Functionalized polymersomes with outlayered polyelectrolyte gels for potential tumor-targeted delivery of multimodal therapies and MR imaging

A novel tumor-targeting polymersome carrier system capable of delivering magnetic resonance imaging (MRI) and chemotherapy is presented in this study. The doxorubicin (DOX)-loaded magnetic polymersomes were first attained by the self-assembly of lipid-containing copolymer, poly(acrylic acid-co-distearin acrylate), in aqueous solution containing citric acid-coated superparamagnetic iron oxide nanoparticles (SPIONs), and followed by DOX loading via electrostatic attraction. To further functionalize these artificial vesicles with superior in vivo colloidal stability, pH-tunable drug release and active tumor-targeting, chitosan and poly(gamma-glutamic acid-co-gamma-glutamyl oxysuccinimide)-g-poly(ethyleneglycol)-folate (FA) were deposited in sequence onto the assembly outer surfaces. The interfacial nanogel layers via complementary electrostatic interactions and in-situ covalent cross-linking were thus produced. These nanogel-caged polymersomes (NCPs) show excellent anti-dilution and serumproteins-repellent behaviors. Triggerable release of the encapsulated DOX was governed by dual external stimuli, pH and temperature. When these theranostic NCPs were effectively internalized by HeLa cells via FA receptor-mediated endocytosis and then exposed to high frequency magnetic fields (HFMF), the combined effects of both pH and magnetic hyperthermia-triggered drug release and thermo-therapy resulted in greater cytotoxicity than the treatment by DOX alone. By virtue of the SPION clustering effect in the assembly inner aqueous compartments, the SPION/DOX-loaded NCPs displayed an r(2) relaxivity value (255.2 Fe mM(-1) S-1) higher than Resovist (183.4 Fe mM(-1) S-1), a commercial SPION-based T-2 contrast agent. The high magnetic relaxivity of the tumor-targeting NCPs coupled with their enhanced cellular uptake considerably promoted the MRI contrast of targeted cancer cells. These results demonstrate the great potential of the FA-decorated SPION/DOX-loaded NCPs as an advanced cancer theranostic nanodevice. (C) 2013 Elsevier B.V. All rights reserved.