Jurczyk Magdalena, Smolarczyk Ryszard, Musiał-Kulik Monika, Ciepła Joanna, Matuszczak Sybilla, Cichoń Tomasz, Czapla Justyna, Bochenek Marcelina, Foryś Aleksander, Wrześniok Dorota, Beberok Artur, Jelonek Katarzyna
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland.
Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Curie-Skłodowska 34 Street, 41-819 Zabrze, Poland.
Mol Pharm. 2025 Aug 4;22(8):4662-4678. doi: 10.1021/acs.molpharmaceut.5c00215. Epub 2025 Jun 25.
Nanoparticles (NPs) dual-targeted with folic acid (FA) and biotin (BIO) are developed to overcome problems associated with conventional chemotherapy and tumor heterogeneity. Although some preliminary studies have been conducted to develop dual-targeted micelles for delivery of docetaxel (Dtx), a more detailed analysis is needed to discover their pharmaceutical potential. Therefore, this manuscript is focused on a comprehensive analysis of the influence of the type and density of targeting ligand on micelles' morphology, physicochemical properties, drug loading and release, cell internalization, cytotoxicity in vitro against several kinds of cells and in vivo on two mice cancer models. For this purpose, three kinds of micelles were obtained: decorated with one type of ligand (FA or BIO) and dual-targeted. The micelles contained different amounts of FA- and/or BIO-functionalized polymer (10, 25, and 50%). Additionally, the dual-targeted micelles were compared with a mixture of two kinds of single-targeted micelles. The study showed that the cytotoxic effect of micelles strongly depends on the type of cancer cells and their surface characteristics. The micelles with a higher density of ligands may have higher efficiency against cells with lower expression of cell surface receptors (SK-BR-3 and MCF-7). Conversely, micelles with lower ligand density may be advantageous against cancer cells with overexpression of surface receptors (HeLa, 4T1). Interestingly, the drug delivered in FA-targeted micelles showed higher cytotoxicity compared to dual-targeted micelles in which two ligands are present on the same NP. However, Dtx delivered in a mixture of micelles single-targeted with FA and BIO showed the highest cytotoxic effect, which was confirmed in vitro and in vivo on the mice model.
开发了用叶酸（FA）和生物素（BIO）进行双靶向的纳米颗粒（NP），以克服与传统化疗和肿瘤异质性相关的问题。尽管已经进行了一些初步研究来开发用于递送多西他赛（Dtx）的双靶向胶束，但仍需要更详细的分析来发现它们的药学潜力。因此，本手稿重点对靶向配体的类型和密度对胶束形态、物理化学性质、载药和释药、细胞内化、对几种细胞的体外细胞毒性以及对两种小鼠癌症模型的体内细胞毒性的影响进行全面分析。为此，获得了三种胶束：用一种类型的配体（FA或BIO）修饰的以及双靶向的。这些胶束含有不同量的FA和/或BIO功能化聚合物（10%、25%和50%）。此外，将双靶向胶束与两种单靶向胶束的混合物进行了比较。研究表明，胶束的细胞毒性作用强烈取决于癌细胞的类型及其表面特征。配体密度较高的胶束对细胞表面受体表达较低的细胞（SK-BR-3和MCF-7）可能具有更高的效率。相反，配体密度较低的胶束可能对表面受体过表达的癌细胞（HeLa、4T1）更有利。有趣的是，与在同一NP上存在两种配体的双靶向胶束相比，FA靶向胶束中递送的药物显示出更高的细胞毒性。然而，在FA和BIO单靶向胶束混合物中递送的Dtx显示出最高的细胞毒性作用，这在体外和小鼠模型体内均得到证实。
