High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.
Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.
Nanomedicine. 2020 Oct;29:102283. doi: 10.1016/j.nano.2020.102283. Epub 2020 Aug 7.
Nanotechnology has demonstrated great promise for the development of more effective and safer cancer therapies. We recently developed a highly selective inhibitor of BCR-ABL fusion tyrosine kinase for chronic myeloid leukemia (CML). However, the poor drug-like properties were hurdles to its further clinical development. Herein, we re-investigate it by conjugating an amphiphilic polymer and self-assembling into a nanoparticle (NP) with a high loading (~10.3%). The formulation greatly improved its solubility and drastically extended its circulation half-life from ~5.3 to ~117 h (>20-fold). In the 150 days long-term engraftment model experiment, long intravenous dosing intervals of the NPs (every 4 or 8 days) exhibited much better survival and negligible toxicities as compared to daily oral administration of the inhibitor. Moreover, the NPs showed excellent inhibition of tumor growth in the subcutaneous xenograft model. All results suggest that the ultra-long circulating pro-drug NP may provide an effective and safe therapeutic strategy for BCR-ABL-positive CML.
纳米技术在开发更有效和更安全的癌症疗法方面展现出巨大的潜力。我们最近开发了一种针对慢性髓性白血病（CML）的高度选择性 BCR-ABL 融合酪氨酸激酶抑制剂。然而，较差的药物样性质是其进一步临床开发的障碍。在此，我们通过将亲脂性聚合物偶联并自组装成具有高载药量（约 10.3%）的纳米颗粒（NP）来重新研究它。该制剂大大提高了它的溶解度，并将其循环半衰期从约 5.3 小时延长至约 117 小时（>20 倍）。在长达 150 天的植入模型实验中，与抑制剂每日口服相比，NP 的长静脉给药间隔（每 4 或 8 天）可显著提高存活率并降低毒性。此外，NP 在皮下异种移植模型中显示出优异的抑制肿瘤生长作用。所有结果均表明，这种超长效循环前药 NP 可能为 BCR-ABL 阳性 CML 提供一种有效且安全的治疗策略。
