title: Functionalized polymersomes with outlayered polyelectrolyte gels for potential tumor-targeted delivery of multimodal therapies and MR imaging.
abstract: 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(γ-glutamic acid-co-γ-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 serum proteins-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 r₂ relaxivity value (255.2 F emM⁻¹ S⁻¹) higher than Resovist (183.4 F emM⁻¹ S⁻¹), a commercial SPION-based T₂ 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.
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Wen-Hsuan
authors.initials: WH
authors.lastname: Chiang
authors.forename: Wen-Chia
authors.initials: WC
authors.lastname: Huang
authors.forename: Chien-Wen
authors.initials: CW
authors.lastname: Chang
authors.forename: Ming-Yin
authors.initials: MY
authors.lastname: Shen
authors.forename: Zong-Fu
authors.initials: ZF
authors.lastname: Shih
authors.forename: Yi-Fong
authors.initials: YF
authors.lastname: Huang
authors.forename: Sung-Chyr
authors.initials: SC
authors.lastname: Lin
authors.forename: Hsin-Cheng
authors.initials: HC
authors.lastname: Chiu
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D005290:Ferric Compounds / Q000008:administration & dosage* / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D008279:Magnetic Resonance Imaging; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D005290:Ferric Compounds; D011108:Polymers; C000499:ferric oxide; D004317:Doxorubicin