Polyethylene Glycol Polyester Block Copolymers: Biocompatible Carriers for Nanoparticulate Drug Delivery - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 58

provide extended release or increased encapsulation. Also, the most
efficient design of a core for natural product delivery is not always
intuitive, as was the case of DOX in which a larger core actually
accelerated the release. This trend was contrary to the release of
other anticancer compounds with increased PCL block lengths. Since
all of these compounds are usually polycyclic lipophilic compounds
with a slight dipole, it is useful to resolve this disparity, and gain an
understanding of drug-core affinity for future core designs.

3.2.2 Flory-Huggins Interaction Parameters Between

Drugs and Polymeric Cores

Flory-Huggins interaction parameters have been employed to
evaluate the thermodynamic affinity of geldanamycin prodrugs,
among other anti-cancer agents for PCL cores [33]. Geldanamycin
(GA) (Figure 3.3) is known to inhibit the ATP binding pocket of Hsp90,
which reduces a cancer cells ability to refold essential proteins and
eventually survive. The interaction parameter analysis facilitated
the design of a novel type of prodrug, and illustrated how increasing
lipophilicity of a target drug can increase the micelle loading capacity,
and ultimately the aqueous solubility. Using functional group
contributions of the drug and PCL chain, partial solubility parameters
were estimated, and Flory-Huggins interaction parameter was
calculated. When this interaction parameter approaches zero,
the PCL chain is completely solvated with drug. A series of GA
derivatives were synthesized with varying lengths of aliphatic chains
at the 17 ¢ position, and were evaluated with MCF-7 breast cancer
cells to gauge the potency relative to GA. Most of these derivatives
cytotoxicity was reduced at least an order of magnitude, however
one bromoester derivative, 17-(ethylamino-2-bromododeconate)-
17-demethoxygeldanamycin (GA 17 ¢ C16Br) (Figure 3.3) IC50
reduced by only a factor of 5 (110 nM). As shown in Figure 3.3b, the
ethylamine ester at the 17 ¢ position will hydrolyze in vivo to activate
the drug, and the addition of the electron withdrawing group (Br)
increases the lability of the ester bond, decreasing the half-life.
GA was poorly soluble in PEO (5 kDa)-PCL (10 kDa) micelles,
however GA 17 ¢ C16Br's solubility was increased two orders of
magnitude over GA and its loading efficiency approached 100% in
the same micelle. Release studies of GA 17 ¢ C16Br at physiological