Jacob Philippa L, Brugnoli Benedetta, Del Giudice Alessandra, Phan Hien, Chauhan Veeren M, Beckett Laura, Gillis Richard B, Moloney Cara, Cavanagh Robert J, Krumins Eduards, Reynolds-Green Morgan, Lentz Joachim C, Conte Claudia, Cuzzucoli Crucitti Valentina, Couturaud Benoit, Galantini Luciano, Francolini Iolanda, Howdle Steven M, Taresco Vincenzo
School of Chemistry, University Park, Nottingham NG7 2RD, United Kingdom.
Dept. of Chemistry, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy.
J Colloid Interface Sci. 2023 Jul;641:1043-1057. doi: 10.1016/j.jcis.2023.03.124. Epub 2023 Mar 22.
Sustainably derived poly(glycerol adipate) (PGA) has been deemed to deliver all the desirable features expected in a polymeric scaffold for drug-delivery, including biodegradability, biocompatibility, self-assembly into nanoparticles (NPs) and a functionalisable pendant group. Despite showing these advantages over commercial alkyl polyesters, PGA suffers from a series of key drawbacks caused by poor amphiphilic balance. This leads to weak drug-polymer interactions and subsequent low drug-loading in NPs, as well as low NPs stability. To overcome this, in the present work, we applied a more significant variation of the polyester backbone while maintaining mild and sustainable polymerisation conditions. We have investigated the effect of the variation of both hydrophilic and hydrophobic segments upon physical properties and drug interactions as well as self-assembly and NPs stability. For the first time we have replaced glycerol with the more hydrophilic diglycerol, as well as adjusting the final amphiphilic balance of the polyester repetitive units by incorporating the more hydrophobic 1,6-n-hexanediol (Hex). The properties of the novel poly(diglycerol adipate) (PDGA) variants have been compared against known polyglycerol-based polyesters. Interestingly, while the bare PDGA showed improved water solubility and diminished self-assembling ability, the Hex variation demonstrated enhanced features as a nanocarrier. In this regard, PDGAHex NPs were tested for their stability in different environments and for their ability to encode enhanced drug loading. Moreover, the novel materials have shown good biocompatibility in both in vitro and in vivo (whole organism) experiments.
可持续衍生的聚己二酸甘油酯（PGA）被认为具有药物递送聚合物支架所需的所有理想特性，包括生物可降解性、生物相容性、自组装成纳米颗粒（NPs）以及可功能化的侧基。尽管与商业烷基聚酯相比具有这些优势，但PGA由于两亲性平衡不佳而存在一系列关键缺点。这导致药物与聚合物之间的相互作用较弱，随后纳米颗粒中的药物负载量较低，以及纳米颗粒稳定性较低。为了克服这一问题，在本研究中，我们在保持温和且可持续的聚合条件的同时，对聚酯主链进行了更显著的改变。我们研究了亲水和疏水链段变化对物理性质、药物相互作用以及自组装和纳米颗粒稳定性的影响。我们首次用亲水性更强的二甘油取代了甘油，并通过引入疏水性更强的1,6 - 正己二醇（Hex）来调节聚酯重复单元的最终两亲性平衡。将新型聚己二酸二甘油酯（PDGA）变体的性质与已知的基于聚甘油的聚酯进行了比较。有趣的是，虽然裸PDGA表现出改善的水溶性和减弱的自组装能力，但Hex变体作为纳米载体表现出增强的特性。在这方面，测试了PDGAHex纳米颗粒在不同环境中的稳定性以及其编码增强药物负载的能力。此外，这些新型材料在体外和体内（整个生物体）实验中均显示出良好的生物相容性。
