Colloidal Vectors and Tissue Transport, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.
Colloidal Vectors and Tissue Transport, UMR5305, LBTI, Institut de Biologie et Chimie des Protéines, Université Lyon 1, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.
Int J Pharm. 2019 Sep 10;568:118569. doi: 10.1016/j.ijpharm.2019.118569. Epub 2019 Jul 26.
Designing potent and safe-of-use therapies against cancers and infections remains challenging despite the emergence of novel molecule classes like checkpoint inhibitors or Toll-Like-Receptor ligands. The latest therapeutic perspectives under development for immune modulator administration exploits vectorization, and biodegradable delivery systems are one of the most promising vehicles. Nanoparticles based on Poly (D,L) Lactic Acid (PLA) as polymer for formulation are widely investigated due to its bioresorbable, biocompatible and low immunogen properties. We propose a PLA-based nanoparticle delivery system to vectorize PamCSK, a lipopeptide TLR1/2 ligand and a potent activator of the proinflammatory transcription factor NF-κB that shows a self-assembling behavior from 30 µg/mL onwards. We demonstrate successful encapsulation of PamCSK in PLA nanoparticles by nanoprecipitation in a 40-180 µg/mL concentration range, with 99% of entrapment efficiency. By molecular modelling, we characterize drug/carrier interactions and conclude that PamCSK forms clusters onto the nanoparticle and is not encapsulated into the hydrophobic core. In silico predictions provide nanoprecipitation optimization and the mechanistic understanding of the particle dynamics. The loaded-PamCSK maintains bioactivity on TLR2, confirmed by in vitro experiments using reporter cell line HEK-Blue hTLR2. Our presented data and results are convincing evidence that PamCSK-loaded in PLA nanoparticles represent a promising immune modulating system.
尽管出现了新型分子类别，如检查点抑制剂或 Toll 样受体配体，针对癌症和感染的有效且安全的治疗方法的设计仍然具有挑战性。目前正在开发的用于免疫调节剂给药的最新治疗方法利用了载体化，而可生物降解的递药系统是最有前途的载体之一。基于聚（D，L）乳酸（PLA）的纳米粒子作为制剂的聚合物因其生物可吸收性、生物相容性和低免疫原性而得到广泛研究。我们提出了一种 PLA 基纳米粒子递药系统，用于载体化 PamCSK，这是一种脂肽 TLR1/2 配体，也是促炎转录因子 NF-κB 的有效激活剂，从 30μg/mL 开始表现出自组装行为。我们通过纳米沉淀成功地将 PamCSK 包封在 PLA 纳米粒子中，浓度范围为 40-180μg/mL，包封效率为 99%。通过分子建模，我们表征了药物/载体相互作用，并得出结论，PamCSK 在纳米粒子上形成簇，而不是封装在疏水性核心内。基于计算机的预测提供了纳米沉淀的优化和颗粒动力学的机制理解。负载 PamCSK 的 PLA 纳米粒子在 TLR2 上保持生物活性，这通过使用报告细胞系 HEK-Blue hTLR2 的体外实验得到证实。我们呈现的数据和结果令人信服地证明了 PamCSK 负载在 PLA 纳米粒子中代表了一种有前途的免疫调节系统。
