Ring-Opening Polymerization-Mediated Controlled Formulation of Polylactide-Drug Nanoparticles
Ring-Opening Polymerization-Mediated Controlled Formulation of Polylactide-Drug Nanoparticles
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DOI：
10.1021/ja8084675
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发表时间：
2009-04-08
影响因子：
15
通讯作者：
Cheng, Jianjun
中科院分区：
文献类型：
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作者：
Tong, Rong;Cheng, Jianjun
我们在这里报告了一种独特的方法，用于配制多柔比星-聚乳酸（Doxo-PLA）缀合物纳米颗粒，称为纳米缀合物（NC），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]，化学和区域选择性聚合的丙交酯（LA），然后纳米沉淀。当Doxo/（BDI）ZnN（TMS）_2与1-芘甲醇（Pyr-OH）和1-芘乙胺（Pyr-NH_2）混合用于LA的聚合时，观察到显著的化学选择性。Pyr-OH被完全消耗并共价连接到PLA的末端，而Pyr-NH 2在聚合溶液中保持完整。当在（BDI）ZnN（TMS）（2）的存在下使用Doxo作为引发剂来引发聚乳酸时，聚合在数小时内完成，具有接近100%Doxo负载效率和100%LA转化率。在LA/Doxo比为10时，可实现高达27%的Doxo负载。无论是螯合配体的空间体积和金属催化剂在引发步骤的区域选择性有显着的影响。当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聚合的引发时，Doxo-14-琥珀酸酯（Doxo-SE）是主要产物。当BDI的空间体积减少时或当BDI配体被去除时，形成显著量的Doxo-4 '，14-双琥珀酸酯（Doxo-2SE）和Doxo-4'，9，14-三琥珀酸酯（Doxo-3SE）。在这样的反应中使用（BDI）MgN（TMS）（2）也导致降低的区域选择性和Doxo-SE和Doxo-2SE的形成。Doxo/（BDI）ZnN（TMS）（2）介导的LA聚合产生了具有良好控制的分子量和多分散性（低至1.02）的Doxo-PLA缀合物。Doxo-PLA的纳米沉淀形成尺寸小于150 nm的具有窄粒度分布的NC。实现了Doxo从Doxo-PLA NC的持续释放，而没有突释。该方法可广泛用于含羟基试剂与聚酯的受控缀合和相应纳米颗粒的形成。
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-NH2) 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-NH2 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.