An increase in the degree of chemical compatibility between drug and polymeric structure in the core has been shown to raise the encapsulation efficiency and lower the rate of drug release from polymeric micelles. In this study, to achieve an optimized polymeric micellar delivery system for the solubilization and controlled delivery of cucurbitacin I (Cut), the Flory-Huggins interaction parameter (chi(sc)) between Cut and poly(epsilon-caprolactone) (PCL), poly(alpha-benzylcarboxylate-epsilon-caprolactone) (PBCL) and poly(alpha-cholesteryl carboxylate-epsilon-caprolactone) (PChCL) structures was calculated by group contribution method (GCM) as an indication for the degree of chemical compatibility between different micellar core structures and Cut. The results pointed to a better compatibility between Cut and PChCL core rationalizing the synthesis of self-associating methoxy poly(ethylene oxide)-b-poly(alpha-cholesteryl carboxylate-e-caprolactone) block copolymer (MePEO-b-PChCL). Novel block copolymer of MePEO-b-PChCL was synthesized through, first, preparation of substituted monomer, that is, (x-cholesteryl carboxylate-E-caprolactone, and further ring opening polymerization of this monomer by methoxy PEO (5000 g mol 1) using stannous octoate as catalyst. Synthesized block copolymers were characterized for their molecular weight and polydispersity by H-1 NMR and gel permeation chromatography. Self-assembled MePEO-b-PChCL micelles were characterized for their size, morphology, critical micellar concentration (CMC), capacity for the physical encapsulation of Cut, and mode of Cut release in comparison to MePEO-b-PCL and MePEO-b-PBCL micelles. Overall, the experimental order for the level of Cut encapsulation in different polymeric micellar formulations was consistent with what was predicted by the Flory-Huggins interaction parameter. Although MePEO-b-PChCL micelles exhibited the highest level of Cut loading, this structure did not show any significant superiority over MePEO-b-PCL in controlling Cut release. The most efficient control over the rate of Cut release was achieved by MePEO-b-PBCL micelles that had more viscous cores than that of MePEO-b-PChCL, instead. The results point to a potential for MePEO-b-PChCL, micelles for the solubilization of cholesterol compatible drugs. It also highlights the inadequacy of the Flory-Huggins interaction parameter calculated by GCM in predicting the order of drug release from different polymeric micellar structures.