Merrimack Pharmaceuticals, Cambridge, MA, USA.
ZoneOne Pharma, San Francisco, CA, USA.
Nat Biomed Eng. 2019 Apr;3(4):264-280. doi: 10.1038/s41551-019-0385-4. Epub 2019 Apr 5.
Antibody-mediated tumour targeting and nanoparticle-mediated encapsulation can reduce the toxicity of antitumour drugs and improve their efficacy. Here, we describe the performance of a nanotherapeutic encapsulating a hydrolytically sensitive docetaxel prodrug and conjugated to an antibody specific for EphA2-a receptor overexpressed in many tumours. Administration of the nanotherapeutic in mice led to slow and sustained release of the prodrug, reduced exposure of active docetaxel in the circulation (compared with administration of the free drug) and maintenance of optimal exposure of the drug in tumour tissue. We also show that administration of the nanotherapeutic in rats and dogs resulted in minimal haematological toxicity, as well as the absence of neutropenia and improved overall tolerability in multiple rodent models. Targeting of the nanotherapeutic to EphA2 improved tumour penetration and resulted in markedly enhanced antitumour activity (compared with administration of free docetaxel and non-targeted nanotherapeutic controls) in multiple tumour-xenografted mice. This nanomedicine could become a potent and safe therapeutic alternative for cancer patients undergoing chemotherapy.
抗体介导的肿瘤靶向和纳米颗粒介导的包裹可以降低抗肿瘤药物的毒性，并提高其疗效。在这里，我们描述了一种纳米疗法的性能，该纳米疗法包裹了一种水解敏感的多西紫杉醇前药，并与 EphA2-a 受体的抗体结合，该受体在许多肿瘤中过度表达。在小鼠中给予该纳米疗法后，前药缓慢而持续释放，减少了循环中活性多西紫杉醇的暴露（与给予游离药物相比），并维持了肿瘤组织中药物的最佳暴露。我们还表明，在大鼠和狗中给予该纳米疗法可导致最小的血液毒性，并且不存在中性粒细胞减少症，并在多种啮齿动物模型中提高了整体耐受性。纳米疗法对 EphA2 的靶向作用提高了肿瘤的穿透性，导致在多种肿瘤异种移植小鼠中，与给予游离多西紫杉醇和非靶向纳米疗法对照相比，抗肿瘤活性显著增强。这种纳米药物可能成为接受化疗的癌症患者的一种有效且安全的治疗选择。
