-((2,6-diisopropylphenyl)-imino)-2-pentene], chemo- and regioselective polymerizations of lactide (LA) followed by nanoprecipitation. When Doxo/(BDI)ZnN(TMS)(2) was mixed with 1-pyrenemethanol (Pyr-OH) and 1-pyrenemethylamine (Pyr-NH(2)) and the mixture was utilized for the polymerization of LA, remarkable chemoselectivity was observed. Pyr-OH was completely consumed and covalently linked to the terminus of the PLA, whereas the Pyr-NH(2) remained intact in the polymerization solution. When Doxo was used as the initiator to polymerize LA in the presence of (BDI)ZnN(TMS)(2), the polymerization was complete within hours, with nearly 100% Doxo-loading efficiency and 100% LA conversion. Doxo loading as high as 27% could be achieved at a LA/Doxo ratio of 10. Both the steric bulk of the chelating ligand and the metal catalyst had dramatic effects on the regioselectivity during the initiation step. When Doxo/(BDI)ZnN(TMS)(2) was mixed with succinic anhydride (SA) to mimic the initiation of Doxo/(BDI)ZnN(TMS)(2)-mediated LA polymerization, Doxo-14-succinic ester (Doxo-SE) was the predominate product. When the steric bulk of BDI was reduced or when the BDI ligand was removed, significant amounts of Doxo-4',14-bis-succinic ester (Doxo-2SE) and Doxo-4',9,14-trisuccinic ester (Doxo-3SE) were formed. The use of (BDI)MgN(TMS)(2) in such a reaction also resulted in reduced regioselectivity and formation of both Doxo-SE and Doxo-2SE. Doxo/(BDI)ZnN(TMS)(2)-mediated LA polymerizations yielded Doxo-PLA conjugates with well-controlled molecular weights and polydispersities (as low as 1.02). The nanoprecipitation of Doxo-PLA formed NCs less than 150 nm in size with narrow particle size distributions. The sustained release of Doxo from Doxo-PLA NCs was achieved without a burst release. This method may have widespread utility for controlled conjugation of hydroxyl-containing agents to polyesters and formation of corresponding nanoparticles.
我们在此报告一种独特的方法，用于制备阿霉素 - 聚丙交酯（Doxo - PLA）共轭纳米颗粒，即通过Doxo/(BDI)ZnN(TMS)₂介导的[(BDI) = 2 - ((2,6 - 二异丙基苯基)氨基) - 4 - ((2,6 - 二异丙基苯基)亚氨基) - 2 - 戊烯]，对丙交酯（LA）进行化学和区域选择性聚合，随后进行纳米沉淀。当将Doxo/(BDI)ZnN(TMS)₂与1 - 芘甲醇（Pyr - OH）和1 - 芘甲胺（Pyr - NH₂）混合，并将该混合物用于LA的聚合时，观察到显著的化学选择性。Pyr - OH完全消耗并共价连接到PLA的末端，而Pyr - NH₂在聚合溶液中保持完整。当使用Doxo作为引发剂在(BDI)ZnN(TMS)₂存在下聚合LA时，聚合在数小时内完成，阿霉素负载效率接近100%，LA转化率为100%。在LA/Doxo比例为10时，阿霉素负载量可高达27%。螯合配体的空间位阻和金属催化剂在引发步骤中对区域选择性都有显著影响。当将Doxo/(BDI)ZnN(TMS)₂与琥珀酸酐（SA）混合以模拟Doxo/(BDI)ZnN(TMS)₂介导的LA聚合引发时，阿霉素-十四烷基琥珀酸酯（Doxo - SE）是主要产物。当BDI的空间位阻减小或BDI配体被去除时，会形成大量的阿霉素-4',14 - 双琥珀酸酯（Doxo - 2SE）和阿霉素-4',9,14 - 三琥珀酸酯（Doxo - 3SE）。在这样的反应中使用(BDI)MgN(TMS)₂也会导致区域选择性降低，并形成Doxo - SE和Doxo - 2SE。Doxo/(BDI)ZnN(TMS)₂介导的LA聚合产生了分子量和多分散性可控（低至1.02）的Doxo - PLA共轭物。Doxo - PLA的纳米沉淀形成了尺寸小于150 nm且粒径分布窄的纳米颗粒。Doxo从Doxo - PLA纳米颗粒中实现了持续释放，没有突释现象。该方法可能在将含羟基试剂与聚酯进行可控共轭以及形成相应纳米颗粒方面具有广泛的应用。
