Targeted- and timed-releasing nanotherapeutics against leukemia stem cells

针对白血病干细胞的靶向和定时释放纳米疗法

• 批准号: 9454297
• 负责人: CHONG-XIAN PAN
• 金额: $ 35.91万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9454297
• 关键词: Acute Myelocytic Leukemia; Autologous Stem Cell Transplantation; Back; Binding; Biodistribution; Biological Models; Blood; Blood Circulation; Blood Vessels; Bone Marrow; C-Type Lectins; Cell Line; Cell Surface Proteins; Cell surface; Cells; Clinical; Collection; Cytotoxic agent; Daunorubicin; Disease; Disulfides; Dose; Drug Delivery Systems; Drug Formulations; Drug resistance; Environment; Feedback; Formulation; Goals; Hematopoietic stem cells; High Dose Chemotherapy; Inpatients; Leukemic Cell; Ligands; Maximum Tolerated Dose; Micelles; Minority; Monitor; Mus; Natural regeneration; Patients; Peptides; Pharmaceutical Preparations; Physiological; Plant Roots; Plasma; Polymers; Population; Recurrence; Regimen; Resistance; Sampling; Solid Neoplasm; Specific qualifier value; Specimen; Stem cells; Supportive care; Surface; Testing; Time; Toxic effect; Treatment outcome; Xenograft procedure; amphiphilicity; aqueous; base; chemotherapy; crosslink; density; disulfide bond; improved; in vivo; intravenous administration; leukemia; leukemic stem cell; mortality; nanoparticle; nanoscale; nanotherapeutic; neoplastic cell; preclinical study; public health relevance; purge; resistance mechanism; stem cell differentiation; systemic toxicity; targeted delivery; targeted treatment; tumor

 DESCRIPTION (provided by applicant): The goal of this project is to develop nanotherapeutics that can specifically deliver the chemotherapeutic drug daunorubicin into acute myeloid leukemia (AML) stem cells (targeted delivery) and release the drug inside the cells (timed release) in order to eradicate this cell population. Current chemotherapy for AML is disappointing in that it can cure only a minority of AML patients and is associated with severe toxicity and significant mortality even with intensive inpatient monitoring and supportive care. Leukemia stem cells (LSC) are relatively resistant to the conventional chemotherapy and can subsequently produce more leukemia cells to cause disease recurrence. In order to cure leukemia, LSC must be eradicated. The C-type lectin-like molecule-1 (CLL-1) is a cell surface protein that is specifically expressed on most AML LSC, but not on normal hematopoietic stem cells. We have developed a peptide that specifically targets CLL1. When this peptide is covalently attached to a nanometer-scale micellar drug formulation, the resulted targeting nanoparticles, called micelles, can specifically deliver the drug load into cells expressing CLL1, including clinical leukemia specimens. The drug-loaded, CLL1-targeting micelles are stable in blood, and can potentially improve therapy against AML by (1) delivering a high local concentration of daunorubicin specifically into LSC, overwhelming the resistant mechanisms and eradicating LSC; (2) killing leukemic cells throughout the body with the release of daunorubicin from the micelles and LSC into circulation; (3) decreasing therapy-induced toxicity and mortality owing to the sequestration of the drug inside the micelles; and (4) allowing administration of high-dose daunorubicin with reduced toxicity through formulation of daunorubicin into micelles.

 描述（由申请人提供）：该项目的目标是开发纳米治疗剂，其可以特异性地将化疗药物柔红霉素递送到急性髓性白血病（AML）干细胞中（靶向递送），并在细胞内释放药物（定时释放），以根除该细胞群。目前AML的化疗令人失望，因为它只能治愈少数AML患者，即使在强化住院监测和支持性护理下，也与严重毒性和显著死亡率相关。白血病干细胞（Leukemia stem cells，LSC）对常规化疗具有较强的抵抗力，可产生更多的白血病细胞，导致疾病复发。为了治愈白血病，必须根除LSC。C型凝集素样分子-1（CLL-1）是一种细胞表面蛋白，在大多数AML LSC上特异性表达，但在正常造血干细胞上不表达。我们开发了一种特异性靶向CLL 1的肽。当这种肽共价连接到纳米级胶束药物制剂时，所产生的靶向纳米颗粒（称为胶束）可以特异性地将药物负载递送到表达CLL 1的细胞中，包括临床白血病标本。载药的CLL 1靶向胶束在血液中是稳定的，并且可以通过（1）将高局部浓度的柔红霉素特异性递送到LSC中，压倒耐药机制并根除LSC;（2）通过柔红霉素从胶束和LSC释放到循环中杀死全身的白血病细胞;（3）由于药物在胶束内的隔离，降低了治疗诱导的毒性和死亡率;和（4）通过将柔红霉素配制成胶束，允许以降低的毒性施用高剂量柔红霉素。