Sustained release formulations of rhVEGF          produce a durable response in a XXXX model of peripheral angiogenesis.

@entity1095 @entity1 @entity14110 @entity7 @entity535 @entity19 @entity1283 @entity7050 @entity35
Local delivery of therapeutic angiogenic agents that stimulate blood vessel formation represents a promising strategy for the treatment of @entity1095 ( @entity1095 ). At present, requirements for temporal and spatial parameters for localized delivery are unclear, with a variety of sustained delivery approaches being examined. Two polymer-based sustained formulations containing the 165 @entity535 isoform of @entity1 recombinant @entity7 (rhVEGF(165)) were evaluated for their potential application in the treatment of @entity1095 following intramuscular injection. Microspheres prepared from a 50:50 ratio of @entity7050 ( @entity7050 ) and a gel of @entity7050 polymer solubilized in @entity14110 ( @entity7050 :NMP) were each loaded with rhVEGF(165) and tested in vitro and in vivo. @entity7050 microspheres averaged    30  m in diameter and contained 8.9% (w/w) rhVEGF(165), while the @entity7050 :NMP gel was formulated with varying amounts of spray freeze-dried rhVEGF(165) to result in final gel formulations having concentrations of 0.36, 0.72, or 3.6 mg/mL rhVEGF(165). In vitro release of rhVEGF(165) from @entity7050 microspheres showed    10% cumulative release by day 6, whereas the cumulative release of rhVEGF(165) from the @entity7050 :NMP gel matrices (0.65% w/w loading) was less than 0.25% at this same time point. While the in vitro release characteristics of these two sustained release formulations were broadly different, the plasma rhVEGF(165) concentration-time profiles following hind-limb intramuscular (IM) injection of these formulations in non-compromised @entity35 revealed similar in vivo pharmacokinetics. Three-dimensional resin casts of vascular architecture were prepared at days 3, 7, 14, 21, 28, 60, and 75 following a single IM dosing of these sustained release microsphere and gel matrix formulations in the gastrocnemius muscle of immune-compromised @entity19 . Scanning electron microscopic visualization of these vascular casts demonstrated spatial arrangement of @entity1283 consistent with profound vascular changes occurring within 3 days of dosing that persisted for 2 months, approximately 1 month beyond the anticipated completion of rhVEGF(165) release from these sustained delivery formulations. Vascular re-modeling events were correlated with histological and immunohistochemical parameters attributed to known biological actions of rhVEGF(165) signaling. Together, these pharmacokinetic and pharmacodynamic results support the use of sustained release @entity7050 -based formulations for the local delivery of rhVEGF(165) to achieve a durable vascular re-modeling response.
