Targeted Liposomal Doxorubicin Delivery to Leukemia

靶向脂质体阿霉素递送至白血病

• 批准号: 7281763
• 负责人: Robert J Lee
• 金额: $ 28.15万
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7281763
• 关键词: Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Adverse effects; Affinity; Animals; Binding; Biological Models; Blast Cell; Blood Circulation; Bypass; Cell surface; Cells; Chinese Hamster Ovary Cell; Clinic; Clinical; Condition; Data; Development; Differentiation Therapy; Disease; Dose; Doxorubicin; Drug Delivery Systems; Drug Efflux; Drug Formulations; Drug Kinetics; Exhibits; FR-beta; Folate; Folic Acid; Goals; Growth; Hematopoietic; Human; In Vitro; Lead; Ligands; Liposomal Doxorubicin; Liposomes; Mediating; Modality; Modeling; Multi-Drug Resistance; Mus; Nuclear Receptors; P-Glycoprotein; P-Glycoproteins; Pathway interactions; Patients; Phenotype; Population; Pre-Clinical Model; Property; Rate; Refractory; Residual Neoplasm; Resistance; Retinoids; Sensitivity and Specificity; Solid Neoplasm; Standards of Weights and Measures; Stem cells; Surface; System; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Index; Time; Toxic effect; Treatment Efficacy; Tretinoin; Up-Regulation; base; cancer cell; cellular targeting; chemotherapy; concept; cytotoxicity; density; folate-binding protein; improved; in vivo; leukemia; neoplastic cell; novel; novel therapeutics; receptor; receptor upregulation; selective expression; success; targeted delivery; tumor; uptake

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(FRB)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FR-β阳性的KG-1和原代AML细胞中特异性地诱导FR-β的表达增加，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1 nM)。重要的是，正常造血细胞表达的FR-β被发现是无功能的，而KG-1 AML细胞和转FR-β的CHO细胞表达的受体介导了叶酸包裹的脂质体的选择性摄取和细胞毒性。全反式维甲酸可进一步增加KG-1细胞对叶酸包裹的阿霉素脂质体(f-L-Dox)的摄取量和细胞毒性，从而诱导FR-β表达上调。在FR阳性的小鼠L1210JF和人KG-1AML腹水瘤模型中，f-L-DOX的治疗效果优于非靶向脂质体DOX。在KG-1移植的小鼠中，全反式维甲酸进一步提高了因f-L-Dox治疗而增加的存活率。FR靶向脂质体Dox传递也被证明绕过了对游离Dox耐药的FR阳性肿瘤细胞中P-糖蛋白介导的药物外排。本项目的目的是评估f-L-Dox联合全反式维甲酸诱导FR-β上调治疗急性髓系白血病的疗效，这是一种基于FR阳性肿瘤细胞的选择性靶向的概念。目的：1.研究ATRA对AML细胞体内FR-β表达的影响。2.评价脂质体剂型和FR-β水平作为影响f-L-Dox与急性髓系白血病细胞结合和体外细胞毒作用的因素，以及脂质体的药代动力学特性，以及膳食叶酸的影响。3.评价f-L-Dox单独或联合全反式维甲酸对急性髓系白血病原始细胞、克隆性祖细胞(CFU)和原始急性髓细胞白血病干细胞(SL-ICs)的选择性杀伤作用：4.评价f-L-Dox单独或联合全反式维甲酸对小鼠白血病模型的体内治疗作用。该项目应该导致开发一种新的治疗策略，该策略基于靶向给药到肿瘤细胞和上调细胞靶点来治疗化疗难治性AML。

项目成果

Synthesis and evaluation of a novel lipophilic folate receptor targeting ligand.

• 发表时间: 2011-05
• 期刊: Anticancer research
• 影响因子: 2
• 作者: Y. Liu;Songlin Xu;Lesheng Teng;Bryant C Yung;Jing Zhu;Hong Ding;Robert J. Lee

Receptor-targeted nanocarriers for therapeutic delivery to cancer.

• DOI: 10.3109/09687688.2010.521200
• 发表时间: 2010-10
• 期刊: Molecular membrane biology
• 作者: Yu B;Tai HC;Xue W;Lee LJ;Lee RJ
• 通讯作者: Lee RJ

Efficient delivery of an antisense oligodeoxyribonucleotide formulated in folate receptor-targeted liposomes.

高效递送在叶酸受体靶向脂质体中配制的反义寡脱氧核糖核苷酸。

• 发表时间: 2006
• 期刊: Anticancer research.
• 作者: Chiu,Shih-Jiuan;Marcucci,Guido;Lee,RobertJ
• 通讯作者: Lee,RobertJ

Tumour-selective drug delivery via folate receptor-targeted liposomes.

• DOI: 10.1517/17425247.1.1.7
• 发表时间: 2004-11-01
• 期刊: Expert opinion on drug delivery
• 影响因子: 6.6
• 作者: Pan, Xiaogang;Lee, Robert J
• 通讯作者: Lee, Robert J