Peptide Decoration of Nanovehicles to Achieve Active Targeting and Pathology-Responsive Cellular Uptake for Bone Metastasis Chemotherapy.

To improve bone metastases chemotherapy, a peptide-conjugated diblock copolymer consisting of chimeric peptide, poly(ethylene glycol) and poly(trimethylene carbonate) (Pep--PEG--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 CKGHPGGPQAsp consists of an osteotropic anionic Asp8, a cathepsin K (CTSK)-cleavable substrate (HPGGPQ) and cationic residue tethered to polymer chain. Pep--PEG--PTMC can spontaneously self-assemble into negatively charged nanomicelles (~75 nm). As to the model drug of doxorubicin, Pep--PEG--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--PEG--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 the cytotoxicity assay and the study in myeloma-bearing 5TGM1 mice model.