Targeting Liposomal Daunorubicin to Myeloid Leukemia

描述(由申请人提供)： 靶向给药有可能提高治疗剂的疗效，同时减少其副作用。叶酸受体β(FR-β)是一种细胞表面标志物，约70%的急性髓系白血病(AML)有选择性表达。全反式维甲酸(ATRA)可在原代AML细胞和FR-b(+)KG-1细胞中特异性地诱导FR-β的表达增加，而不会诱导细胞分化或生长抑制。叶酸是FR-β(Kd&lt；1 NM)的高亲和力配体。重要的是，正常造血细胞表达的FR-β不能与叶酸结合，而在原代AML细胞、KG-1细胞和转FR-β基因的CHO细胞中，这些细胞都介导了叶酸包裹的脂质体阿霉素(f-L-DOX)的选择性摄取和细胞毒性。通过全反式维甲酸诱导FR-β的上调，进一步增强了f-L-DOX对FR-β的靶向性摄取和细胞毒性。在FR(+)小鼠L1210JF和人KG-1AML腹水瘤模型中，F-L-DOX的治疗效果也优于非靶向脂质体(L-DOX)。此外，全反式维甲酸治疗进一步提高了与f-L-DOX治疗反应的KG-1细胞移植SCID小鼠的存活率。FR靶向脂质体DOX传递也被证明绕过了P-糖蛋白介导的药物在对游离DOX耐药的FR(+)肿瘤细胞中的外排。 该第一阶段项目的目标是利用一种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植入模型来扩大和进一步确立这种类型的选择性靶向的价值。F-L-柔红霉素联合全反式维甲酸，将使用更接近于人类白血病的动物模型进行评估，作为治疗急性髓细胞白血病的方法。其具体目的是：1)将人、小鼠NOD/SCID移植模型推广到不同的AML亚型；2)评价全反式维甲酸对NOD/SCID模型中AML细胞FR-β表达的影响；3)评价f-L柔红霉素单独或联合全反式维甲酸治疗NOD/SCID模型的疗效。这些数据将用于制定二期项目中f-L-柔红霉素/全反式维甲酸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.