Synthesis of Thermosensitive Conjugated Triblock Copolymers by Sequential Click Couplings for Drug Delivery and Cell Imaging

Kaicheng Deng; Xuezhi Zhao; Fangjun Liu; Jinlei Peng; Chao Meng; Yupeng Huang; Liwei Ma; Cong Chang; Hua Wei

doi:10.1021/acsbiomaterials.9b00664

Synthesis of Thermosensitive Conjugated Triblock Copolymers by Sequential Click Couplings for Drug Delivery and Cell Imaging

ACS Biomater Sci Eng. 2019 Jul 8;5(7):3419-3428. doi: 10.1021/acsbiomaterials.9b00664. Epub 2019 Jun 26.

Authors

Kaicheng Deng¹, Xuezhi Zhao¹, Fangjun Liu¹, Jinlei Peng¹, Chao Meng¹, Yupeng Huang¹, Liwei Ma¹, Cong Chang², Hua Wei¹

Affiliations

¹ State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China.
² Department of Pharmaceutics, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, China.

PMID: 33405726
DOI: 10.1021/acsbiomaterials.9b00664

Abstract

The elegant integration of an excellent light-emitting segment and a biorelevant signal-responsive moiety could generate advanced polymeric delivery systems with simultaneously favorable diagnostic and therapeutic functions with respect to cancer theranostics. Although polymeric delivery systems based on fluorescent polyfluorene (PF) or thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) have been extensively developed, the preparation of a ternary polymer formulation composed of a PF block, a PNIPAAm sequence, and a hydrophilic moiety remains rarely explored likely because of the difficulty in integrating different synthesis strategies for polymer synthesis. To this end, herein we reported the design and controlled synthesis of a PF- and PNIPAAm-based amphiphilic triblock copolymer, PF₁₁-b-PNIPAAm₁₂₀-b-poly(oligo(ethylene glycol) monomethyl ether methacrylate)₁₇ (PF₁₁-b-PNIPAAm₁₂₀-b-POEGMA₁₇), with a well-defined structure by a strategy of sequential click couplings between Suzuki-coupling-generated PF and atom-transfer radical polymerization (ATRP)-produced PNIPAAm and POEGMA. The as-prepared triblock copolymers can self-assemble into micelles with a core-shell-corona (CSC) structure that is composed of an inner hydrophobic core of the PF moiety for fluorescent tracking and drug encapsulation, a thermosensitive middle shell of PNIPAAm block for thermomodulated drug loading and release, and a hydrophilic outer corona of the POEGMA segment for micelle stabilization. Interestingly, the doxorubicin (DOX)-loaded micelles prepared at 25 °C had a greater drug loading capacity than the analogues fabricated at 37 °C due to the better stability of the former formulation, leading to its higher in vitro cytotoxicity in HeLa cells. Together with the integration of a localized hyperthermia-triggered drug release profile and efficiently intracellular trafficking of the nanocarriers by monitoring the fluorescence of the PF moiety, this formulation demonstrates a great potential for cancer theranostics.

Keywords: cell imaging; controlled drug release; poly(N-isopropylacrylamide); polyfluorene; sequential click couplings; thermo-sensitivity.