Development of novel polymeric micellar drug conjugates and nano-containers with hydrolyzable core structure for doxorubicin delivery

Novel micelle-forming poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) block copolymers hearing doxorubicin (DOX) side groups (PEO-b-P(CL-DOX)) on the PCL block were synthesized. Prepared block copolymers were characterized, assembled to polymeric drug conjugates and assessed for the level of DOX release at pH 7.4 and pH 5.0 using a dialysis membrane to separate released and conjugated drug. The possibility for the degradation of PCL backbone for PEO-b-P(CL-DOX) micelles was investigated using gel permeation chromatography. Micelle-forming DOX Conjugate did not show any signs of DOX release at 37 degrees C within 72 h of incubation at both pHs, but revealed signs of poly(ester) core degradation at pH 5.0. In further studies, PEO-b-PCL micelles hearing benzyl, carboxyl or DOX groups ill the Core Were also used as rnicellar nano-containers for the physical encapsulation of DOX, where maximum level of drug-loading and control over the rate of DOX release was achieved by polymeric micelles containing benzyl groups in their core, i.e., PEO-b-poly(alpha-benzylcarboxylate-epsilon-caprolactone) (PEO-b-PBCL) micelles. The in vitro cytotoxicity of chemically conjugated DOX as part of PEO-b-P(CL-DOX) and physically encapsulated DOX in PEO-b-PBCL against B16F10 murine melanoma cells was assessed and compared to that of free DOX. Consistent with the results Of ill Vitro release Study, cytotoxicity of micellar PEO-b-P(CL-DOX) conjugate (IC50 of 3.65 mu g/mL) was lower than that of free and physically encapsulated DOX in PEO-b-PBCL (IC50 of 0.09 and 3.07 mu g/mL, respectively) after 24 h of incubation. After 48 h of incubation, the cytotoxity of conjugated DOX (IC50 of 0.50 mu g/mL was still lower than the cytotoxicity of free DOX (IC50 of 0.03 mu g/mL), but surpassed that of physically encapsulated DOX in PEO-b-PBCL (IC50 of 1.54 mu g/mL). The results point to a potential for PEO-b-P(CL-DOX) and PEO-b-PBCL as novel polymeric micellar drug Conjugates and nano-containers bearing hydrolyzable cores for DOX delivery. (C) 2008 Elsevier B.V. All rights reserved.