title: Multifunctional unimolecular micelles for cancer-targeted drug delivery and positron emission tomography imaging.
abstract: A multifunctional unimolecular micelle made of a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for cancer-targeted drug delivery and non-invasive positron emission tomography (PET) imaging in tumor-bearing mice. The hyperbranched amphiphilic block copolymer, Boltorn(®) H40-poly(L-glutamate-hydrazone-doxorubicin)-b-poly(ethylene glycol) (i.e., H40-P(LG-Hyd-DOX)-b-PEG), was conjugated with cyclo(Arg-Gly-Asp-D-Phe-Cys) peptides (cRGD, for integrin α(v)β(3) targeting) and macrocyclic chelators (1,4,7-triazacyclononane-N, N', N''-triacetic acid [NOTA], for (64)Cu-labeling and PET imaging) (i.e., H40-P(LG-Hyd-DOX)-b-PEG-OCH(3)/cRGD/NOTA, also referred to as H40-DOX-cRGD). The anti-cancer drug, doxorubicin (DOX) was covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arms (i.e., PLG) via a pH-labile hydrazone linkage to enable pH-controlled drug release. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. cRGD-conjugated unimolecular micelles (i.e., H40-DOX-cRGD) exhibited a much higher cellular uptake in U87MG human glioblastoma cells due to integrin α(v)β(3)-mediated endocytosis than non-targeted unimolecular micelles (i.e., H40-DOX), thereby leading to a significantly higher cytotoxicity. In U87MG tumor-bearing mice, H40-DOX-cRGD-(64)Cu also exhibited a much higher level of tumor accumulation than H40-DOX-(64)Cu, measured by non-invasive PET imaging and confirmed by biodistribution studies and ex vivo fluorescence imaging. We believe that unimolecular micelles formed by hyperbranched amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics.
authors.affiliation: Department of Biomedical Engineering and Wisconsin Institutes for Discovery, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Xiao
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.forename: Alireza
authors.initials: A
authors.lastname: Javadi
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Engle
authors.forename: Wenjin
authors.initials: W
authors.lastname: Xu
authors.forename: Yunan
authors.initials: Y
authors.lastname: Yang
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Todd E
authors.initials: TE
authors.lastname: Barnhart
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
authors.forename: Shaoqin
authors.initials: S
authors.lastname: Gong
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000138:chemical synthesis*; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008823:Micelles; D049268:Positron-Emission Tomography / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D004317:Doxorubicin