Facile construction of bioreducible crosslinked polypeptide micelles for enhanced cancer combination therapy

• Published in: Acta biomaterialia 2017-11, Vol.63, p.135-149
• Main Authors: Ruttala, Hima Bindu, Chitrapriya, Natarajan, Kaliraj, Kaliappan, Ramasamy, Thiruganesh, Shin, Woo Hyun, Jeong, Jee-Heon, Kim, Jae Ryong, Ku, Sae Kwang, Choi, Han-Gon, Yong, Chul Soon, Kim, Jong Oh
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Aspartic acid; Biocompatible Materials - chemistry; Block copolymers; Calorimetry, Differential Scanning; Cancer; Cell Death - drug effects; Cell Line, Tumor; Chemotherapy; Combination; Cross-Linking Reagents - chemistry; Crosslinking; Destabilization; Docetaxel; Drug delivery systems; Drug development; Drug Liberation; Endocytosis - drug effects; Glutathione - metabolism; Humans; Hydrogen-Ion Concentration; Intracellular; Lonidamine; Male; Mice, Nude; Micelles; Neoplasms - drug therapy; Neoplasms - pathology; Oxidation-Reduction; Oxidative stress; Peptides - pharmacology; Peptides - therapeutic use; pH effects; Polyethylene glycol; Polypeptide polymers; Polypeptides; Reactive oxygen species; Reactive Oxygen Species - metabolism; Redox responsive; Side effects; Signal Transduction - drug effects; Spectroscopy, Fourier Transform Infrared; Tissue Distribution - drug effects; Tumors; Tyrosine; Xenograft Model Antitumor Assays
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2017.09.002

[Display omitted] In this study, we developed pH and redox-responsive crosslinked polypeptide-based combination micelles for enhanced chemotherapeutic efficacy and minimized side effects. The stability and drug release properties of the polypeptide micelles were efficiency balanced by the corona-crosslinking of the triblock copolymer, poly(ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine) (PEG-b-pAsp-b-pTyr) with coordinated redox and pH dual-sensitivity by introducing disulfide crosslinkages. Because of the crosslinking of the middle shell of the triblock polypeptide micelles, their robust structure was maintained in strong destabilization conditions and exhibited excellent stability. GSH concentrations were significantly higher in tumor tissue than in normal tissue, which formed the basis for our design. Drug release was elevated under redox and low acidic conditions. Furthermore, crosslinked micelles showed a superior anticancer effect compared to that of non-crosslinked micelles. Incorporation of docetaxel (DTX) and lonidamine (LND) in crosslinked polypeptide micelles increased the intracellular reactive oxygen species (ROS) level and oxidative stress and caused damage to intracellular components that resulted in greater apoptosis of cancer cells than when DTX or LND was used alone. The combination of DTX and LND in crosslinked micelles exhibited efficacious inhibition of tumor growth with an excellent safety profile compared to that reported for drug cocktail combinations and non-crosslinked micelles. Overall, redox/pH-responsive polypeptide micelles could be an interesting platform for efficient chemotherapy. We have synthesized a biodegradable polypeptide block copolymer to construct a facile pH and redox-responsive polymeric micelle asan advanced therapeutic system for cancer therapy. We have designed a corona-crosslinked triblock copolymer (poly (ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine) (PEG-b-pAsp-b-pTyr)) micelles co-loaded with docetaxel and lonidamine (cl-M/DL). The corona of triblock polymer was crosslinked to maintain its structural integrity in the physiological environment. The mitochondrial targeting LND is expected to generate ROS, oxidative stress and thereby synergize the chemotherapeutic efficacy of DTX in killing cancer cells. Consistently, cl-M/DL exhibited excellent antitumor efficacy in xenograft tumor model with remarkable tumor regression. Overall, we demonstrated the construction of bioreducible nanosystem