一种 PEG 化的丙氯苯嗪脂质体制剂,可限制脑部暴露,但仍能保持动态胺 II 的活性:接受化疗 mAbs 的癌症患者的潜在辅助疗法

IF 4.2 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Nanomedicine : nanotechnology, biology, and medicine Pub Date : 2024-01-08 DOI:10.1016/j.nano.2024.102733
Christopher N. Subasic , Fiona Simpson , Rodney F. Minchin , Lisa M. Kaminskas
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引用次数: 0

摘要

由于与抗体结合的细胞表面受体的快速内吞作用,抗癌单克隆抗体往往无法为受体阳性患者带来治疗效果。大剂量联合使用丙氯苯嗪(PCZ)可抑制内吞,并通过抑制动态胺 II 使肿瘤对 mAbs 敏感,但也会带来神经系统副作用。我们研究了使用 PCZ 的 PEG 化脂质体制剂(LPCZ)的可能性,以保留 PCZ 的抗癌效果,但限制脑部吸收。不带电的脂质体显示出完全的药物包囊和pH值依赖性药物释放,而阳离子脂质体则显示出有限的药物包囊和缺乏pH值依赖性药物释放。在KJD细胞中,不带电的LPCZ对表皮生长因子受体内化的抑制作用与游离PCZ相当。大鼠静脉注射 PCZ 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。这些结果表明,LPCZ作为一种辅助疗法,可为接受mAb治疗的癌症患者带来比PCZ更多的益处。
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A PEGylated liposomal formulation of prochlorperazine that limits brain exposure but retains dynamin II activity: A potential adjuvant therapy for cancer patients receiving chemotherapeutic mAbs

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.

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来源期刊
CiteScore
11.10
自引率
0.00%
发文量
133
审稿时长
42 days
期刊介绍: The mission of Nanomedicine: Nanotechnology, Biology, and Medicine (Nanomedicine: NBM) is to promote the emerging interdisciplinary field of nanomedicine. Nanomedicine: NBM is an international, peer-reviewed journal presenting novel, significant, and interdisciplinary theoretical and experimental results related to nanoscience and nanotechnology in the life and health sciences. Content includes basic, translational, and clinical research addressing diagnosis, treatment, monitoring, prediction, and prevention of diseases.
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