Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 545, Issue 1-2, Pages 64-73Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2018.04.027
Keywords
pHLIP; Peptide drug delivery; Targeted drug delivery; Tumor acidity; Doxorubicin; Endocytosis
Categories
Funding
- NRL Base Funding Program
- Research Associateship through the National Research Council
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In this study, we developed a peptide-dendrimer-drug conjugate system for the pH-triggered direct cytosolic delivery of the cancer chemotherapeutic doxorubicin (DOX) using the pH Low Insertion Peptide (pHLIP). We synthesized a pHLIP-dendrimer-DOX conjugate in which a single copy of pHLIP displayed a generation three dendrimer bearing multiple copies of DOX via disulfide linkages. Biophysical analysis showed that both the dendrimer and a single DOX conjugate inserted into membrane bilayers in a pH-dependent manner. Time-resolved confocal microscopy indicate the single DOX conjugate may undergo a faster rate of membrane translocation, due to greater nuclear localization of DOX at 24 h and 48 h post delivery. At 72 h, however, the levels of DOX nuclear accumulation for both constructs were identical. Cytotoxicity assays revealed that both constructs mediated similar to 80% inhibition of cellular proliferation at 10 mu M, the dendrimer complex exhibited a 17% greater cytotoxic effect at lower concentrations and greater than three-fold improvement in IC50 over free DOX. Our findings show proof of concept that the dendrimeric display of DOX on the pHLIP carrier (1) facilitates the pH-dependent and temporally-controlled release of DOX to the cytosol, (2) eliminates the endosomal sequestration of the drug cargo, and (3) augments DOX cytotoxicity relative to the free drug.
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