Delivery of Flt3 ligand (Flt3L) using a poloxamer-based formulation increases biological activity in mice

被引:18
作者
Robinson, SN
Chavez, JM
Pisarev, VM
Mosley, RL
Rosenthal, GJ
Blonder, JM
Talmadge, JE
机构
[1] Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA
[2] RxKinetix Inc, Louisville, CO USA
关键词
Flt3 ligand (Flt3L); sustained delivery poloxamer-based matrix; hematopoiesis; mobilization;
D O I
10.1038/sj.bmt.1703816
中图分类号
Q6 [生物物理学];
学科分类号
071011 ;
摘要
Fms-like tyrosine kinase (Flt3L) is a potent stimulator of hematopoietic progenitor cell (HPC) expansion and mobilization; however, this requires 7-10 days of administration. We investigated whether sustained delivery of Flt3L using a poloxamer-based matrix (PG) could accelerate and/or improve the hematopoietic activity of Flt3L in mice. A single injection of PG-Flt3L stimulated significantly more rapid and greater HPC mobilization to the spleen and peripheral blood than the daily injection of Flt3L formulated in saline. Pharmacokinetic analysis demonstrated that the formulation of Flt3L in PG prolonged its elimination (Tbeta) half-life (2.3-fold) and increased its bioavailability (>two fold) and the time to maximum serum concentration (T-max) (2.7-fold). Further, coadministration of G-CSF and PG-Flt3L allowed lower doses of Flt3L to be active, with significantly greater hematopoietic and mobilization activity, compared to the same total dose of G-CSF, Flt3L or G-CSF and Flt3L formulated in saline. These data demonstrate that formulation of Flt3L in PG significantly accelerates and increases HPC expansion and mobilization. The observation of increased bioactivity by PG-Flt3L in rodents suggests the potential for improved clinical efficacy of Flt3L by reducing the time required for HPC mobilization.
引用
收藏
页码:361 / 369
页数:9
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