ABSTRACT
In this study, a transferrin-anchored albumin nanoplatform with PEGylated lipid bilayers (Tf-L-APVN) was developed for the targeted co-delivery of paclitaxel and vorinostat in solid tumors. Tf-L-APVN exhibited a sequential and controlled release profile of paclitaxel and vorinostat, with an accelerated release pattern at acidic pH. At cellular levels, Tf-L-APVN significantly enhanced the synergistic effects of paclitaxel and vorinostat on the proliferation of MCF-7, MDA-MB-231, and HepG2 cancer cells. Vorinostat could significantly enhance the cytotoxic potential of paclitaxel, induce marked cell apoptosis, alter cell cycle patterns, and inhibit the migratory capacity of cancer cells. In addition, Tf-L-APVN showed prolonged circulation in the blood and maintained an effective ratio of 1:1 (for paclitaxel and vorinostat) throughout the study period. In HepG2 tumor-bearing mice, Tf-L-APVN displayed excellent antitumor efficacy and the combination of paclitaxel and vorinostat significantly inhibited the tumor growth. Taken together, dual drug-loaded Tf receptor-targeted nanomedicine holds great potential in chemotherapy of solid tumors.
Subject(s)
Adenoma, Liver Cell/drug therapy , Histone Deacetylase Inhibitors/pharmacology , Lipids/chemistry , Liver Neoplasms/drug therapy , Nanoparticles/administration & dosage , Paclitaxel/pharmacology , Adenoma, Liver Cell/metabolism , Adenoma, Liver Cell/pathology , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Drug Synergism , Drug Therapy, Combination , Humans , Hydroxamic Acids/pharmacology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred BALB C , Molecular Targeted Therapy , Nanoparticles/chemistry , Tumor Cells, Cultured , Vorinostat , Xenograft Model Antitumor AssaysABSTRACT
In this study, we report a facile method to construct a bioactive (poly(phenylalanine)-b-poly(l-histidine)-b-poly(ethylene glycol) polypeptide nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The smart pH-sensitive nanovehicle was fabricated with precisely tailored drug-to-carrier ratio that resulted in accelerated, sequential drug release. As a result of ratiometric loading, QUR could significantly enhance the cytotoxic potential of DOX, induced marked cell apoptosis; change cell cycle patterns, inhibit the migratory capacity of sensitive and resistant cancer cells. In particular, pro-oxidant QUR from DQ-NV remarkably reduced the GSH/GSSG ratio, indicating high oxidative stress and damage to cellular components. DQ-NV induced tumor shrinkage more effectively than the single drugs in mice carrying subcutaneous SCC-7 xenografts. DQ-NV consistently induced high expression of caspase-3 and PARP and low expression of Ki67 and CD31 immunomarkers. In summary, we demonstrate the development of a robust polypeptide-based intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy. STATEMENT OF SIGNIFICANCE: In this study, we report a facile method to construct bioactive and biodegradable polypeptide nanovehicles as an advanced platform technology for application in cancer therapy. We designed a robust (poly(phenylalanine)-b-poly(l-histidine)-b-poly(ethylene glycol) nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The conformational changes of the histidine block at tumor pH resulted in accelerated, sequential drug release. QUR could significantly enhance the cytotoxic potential of DOX, induce marked cell apoptosis, change cell cycle patterns, and inhibit the migratory capacity of sensitive and resistant cancer cells. DQ-NV induced tumor shrinkage more effectively than the single drugs and the 2-drug cocktail in tumor xenografts. In summary, we demonstrate the development of an intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy.
