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.

纳米技术已显示出开发更有效，更安全的癌症疗法的巨大希望。我们最近开发了一种针对慢性粒细胞白血病（CML）的BCR-ABL融合酪氨酸激酶的高选择性抑制剂。然而，不良的类药物特性阻碍了其进一步的临床开发。在这里，我们通过结合两亲性聚合物并自组装成高负载量（〜10.3％）的纳米颗粒（NP）对其进行了重新研究。该制剂极大地提高了其溶解度，并将其循环半衰期从〜5.3 h大幅延长至〜117 h（> 20倍）。在150天的长期植入模型实验中，与每天口服抑制剂相比，NP的较长静脉内给药间隔（每4或8天）表现出更好的存活率和可忽略的毒性。此外，在皮下异种移植模型中，NP显示出对肿瘤生长的极好的抑制作用。所有结果表明，超长循环前药NP可能为BCR-ABL阳性CML提供有效且安全的治疗策略。