<br>脂质体伊立替康（Onivyde）：举例说明纳米治疗药物的益处,Cancer Science

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脂质体伊立替康（Onivyde）：举例说明纳米治疗药物的益处
Cancer Science ( IF 4.5 ) Pub Date : 2022-04-21 , DOI: 10.1111/cas.15377
Gérard Milano ₁ , Federico Innocenti ₂ , Hironobu Minami ₃

Affiliation

伊立替康是一种拓扑异构酶抑制剂，广泛用于治疗包括胰腺导管腺癌 (PDAC) 在内的恶性肿瘤，作为 FOLFIRINOX 方案的一部分，在多个国家被规定为一线治疗。然而，伊立替康尚未成功作为胰腺癌的二线治疗药物，并且很少有随机临床研究评估其附加价值。 III 期 NAPOLI-1 试验报告了脂质体伊立替康 (nal-IRI) 联合 5-氟尿嘧啶和亚叶酸 (5-FU/LV) 在吉西他滨治疗失败后治疗转移性 PDAC 中的疗效。与非脂质体伊立替康相比，nal-IRI 药代动力学 (PK) 的几个特征可能会带来更好的结果。伊立替康是一种前药，可通过羧酸酯酶转化为活性 SN-38，并被细胞色素 P450 3A4/3A5 灭活。 SN-38 被 UGT1A1 酶灭活。其表达和活性的个体差异可能会影响局部伊立替康活性和毒性的增强。脂质体伊立替康利用癌症中增强的渗透性和保留作用，在肿瘤组织中积累。与非脂质体伊立替康相比，脂质体伊立替康还具有更长的半衰期和更大的浓度-时间曲线下面积（0-∞），因为脂质体制剂可以保护药物免受血浆中过早代谢的影响。这导致肿瘤组织中伊立替康激活，从而增强细胞毒性。重要的是，尽管暴露时间较长，nal-IRI 的总体毒性并不比非脂质体伊立替康差。脂质体伊立替康例证了化疗药物的脂质体封装如何改变其 PK 特性，从而改善患者的临床结果。目前正在研究脂质体伊立替康治疗其他恶性肿瘤的效果，包括胆道癌（以及其他胃肠道癌症）、脑肿瘤和小细胞肺癌。

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Liposomal irinotecan (Onivyde): Exemplifying the benefits of nanotherapeutic drugs

Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first-line treatment in several countries. However, irinotecan has not been successfully introduced as a second-line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal-IRI) combined with 5-fluorouracil and leucovorin (5-FU/LV) was reported in the phase III NAPOLI-1 trial in metastatic PDAC following failure of gemcitabine-based therapy. Several features of nal-IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal irinotecan. Irinotecan is a prodrug that is converted to active SN-38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN-38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half-life and higher area under the concentration-time curve (0–∞) than nonliposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for nal-IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small-cell lung cancer.

更新日期：2022-04-21

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