Targeting Liposomal Daunorubicin to Myeloid Leukemia

描述（由申请人提供）： 靶向药物递送具有提高治疗剂的功效同时减少其副作用的潜力。叶酸受体β（FR-β）是一种细胞表面标记物，约70%的急性髓性白血病（AML）选择性表达。在原代AML细胞和FR-b（+）KG-1细胞中，全反式维甲酸（ATRA）可特异性诱导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，由正常造血细胞表达的FR-β不能结合叶酸，这与原代AML细胞、KG- 1细胞和FR-β转染的CHO细胞相反，所有这些细胞都介导叶酸包被的脂质体多柔比星（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FR-β靶向摄取和f-L-DOX的细胞毒性。在FR（+）鼠L1210 JF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）更大的治疗功效。此外，ATRA治疗进一步增加了移植KG-1细胞的SCID小鼠对f-L-DOX治疗的应答存活率。FR靶向的脂质体DOX递送也已显示在对游离DOX表现出抗性的FR（+）肿瘤细胞中绕过P-糖蛋白介导的药物流出。 该I期项目的目的是使用相关但潜在的上级蒽环类药物柔红霉素（DNR）和上级NOD/SCID移植模型来扩展和进一步确立这种类型的选择性靶向的价值。F-L-DNR联合ATRA将使用更接近模拟人类白血病的动物模型作为AML的治疗进行评估。具体目标是：1）将人AML鼠NOD/SCID移植模型扩展到不同的AML亚型; 2）评估ATRA对NOD/SCID模型中AML细胞的FR-β表达的影响; 3）评估单独或与ATRA组合的f-L-DNR在NOD/SCID模型中的治疗功效。这些数据将用于制定II期项目中f-L-DNR/ATRA治疗的临床研究计划。

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.