Anti-cancer monoclonal antibodies often fail to provide therapeutic benefit in receptor-positive patients due to rapid endocytosis of antibody-bound cell surface receptors. High dose co-administration of prochlorperazine (PCZ) inhibits endocytosis and sensitises tumours to mAbs by inhibiting dynamin II but can also introduce neurological side effects. We examined the potential to use PEGylated liposomal formulations of PCZ (LPCZ) to retain the anti-cancer effects of PCZ, but limit brain uptake. Uncharged liposomes showed complete drug encapsulation and pH-dependent drug release, but cationic liposomes showed limited drug encapsulation and lacked pH-dependent drug release. Uncharged LPCZ showed comparable inhibition of EGFR internalisation to free PCZ in KJD cells. After IV administration to rats, LPCZ reduced the plasma clearance and brain uptake of PCZ compared to IV PCZ. The results suggest that LPCZ may offer some benefit over PCZ as an adjunct therapy in cancer patients receiving mAb treatment.

由于抗体结合的细胞表面受体的快速内吞作用，抗癌单克隆抗体通常无法为受体阳性患者提供治疗益处。高剂量联合给予丙氯拉嗪 (PCZ) 可抑制内吞作用，并通过抑制动力 II 使肿瘤对单克隆抗体敏感，但也会引起神经副作用。我们研究了使用聚乙二醇化 PCZ 脂质体制剂 (LPCZ) 来保留 PCZ 的抗癌作用，但限制大脑摄取的可能性。不带电荷的脂质体表现出完整的药物封装和pH依赖性药物释放，但阳离子脂质体表现出有限的药物封装和缺乏pH依赖性药物释放。在 KJD 细胞中，不带电的 LPCZ 对 EGFR 内化的抑制作用与游离的 PCZ 相当。大鼠静脉注射后，与静脉注射 PCZ 相比，LPCZ 降低了 PCZ 的血浆清除率和脑摄取量。结果表明，作为接受 mAb 治疗的癌症患者的辅助疗法，LPCZ 可能比 PCZ 提供一些益处。