title: Peptide Decoration of Nanovehicles to Achieve Active Targeting and Pathology-Responsive Cellular Uptake for Bone Metastasis Chemotherapy.
abstract: To improve bone metastases chemotherapy, a peptide-conjugated diblock copolymer consisting of chimeric peptide, poly(ethylene glycol) and poly(trimethylene carbonate) (Pep-b-PEG-b-PTMC) is fabricated as a drug carrier capable of bone-seeking targeting as well as pathology-responsive charge reversal to ensure effective cellular uptake at the lesion sites. The chimeric peptide CKGHPGGPQAsp8consists of an osteotropic anionic Asp8, a cathepsin K (CTSK)-cleavable substrate (HPGGPQ) and cationic residue tethered to polymer chain. Pep-b-PEG-b-PTMC can spontaneously self-assemble into negatively charged nanomicelles (~75 nm). As to the model drug of doxorubicin, Pep-b-PEG-b-PTM shows 30.0 ± 1 % and 90.1 ± 2 % for loading content and loading efficiency, respectively. High bone binding capability is demonstrated with that 66 % of Pep-b-PEG-b-PTMC micelles are able to bind to hydroxyl apatite, whereas less than 15 % is for Pep-free micelles. The nanomicelles exhibit a negative-to-positive charge conversion from -18.5 ± 1.9 mV to 15.2 ± 1.8 mV upon exposure to CTSK, an enzyme overexpressed in bone metastatic microenvironments. Such a pathology-responsive transition would lead to remarkably enhanced cellular uptake of the nanomicelles upon reaching lesion sites, thus improving the drug efficacy as verified by thein vitrocytotoxicity assay and thein vivostudy in myeloma-bearing 5TGM1 mice model.
authors.affiliation: Division of Radiobiology, School of Medicine, University of Utah, 729 Arapeen Drive, Rm 2334, Salt Lake City, 84108, USA.
authors.forename: Xuli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Division of Hematology, Oncology, and Blood & Marrow Transplant, University of Iowa, Iowa City, IA 52242.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
authors.forename: Huizhen
authors.initials: H
authors.lastname: Jia
authors.affiliation: Division of Radiobiology, School of Medicine, University of Utah, 729 Arapeen Drive, Rm 2334, Salt Lake City, 84108, USA.
authors.forename: Wanjian
authors.initials: W
authors.lastname: Jia
authors.affiliation: Division of Radiobiology, School of Medicine, University of Utah, 729 Arapeen Drive, Rm 2334, Salt Lake City, 84108, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Miller
authors.affiliation: Division of Radiobiology, School of Medicine, University of Utah, 729 Arapeen Drive, Rm 2334, Salt Lake City, 84108, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Bowman
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Internal Medicine, Division of Hematology, Oncology, and Blood & Marrow Transplant, University of Iowa, Iowa City, IA 52242.
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
keywords: MTSK-induced charge reversal; active targeting; bone metastases; nanomicelle; peptide