Targeted Liposomal Doxorubicin Delivery to Leukemia

靶向脂质体阿霉素递送至白血病

• 批准号: 6748983
• 负责人: Robert J Lee
• 金额: $ 29.69万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748983
• 关键词: NOD mouse; SCID mouse; acute myelogenous leukemia; all trans retinol; cell surface receptors; clinical research; cytotoxicity; doxorubicin; drug screening /evaluation; folate; human tissue; liposomes; neoplasm /cancer chemotherapy; neoplastic cell; nonhuman therapy evaluation; pharmacokinetics; receptor expression; 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 (FRB) is a cell surface marker selectively expressed by approximately70 percent of acute myeloid leukemias (AMLs). Increased FR-beta expression can be specifically induced by all trans retinoic acid (ATRA) in FR-beta-positive KG-1 and primary AML cells, without inducing cellular differentiation or growth inhibition. Folic acid is a high affinity ligand for FR-beta (Kd approximately 1 nM). Importantly, FR-beta expressed by normal hematopoietic cells has been found to be non-functional, whereas the receptor expressed by KG-1 AML cells and FR-beta-transfected CHO cells mediates selective uptake and cytotoxicity of folate-coated liposomes. Both uptake and cytotoxicity of folate coated liposome doxorubicin (f-L-Dox) in KG-1 cells were further increased by ATRA, which induced FR-beta upregulation. Moreover, f-L-DOX exhibited greater therapeutic efficacy than non-targeted liposomal DOX (LDox) in FR positive murine L1210JF and human KG-1 AML ascitic tumor models. Increased survival due to treatment with f-L-Dox was further enhanced by ATRA in the KG-1 engrafted mice. FR-targeted liposomal Dox delivery has also been shown to bypass the P-glycoprotein-mediated drug efflux in FR positive tumor cells exhibiting resistance to free Dox. The objective of this project is to evaluate f-L-Dox, combined with ATRA-induction of FR-beta upregulation, for the treatment of AML, a concept based on the selective targeting of the FR positive tumor cells. The specific aims are: 1. To evaluate the effect of ATRA on FR-beta expression by AML cells in vivo. 2. To evaluate liposome formulation and FR-beta level as factors in the binding and in vitro cytotoxicity of f-L-Dox to AML cells, as well as the pharmacokinetic properties of the liposomes; the effect of dietary folate will also be studied. 3. To evaluate the selective cytotoxicity of f-L-Dox, alone or combined with ATRA, against AML blast cells, clonogenic progenitor cells (CFUs), and primitive AML stem cells (SL-Ics); and 4. To evaluate the in vivo therapeutic efficacy of f-L-Dox alone or combined with ATRA in murine leukemia models. This project should lead to the development of a novel therapeutic strategy based on the combination of targeted drug delivery to tumor cells and upregulation of the cellular target for the treatment of chemotherapy refractory AMLs.

描述（由申请人提供）：靶向药物递送有可能提高治疗剂的功效，同时减少其副作用。 β 型叶酸受体 (FRB) 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 FR-β 阳性 KG-1 和原代 AML 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 约为 1 nM）。 重要的是，正常造血细胞表达的 FR-β 被发现没有功能，而 KG-1 AML 细胞和 FR-β 转染的 CHO 细胞表达的受体介导叶酸包被脂质体的选择性摄取和细胞毒性。 ATRA 进一步增加了 KG-1 细胞中叶酸包被的脂质体阿霉素 (f-L-Dox) 的摄取和细胞毒性，从而诱导 FR-β 上调。 此外，在 FR 阳性小鼠 L1210JF 和人 KG-1 AML 腹水肿瘤模型中，f-L-DOX 比非靶向脂质体 DOX (LDox) 表现出更好的治疗效果。在 KG-1 移植小鼠中，ATRA 进一步增强了 f-L-Dox 治疗带来的存活率增加。 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 阳性肿瘤细胞中 P-糖蛋白介导的药物流出。 该项目的目的是评估 f-L-Dox 与 ATRA 诱导的 FR-β 上调相结合，用于治疗 AML，这是一个基于选择性靶向 FR 阳性肿瘤细胞的概念。 具体目的是： 1. 体内评价ATRA对AML细胞FR-β表达的影响。 2. 评价脂质体配方和FR-β水平作为f-L-Dox与AML细胞结合和体外细胞毒性的因素，以及脂质体的药代动力学特性；膳食叶酸的影响也将被研究。 3. 评估f-L-Dox单独或与ATRA联合使用时对AML母细胞、克隆祖细胞（CFU）和原始AML干细胞（SL-Ics）的选择性细胞毒性； 4.评价f-L-Dox单独或联合ATRA在小鼠白血病模型中的体内治疗效果。 该项目应导致开发一种新的治疗策略，该策略基于将靶向药物递送至肿瘤细胞和上调细胞靶标相结合，用于治疗化疗难治性 AML。