(431m) Hydrolysable Prodrugs of Geldanamycin for Efficient Nanoencapsulation and Sustained Release

Geldanamycin, a potent heat shock
protein 90 (Hsp90) inhibitor and potential chemotherapeutic, is relatively
large (MW 560) and amphiphilic (logP_oil/water 1.3) making
formulation difficult.  The purpose of this work was to develop prodrugs of
geldanamycin that are solubilized by polymeric micelle formulations. 

Geldanamycin was poorly
encapsulated by peglylated poly-ε-caprolactone (PEG-PCL), < 1% w/w, and
PEG-phospholipid micelles, < 4% w/w.  We hypothesized the amphiphilic nature
of geldanamycin hinders drug incorporation into the hydrophobic micelle core
and postulated reversible conjugation of fatty chains would increase
lipophilicity and improve micelle loading.  Geldanamycin was derivatized at the
C17 position to introduce an unhindered hydroxyl group via a short acyl chain
for facile esterification.   A series of fatty acid derivatives was then
synthesized, and drug loading into PEG-PCL 5000:10000 Da micelles was evaluated.

Increased drug loading was observed
for the fatty acid derivatives (6 to 16 carbons).  Hexadecanoate derivatives of
geldanamycin were encapsulated at over 15% w/w.  Drug release kinetics were
evaluated in vitro, and micelle formulations demonstrated sustained drug
release (t_50% > 60 h) at physiological conditions (pH 7.4, 37°C).

In conclusion, a series of geldanamycin
prodrugs was developed capable of high loading in polymeric block-copolymer
micelles and sustained release at physiological conditions.