Centre for Pharmacy, Department of Clinical Science, University of Bergen, Bergen, Norway; Hospital Pharmacies Enterprise, Western Norway, Bergen, Norway.
Centre for Pharmacy, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway.
Int J Pharm. 2022 Jan 25;612:121296. doi: 10.1016/j.ijpharm.2021.121296. Epub 2021 Nov 15.
Treatment of acute myeloid leukaemia (AML) relies on decades-old drugs, and while recent years have seen some breakthroughs, AML is still characterised by poor prognosis and survival rate. Drug repurposing can expedite the preclinical development of new therapies, and by nanocarrier encapsulation, the number of potentially viable drug candidates can be further expanded. The anti-psychotic drug chlorpromazine (CPZ) has been identified as a candidate for repurposing for AML therapy. Nanoencapsulation may improve the suitability of CPZ for the treatment of AML by reducing its effect on the central nervous system. Using the emulsion-evaporation technique, we have developed PEGylated PLGA nanoparticles loaded with CPZ for AML therapy. The nanoparticles were characterised to be between 150 and 300 nm by DLS, of spherical morphology by TEM, with a drug loading of at least 6.0% (w/w). After an initial burst release of adsorbed drug, the remaining 80% of the drug was retained in the PLGA nanoparticles for at least 24 h. The CPZ-loaded nanoparticles had equal cytotoxic potential towards AML cells to free CPZ, but acted more slowly, in line with the protracted drug release. Crucially, nanoparticles injected intravenously into zebrafish larvae did not accumulate in the brain, and nanoencapsulation also prevented CPZ from crossing an artificial membrane model. This demonstrates that the purpose for nanoencapsulation of CPZ is fulfilled, namely avoiding effects on the central nervous system while retaining the anti-AML activity of the drug.
急性髓细胞白血病（AML）的治疗依赖于几十年来的药物，尽管近年来取得了一些突破，但 AML 仍然以预后不良和生存率低为特征。药物再利用可以加速新疗法的临床前开发，并且通过纳米载体包封，可以进一步扩大潜在可行的药物候选物的数量。抗精神病药物氯丙嗪（CPZ）已被确定为用于 AML 治疗的再利用候选药物。纳米封装可以通过减少 CPZ 对中枢神经系统的影响来提高其治疗 AML 的适用性。我们使用乳液蒸发技术开发了用于 AML 治疗的载有 CPZ 的 PEGylated PLGA 纳米颗粒。通过 DLS 测量，纳米颗粒的粒径在 150 至 300nm 之间，TEM 显示为球形形态，药物载量至少为 6.0%（w/w）。在吸附药物的初始突释之后，至少 80%的药物保留在 PLGA 纳米颗粒中至少 24 小时。载有 CPZ 的纳米颗粒对 AML 细胞的细胞毒性与游离 CPZ 相当，但作用较慢，符合药物释放的延长。至关重要的是，静脉注射到斑马鱼幼虫体内的载有 CPZ 的纳米颗粒不会在大脑中积累，纳米封装还可以防止 CPZ 穿过人工膜模型。这表明 CPZ 的纳米封装目的已经实现，即避免对中枢神经系统的影响，同时保留药物的抗 AML 活性。
