Ring-Opening Polymerization-Mediated Controlled Formulation of Polylactide−Drug Nanoparticles

• Published in: Journal of the American Chemical Society 2009-04, Vol.131 (13), p.4744-4754
• Main Authors: Tong, Rong, Cheng, Jianjun
• Format: Article
• Language: English
• Subjects: Catalysis; Doxorubicin - chemical synthesis; Doxorubicin - chemistry; Drug Carriers - chemical synthesis; Drug Carriers - chemistry; Ligands; Metals - chemistry; Nanoparticles - chemistry; Polyesters - chemical synthesis; Polyesters - chemistry; Stereoisomerism
• ISSN: 0002-7863; 1520-5126
• 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-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.