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Granzyme B-loaded, cell-selective penetrating and reduction-responsive polymersomes effectively inhibit progression of orthotopic human lung tumor in vivo.
- Source :
-
Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2018 Nov 28; Vol. 290, pp. 141-149. Date of Electronic Publication: 2018 Oct 10. - Publication Year :
- 2018
-
Abstract
- The clinical use of protein therapeutics with intracellular targets is hampered by its in vivo fragility and low cell permeability. Here, we report that cell-selective penetrating and reduction-responsive polymersomes (CPRPs) mediate high-efficiency targeted delivery of granzyme B (GrB) to orthotopic human lung tumor in vivo. Model protein studies using FITC-labeled cytochrome C (FITC-CC) revealed efficient and high protein loading up to 17.2 wt% for CPRPs. FITC-CC-loaded CPRPs exhibited a small size of 82-90 nm, reduction-responsive protein release, as well as greatly enhanced internalization and cytoplasmic protein release in A549 lung cancer cells compared with the non-targeted FITC-CC-loaded RPs control. GrB-loaded CPRPs showed a high potency toward A549 lung cancer cells with a half maximal inhibitory concentration (IC <subscript>50</subscript> ) of 20.7 nM. Under the same condition, free GrB was essentially non-toxic. Importantly, installing cell-selective penetrating peptide did not alter the circulation time but did enhance tumor accumulation of RPs. Orthotopic A549-Luc lung tumor-bearing nude mice administered with GrB-loaded CPRPs at a dosage of 2.88 nmol GrB equiv./kg showed complete tumor growth inhibition with little body weight loss throughout the treatment period, resulting in significantly improved survival rate over the non-targeted and non-treated controls. These cell-selective penetrating and reduction-responsive polymersomes provide a targeted protein therapy for cancers.<br /> (Copyright © 2018 Elsevier B.V. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1873-4995
- Volume :
- 290
- Database :
- MEDLINE
- Journal :
- Journal of controlled release : official journal of the Controlled Release Society
- Publication Type :
- Academic Journal
- Accession number :
- 30312720
- Full Text :
- https://doi.org/10.1016/j.jconrel.2018.10.013