title: Poly(2-ethyl-2-oxazoline)-doxorubicin conjugate-based dual endosomal pH-sensitive micelles with enhanced antitumor efficacy.
abstract: Dual endosomal pH-sensitive micelles were designed and fabricated to deliver doxorubicin (DOX) for treating breast cancer based on a poly(2-ethyl-2-oxazoline) (PEOz)-DOX (PEOz-hyd-DOX) conjugate. PEOz-hyd-DOX was successfully synthesized by connecting DOX to PEOz via an acid cleavable hydrazone linker and self-assembled into nanosized micelles, which further physically encapsulated DOX. The conjugate and DOX-loaded conjugate micelles displayed faster release of DOX at pH 5.0 than at pH 7.4. This pH-dependent release behavior might assist the quick diffusion of DOX from acidic endosomes or lysosomes and the intracellular transfer into the nucleus after internalization, which was confirmed by confocal laser scanning microscopy images. As expected, PEOz-hyd-DOX conjugate and DOX-loaded conjugate micelles maintained cytotoxicity of DOX. In addition, the dual endosomal pH-sensitive micelles were found to substantially enhance antitumor efficacy and reduce side effects compared with free DOX. Therefore, PEOz-hyd-DOX conjugate-based micelles might be potential drug delivery vehicles of DOX for safe and effective breast cancer therapy.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University , Beijing 100191, China.
authors.forename: Jinwen
authors.initials: J
authors.lastname: Li
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Zhou
authors.forename: Chengwei
authors.initials: C
authors.lastname: Li
authors.forename: Dishi
authors.initials: D
authors.lastname: Wang
authors.forename: Yajie
authors.initials: Y
authors.lastname: Gao
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Yushu
authors.initials: Y
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Xinru
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D004317:Doxorubicin / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D065546:Drug Liberation; D011992:Endosomes / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D011073:Polyamines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D011073:Polyamines; C511916:poly(2-ethyl-2-oxazoline); D004317:Doxorubicin