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

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.

Dose-dependent hyperlipidemia in rabbits following administration of poloxamer 407 gel.

Poloxamer 407 (P-407) is a tri-block polymer that exhibits concentration-dependent reverse thermal gelation, a characteristic potentially useful for developing sustained release injectable drugs. While some reports suggest that P-407 is 'non-toxic', rodent studies demonstrate that P-407 induces hyperlipidemia, an action that makes this polymer a questionable drug delivery vehicle. Unfortunately, the majority of earlier studies employed supra-physiologic doses of P-407. The present study examined if lower, clinically useful, doses of gel-forming concentrations of P-407 induced hyperlipidemia in rabbits. Male and female rabbits were injected with 5.5 mg/kg (0.025 mL/kg), 27.5 mg/kg (0.125 mL/kg), or 137.5 mg/kg (0.625 mL/kg) of 22% P-407 and the actions of this polymer on blood chemistry were assessed at 6 h, 1 d, 2 d, 7 d, and 14 d following injection. Control rabbits received no injection. The highest dose of P-407 (137.5 mg/kg) significantly increased serum triglycerides and cholesterol in both male and female rabbits with the maximum increase observed at 2 d after injection. Male rabbits were more sensitive to P-407 than females following injection of 137.5 mg/kg P-407. The lower doses of P-407 did not alter serum triglycerides or cholesterol. In all groups, serum triglycerides and cholesterol were at baseline levels by 14 d. P-407 did not affect other blood chemistry parameters. Although P-407 induces a dose-dependent hyperlipidemia in rabbits, low doses of this polymer may be used in controlled release drug delivery applications without the untoward hyperlipidemic effect.

Polynitroxyl albumin plus tempol attenuates liver injury and inflammation after hepatic ischemia and reperfusion.

PNA+Tempol, albumin containing conjugated (polynitroxyl albumin; PNA) and free (4-hydroxyl-2,2,6,6-tetramethyl-piperidinyl-1-oxyl; Tempol) nitroxide may protect against injury caused by reactive oxygen species. Therefore, the actions of PNA+Tempol on liver injury and inflammation induced by hepatic ischemia and reperfusion (I/R) were examined. Rats were subjected to 1 h ischemia followed by 24 h reperfusion in the absence (I/R) or presence of PNA+Tempol (25%; 15 mL/kg, i.v.) (I/R+PNA+Tempol) or human serum albumin (23%; 13.5 mL/kg, i.v.) (I/R+HSA). Test solutions were administered prior to and for 2 h during reperfusion. Sham-operated rats underwent surgery with neither ischemia nor infusion. I/R+PNA+Tempol rats had significantly less liver injury and inflammation than I/R rats. I/R+PNA+Tempol livers exhibited focal lesions whereas I/R livers exhibited global necrosis. Likewise, plasma ALT activity was significantly lower in I/R+PNA+Tempol rats. PNA+Tempol reduced I/R-induced neutrophil accumulation and intercellular adhesion molecule-1 (ICAM-1) expression. HSA did not alter I/R-induced liver injury or inflammation. Sham-operated rats exhibited normal liver morphology and no inflammation. Attenuation of I/R liver injury by PNA+Tempol may be mediated by its effect on inflammation, the major contributor to I/R injury. Reduction of inflammation by PNA+Tempol is most likely due to the antioxidative nature of the nitroxides.