Engineering of cell microenvironment-responsive polypeptide nanovehicle co-encapsulating a synergistic combination of small molecules for effective chemotherapy in solid tumors

• Published in: Acta biomaterialia 2017-01, Vol.48, p.131-143
• Main Authors: Ramasamy, Thiruganesh, Ruttala, Hima Bindu, Chitrapriya, Nataraj, Poudal, Bijay Kumar, Choi, Ju Yeon, Kim, Ssang Tae, Youn, Yu Seok, Ku, Sae Kwang, Choi, Han-Gon, Yong, Chul Soon, Kim, Jong Oh
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Biocompatibility; Biodegradability; Biodegradation; Blotting, Western; Cancer; Cancer therapies; Caspase; Caspase-3; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cellular Microenvironment - drug effects; Chemotherapy; Combination; Cytotoxicity; Doxorubicin; Doxorubicin - pharmacology; Drug Carriers - chemistry; Drug delivery systems; Drug Synergism; Drugs; Encapsulation; Endocytosis - drug effects; Engineering; Flow Cytometry; Histidine; Hydrodynamics; Hydrogen-Ion Concentration; Immunohistochemistry; Intracellular; Mice; Nanoparticles - chemistry; Nanostructure; Nanovehicle; Neoplasms - drug therapy; Neoplasms - pathology; Oxidative stress; Oxidative Stress - drug effects; Particle Size; Peptides; pH effects; Phenylalanine; Poly(ADP-ribose) polymerase; Polyethylene glycol; Polypeptide; Polypeptides; Quercetin; Shrinkage; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; Solid tumors; Tissue Engineering - methods; Treatment Outcome; Tumors; Xenografts
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2016.10.034

[Display omitted] 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. 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.