Targeting Liposomal Daunorubicin to Myeloid Leukemia

脂质体柔红霉素靶向治疗髓系白血病

• 批准号: 6682376
• 负责人: XING Q PAN
• 金额: $ 14.22万
• 依托单位: SIBYL PHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6682376
• 关键词: NOD mouse; SCID mouse; acute myelogenous leukemia; combination chemotherapy; daunorubicin; disease /disorder model; drug delivery systems; drug design /synthesis /production; flow cytometry; folate; human therapy evaluation; human tissue; liposomes; model design /development; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; pharmacokinetics; receptor expression; retinoate; vitamin receptor; xenotransplantation

DESCRIPTION (provided by applicant): Targeted drug delivery has the potential to improve the efficacy of a therapeutic agent while reducing its side effects. Folate receptor type-beta (FR-beta) is a cell surface marker selectively expressed by approximately 70% of acute myeloid leukemias (AMLs). Increased FR-beta expression can be specifically induced by all-trans retinoic acid (ATRA) in primary AML cells and in FR-b (+) KG-1 cells, without inducing cellular differentiation or growth inhibition. Folic acid is a high affinity ligand for FR-beta (Kd < 1 nM). Importantly, FR-beta expressed by normal hematopoietic cells cannot bind folate in contrast to that in primary AML cells, KG- 1 cells, and FR-beta-transfected CHO cells, all of which mediate selective uptake and cytotoxicity of folate-coated liposomal doxorubicin (f-L-DOX). FR-beta-targeted uptake and cytotoxicity of f-L-DOX were further enhanced by inducing FR-beta upregulation using ATRA. F-L-DOX also exhibited greater therapeutic efficacy than non-targeted liposomal DOX (L-DOX) in FR (+) murine L1210JF and human KG-1 AML ascitic tumor models. Moreover, ATRA treatment further increased survival in response to treatment with f-L-DOX in the KG-1 cell engrafted SCID mice. FR-targeted liposomal DOX delivery has also been shown to bypass P-glycoprotein-mediated drug efflux in FR (+) tumor cells exhibiting resistance to free DOX. The objective of this Phase I project is to extend and further establish the value of this type of selective targeting using a related but potentially superior anthracycline drug, daunorubicin (DNR) and the superior NOD/SCID engraftment model. F-L-DNR combined with ATRA, will be evaluated as a therapy for AML using an animal model that more closely mimics human leukemia. The Specific Aims are: 1) to extend a human AML murine NOD/SCID engraftment model to different AML subtypes; 2) to evaluate the effect of ATRA on FR-beta expression by AML cells in the NOD/SCID model; 3) to evaluate the therapeutic efficacy of f-L-DNR, alone or combined with ATRA, in the NOD/SCID model. The data will be used to develop a plan for clinical studies of f-L-DNR/ATRA therapy in a Phase II project.

描述（由申请人提供）： 靶向药物递送有可能提高治疗剂的疗效，同时减少其副作用。叶酸β型受体 (FR-β) 是一种细胞表面标志物，约 70% 的急性髓系白血病 (AML) 选择性表达。在原代 AML 细胞和 FR-b (+) KG-1 细胞中，全反式视黄酸 (ATRA) 可以特异性诱导 FR-β 表达增加，而不诱导细胞分化或生长抑制。叶酸是 FR-β 的高亲和力配体 (Kd < 1 nM)。重要的是，正常造血细胞表达的 FR-β 不能与原代 AML 细胞、KG-1 细胞和 FR-β 转染的 CHO 细胞中的叶酸结合，所有这些细胞均介导叶酸包被的脂质体阿霉素 (f-L-DOX) 的选择性摄取和细胞毒性。通过使用 ATRA 诱导 FR-β 上调，进一步增强了 f-L-DOX 的 FR-β 靶向摄取和细胞毒性。在 FR (+) 鼠 L1210JF 和人 KG-1 AML 腹水肿瘤模型中，F-L-DOX 也表现出比非靶向脂质体 DOX (L-DOX) 更高的治疗效果。此外，ATRA 治疗进一步提高了 KG-1 细胞移植 SCID 小鼠对 f-L-DOX 治疗的存活率。 FR 靶向脂质体 DOX 递送也被证明可以绕过对游离 DOX 具有抗性的 FR (+) 肿瘤细胞中 P-糖蛋白介导的药物外流。 该第一阶段项目的目标是使用相关但可能更优越的蒽环类药物柔红霉素 (DNR) 和优越的 NOD/SCID 植入模型来扩展并进一步确立此类选择性靶向的价值。 F-L-DNR 与 ATRA 相结合，将使用更接近人类白血病的动物模型来评估其作为 AML 的治疗方法。具体目标是： 1) 将人类 AML 小鼠 NOD/SCID 植入模型扩展到不同的 AML 亚型； 2)在NOD/SCID模型中评估ATRA对AML细胞表达FR-β的影响； 3)评价f-L-DNR单独或联合ATRA在NOD/SCID模型中的治疗效果。这些数据将用于制定 II 期项目中 f-L-DNR/ATRA 疗法的临床研究计划。