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.