Targeted-and timed-releasing nanotherapeutics against leukemia stem cells

针对白血病干细胞的靶向定时释放纳米疗法

• 批准号: 10162055
• 负责人: CHONG-XIAN PAN
• 金额: $ 10.88万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162055
• 关键词: Targeted; timed; releasing; nanotherapeutics; against

 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（申请人提供）：该项目的目标是开发纳米疗法，能够将化疗药物柔红霉素特异性递送至急性髓性白血病（AML）干细胞（靶向递送）并按顺序在细胞内释放药物（定时释放）目前针对 AML 的化疗方法令人失望，因为它只能治愈少数 AML 患者，而且即使在加强住院患者监测和支持的情况下，也会产生严重的毒性和显着的死亡率。白血病干细胞（LSC）对常规化疗相对耐药，随后会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。纳米级胶束药物制剂中，产生的靶向纳米粒子（称为胶束）可以将药物特异性递送到表达 CLL1 的细胞中，包括临床白血病样本。载药的、靶向 CLL1 的胶束在血液中是稳定的，并且有潜力。通过以下方式改善 AML 的治疗：(1) 将高浓度的柔红霉素专门递送至 LSC，压倒耐药机制并根除 LSC；(2) 杀死全身的白血病细胞；柔红霉素从胶束和 LSC 释放到循环中；(3) 减少治疗引起的毒性和药物在胶束内隔离的死亡率；以及 (4) 允许通过配制降低毒性的高剂量柔红霉素。柔红霉素进入胶束。