Dual oligopeptides modification mediates arsenic trioxide containing nanoparticles to eliminate primitive chronic myeloid leukemia cells inside bone marrow niches

• Published in: International journal of pharmaceutics 2020-04, Vol.579, p.119179, Article 119179
• Main Authors: Fan, Luhui, Liu, Cong, Hu, Anzhi, Liang, Jing, Li, Fanzhu, Xiong, Yang, Mu, Chao-Feng
• Format: Article
• Language: English
• Subjects: Acetates - chemistry; Animals; Arsenic Trioxide - chemistry; Arsenic Trioxide - pharmacology; Bone Marrow - chemistry; Bone marrow microenvironment; Cell Proliferation - drug effects; Cells, Cultured; Drug Delivery Systems - methods; Female; Human Umbilical Vein Endothelial Cells - drug effects; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - prevention & control; Mice; Nanoparticles - chemistry; Neoplastic Stem Cells - drug effects; Oligopeptides - chemistry; Organometallic Compounds - chemistry; Polymeric nanoparticles; Polymers - chemistry; Targeted drug delivery; Transitional metal compound; Tumor Stem Cell Assay - statistics & numerical data
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2020.119179

[Display omitted] Chronic myeloid leukemia (CML) is one type of hematopoietic stem cell diseases. Although BCR-ABL1 tyrosine kinase inhibitors are remarkably effective in inducing remission in chronic phase patients, they are not curative in a majority of patients due to their failure to eradicate residual CML stem/progenitor cells, which reside in bone marrow niches. Here, we presented novel dual oligopeptides-conjugated nanoparticles and demonstrated their effective delivery of arsenic trioxide in bone marrow niches for the elimination of primitive CML cells. We encapsulated As-Ni transitional metal compounds into polymeric nanoparticles based on the reverse micelle rationale. The loading density and stability of arsenic trioxide in nanoparticles were improved. In vitro experiments demonstrated that dual oligopeptides conjugated nanoparticles could deliver arsenic trioxide into bone marrow niches including endosteal niches and vascular niches. The colony-forming activity of CML cells was remarkably restrained in the presence of metaphyseal bone fragments pre-incubated with bone marrow niche targeted arsenic nanoparticles. The in vitro vascular niche model suggested that CML cell proliferation was also successfully inhibited through a tight contact with HUVECs, which were pre-treated using niche-targeted arsenic nanoparticles. This bone marrow niche targeted delivery strategy has a potential usage for the treatment of CML and other malignant hematologic disorders originated from the bone marrow.