Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA.
Drug Deliv Transl Res. 2014 Dec;4(5-6):389-94. doi: 10.1007/s13346-014-0209-8.
A new drug-free nanotherapeutic approach for B-cell malignancies was developed. Exposure of B-cells to an anti-CD20 Fab'-morpholino oligonucleotide1 (MORF1) conjugate decorated the cell surface with MORF1; further exposure of the decorated cells to multivalent polymer-oligonucleotide2 conjugates (P-MORF2) resulted in CD20 clustering at the cell surface with induction of apoptosis. We evaluated this concept in chronic lymphocytic leukemia (CLL) cells isolated from 10 patients. Apoptosis and cytotoxicity were observed in eight samples, including 2 samples with the 17p13 deletion, which suggested a p53-independent mechanism of apoptosis induction. When compared to an anti-CD20 monoclonal antibody (mAb), the nanotherapeutic showed significantly more potent apoptosis-inducing activity and cytotoxicity. This was due to the multivalency effect (8 binding sites per polymer chain) of our design in comparison to the divalent mAb. In conclusion, we have developed a novel and potent therapeutic system against CLL and other B-cell malignancies with significant advantages over conventional chemo-immunotherapy.
开发了一种针对 B 细胞恶性肿瘤的新型无药物纳米治疗方法。将抗 CD20 Fab'- 吗啉代寡核苷酸 1（MORF1）缀合物暴露于 B 细胞会使细胞表面带有 MORF1；进一步将经过修饰的细胞暴露于多价聚合物-寡核苷酸 2 缀合物（P-MORF2）会导致 CD20 在细胞表面聚集，并诱导细胞凋亡。我们在从 10 名患者中分离出的慢性淋巴细胞白血病（CLL）细胞中评估了这一概念。在 8 个样本中观察到了细胞凋亡和细胞毒性，包括 2 个具有 17p13 缺失的样本，这表明细胞凋亡的诱导机制与 p53 无关。与抗 CD20 单克隆抗体（mAb）相比，纳米治疗显示出更强的细胞凋亡诱导活性和细胞毒性。这是由于我们的设计具有多价效应（每个聚合物链 8 个结合位点），与二价 mAb 相比具有明显的优势。总之，我们开发了一种针对 CLL 和其他 B 细胞恶性肿瘤的新型有效治疗系统，与传统的化疗免疫治疗相比具有显著优势。
