title: Polymersomes via Self-Assembly of Amphiphilic β-Cyclodextrin-Centered Triarm Star Polymers for Enhanced Oral Bioavailability of Water-Soluble Chemotherapeutics.
abstract: To date, improving oral bioavailability of water-soluble drugs with poor membrane permeability is still challenging. An example of this includes doxorubicin hydrochloride (DOX·HCl), a widely used chemotherapeutic. We therefore developed a novel DOX·HCl-loaded polymersome (Ps-DOX·HCl) self-assembled by amphiphilic β-cyclodextrin-centered triarm star polymer (mPEG(2k)-PLA(3k))3-CD with the considerable drug loading capability. Using Madin-Darby canine kidney (MDCK) cells trans-well models, it was found that the cellular uptake and absorptive transport of DOX·HCl was significantly increased and the efflux was attenuated when delivered through polymersomes than free drugs. This phenomenon was further verified in mechanistic studies, which was attributed to the change in membrane transport pathway from paracellular route (free DOX·HCl) to active transcellular transport (drug-loaded polymersomes). Moreover, in vivo pharmacokinetic studies in mice demonstrated a significant increase in the oral bioavailability of Ps-DOX·HCl compared with free DOX·HCl (7.32-fold), as well as extended half-life (8.22-fold). This resulted in a substantial anticancer efficacy against mouse sarcoma 180 (S180) tumor in vivo. The cardiotoxicity, which is intrinsically induced by DOX·HCl, and toxicity toward gastrointestinal tissues were avoided according to histological studies. These findings indicate that (mPEG(2k)-PLA(3k))3-CD copolymer displays great potential as a vehicle for the effective oral delivery of water-soluble drugs with low permeability.
authors: College of Pharmaceutical Sciences, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, China.
authors: Mengying
authors: M
authors: Hu
authors: Ministry of Educational (MOE) Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University , 38 Zheda Road, Hangzhou 310027, China.
authors: Yurun
authors: Y
authors: Shen
authors: College of Pharmaceutical Sciences, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, China.
authors: Lu
authors: L
authors: Zhang
authors: Ministry of Educational (MOE) Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University , 38 Zheda Road, Hangzhou 310027, China.|Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu 610041, China.
authors: Liyan
authors: L
authors: Qiu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D066126:Cardiotoxicity; D045744:Cell Line, Tumor; D004285:Dogs; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D057927:Hydrophobic and Hydrophilic Interactions; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008813:Mice, Inbred ICR; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D014018:Tissue Distribution; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D011091:Polyesters; D047392:beta-Cyclodextrins; D011092:Polyethylene Glycols; C033616:poly(lactide); D004317:Doxorubicin; C031215:betadex