European Institute for Molecular Imaging, University of Münster, Waldeyerstr. 15, 48159, Münster, Germany.
Interdisciplinary Center of Clinical Research (IZKF), University of Münster, Albert-Schweitzer Campus 1, 48149, Münster, Germany.
Angew Chem Int Ed Engl. 2022 Jan 3;61(1):e202109769. doi: 10.1002/anie.202109769. Epub 2021 Nov 25.
Ibrutinib is an inhibitor of Bruton's tyrosine kinase that has been approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia and is connected with toxicities. To minimize its toxicities, we linked ibrutinib to a cell-targeted, internalizing antibody. To this end, we synthesized a poly-anionic derivate, ibrutinib-Cy3.5, that retains full functionality. This anionic inhibitor is complexed by our anti-CD20-protamine targeting conjugate and free protamine, and thereby spontaneously assembles into an electrostatically stabilized vesicular nanocarrier. The complexation led to an accumulation of the drug driven by the CD20 antigen internalization to the intended cells and an amplification of its pharmacological effectivity. In vivo, we observed a significant enrichment of the drug in xenograft lymphoma tumors in immune-compromised mice and a significantly better response to lower doses compared to the original drug.
伊布替尼是布鲁顿酪氨酸激酶抑制剂，已获准用于治疗慢性淋巴细胞白血病、套细胞淋巴瘤和华氏巨球蛋白血症患者，并伴有毒性。为了最大限度地降低其毒性，我们将伊布替尼与靶向细胞、内化抗体连接起来。为此，我们合成了一种带负电荷的衍生物伊布替尼-Cy3.5，它保留了完整的功能。这种阴离子抑制剂与我们的抗 CD20-鱼精蛋白靶向缀合物和游离鱼精蛋白复合，并因此自发组装成静电稳定的囊泡纳米载体。这种复合物的形成导致药物的积累，这是由 CD20 抗原内化到靶细胞驱动的，并且增强了其药理效力。在体内，我们观察到在免疫功能低下的小鼠异种移植淋巴瘤肿瘤中药物的显著富集，并且与原始药物相比，较低剂量的药物反应更好。
