Synthesis of enzyme-responsive theranostic amphiphilic conjugated bottlebrush copolymers for enhanced anticancer drug delivery

• Published in: Acta biomaterialia 2022-05, Vol.144, p.15-31
• Main Authors: Liu, Fangjun, Wang, Dun, Zhang, Miao, Ma, Liwei, Yu, Cui-Yun, Wei, Hua
• Format: Article
• Language: English
• Subjects: Animals; Anticancer drug delivery; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor agents; Biocompatibility; Brushes; Cell imaging; Chain branching; Conjugated bottlebrush copolymers; Copolymers; Coupling; Coupling (molecular); Degradation; Doxorubicin - chemistry; Drug Carriers - chemistry; Drug delivery; Drug Liberation; Efficiency; Endopeptidase K; Entrapment; Enzyme-responsive; Enzymes; Fluorescence; Hydrophilicity; In vivo methods and tests; Intracellular; Micelles; Molecular structure; Neoplasms - drug therapy; Polymers - chemistry; Polypeptides; Precision Medicine; Proteinase; Theranostic micelles; Toxicity; Tumor Microenvironment; Tumors
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2022.03.028

Synthesis of polyfluorene (PF) based theranostic amphiphilic copolymers with simultaneously high drug loading efficiency and tumor microenvironment-specific responsiveness for promoted intracellular drug release and enhanced cancer therapy has been rarely reported likely due to the lack of efficient synthetic approaches to integrate these desirable properties. In this work, we recorded the successful preparation of well-defined theranostic amphiliphilic bottlebrush copolymers composing of fluorescent backbone of PF and tunable enzyme-degradable side chains of polytyrosine (PTyr) and POEGMA by integrating Suzuki coupling, NCA ROP and ATRP techniques. Notably, the resulting copolymer, PF25-g-(PTyr26-b-(POEGMA28)2 (P4) with two branched POEGMA brushes tethered to one PTyr termini for each unit could form steady unimolecular micelles with higher fluorescence quantum yield of 18.3% in aqueous and greater entrapment efficiency (EE) of 91.0% for DOX ascribed to the efficient π–π stacking interactions between PTyr blocks and drug molecules and the unique structure of branched hydrophilic brushes with a moderate chain length. DOX@P4 micelles revealed visualization of intracellular trafficking and accelerated drug release due to the enzyme-triggered degradation of PTyr blocks with proteinase K and subsequent deshielding of POEGMA corona for micelle destruction. In vitro and In vivo animal study further verified the intensive therapeutic efficiency with attenuated systematic toxicity. Taken together, we provided a universal strategy toward multifunctional polymeric delivery vehicles based on conjugated PF and biocompatible and degradable polypeptide by integratied Suzuki coupling and NCA ROP, and identified the branched structure of hydrophilic brushes for better performance of bottlebrush copolymers-based micelles for drug delivery applications. Synthesis of polyfluorene (PF)-based theranostic amphiphilic copolymers with simultaneously high drug loading efficiency and tumor microenvironment-specific responsiveness for promoted intracellular drug release and enhanced cancer therapy has been rarely reported likely due to the lack of efficient synthetic approaches to integrate these desirable properties. We reported herein successful preparation of enzyme-responsive theranostic amphiliphilic bottlebrush copolymers with simultaneously high drug loading efficiency and tumor microenvironment-specific responsiveness for enhanced chemotherapy in vivo. This study therefore n