English

Photocrosslinking-Immobilized Polymer Vesicles for Lowering Temperature Triggered Drug Release

• Yuyao Liao ^{1, 2,} ,
• Zhen Fan ^{2, 3, ,} ,
• Jianzhong Du ^{1, 2, 4, ,}

• 1.

  Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China

• 2.

  Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, Shanghai 201804, China

• 3.

  Institute for Advanced Study, Tongji University, Shanghai 200092, China

• 4.

  Key Laboratory of Advanced Civil Engineering Materials of Ministry of Education, Tongji University, Shanghai 201804, China

Corresponding author: Zhen Fan, fanzhen2018@tongji.edu.cn Jianzhong Du, jzdu@tongji.edu.cn

• Received Date: 23 December 2019
  Accepted Date: 18 February 2020
  Revised Date: 13 February 2020
  Available Online: 15 October 2021
• Fund Project:

Abstract: The stability of nanocarriers in physiological environments is of importance for biomedical applications. Among the existing crosslinking approaches for enhancing the structural integrity and stability, photocrosslinking has been considered to be an ideal crosslinking chemistry, as it is non-toxic and cost-effective, and does not require an additional crosslinker or generate by-products. Meanwhile, most current temperature-responsive nanocarriers are designed and synthesized for drug release by increasing temperature. However, heating may induce cell damage during triggered drug release. Therefore, lowering temperature-triggered nanocarriers need to be developed for drug delivery and safe drug release during therapeutic hypothermia. In this study, we prepared an amphiphilic block copolymer, poly(ethylene oxide)-block-poly[N-isopropyl acrylamide-stat-7-(2-methacryloyloxyethoxy)-4-methylcoumarin]-block-poly(acrylic acid) [PEO₄₃-b-P(NIPAM₇₁-stat-CMA₈)-b-PAA₁₃], by reversible addition fragmentation chain transfer (RAFT) polymerization. Successful synthesis of the polymer was verified by proton nuclear magnetic resonance (¹H NMR) and size exclusion chromatography (SEC). The copolymers self-assembled into vesicles in aqueous solution, with the P(NIPAM-stat-CMA) block forming an inhomogeneous membrane and the PEO chains and PAA chains forming mixed coronas. The cavity of this vesicle could be utilized to load hydrophilic drugs. The CMA groups could undergo photocrosslinking and enhance the stability of vesicles in biological applications, and the PNIPAM moiety endowed the vesicle with temperature-responsive properties. Upon decreasing the temperature, the vesicles swelled and released the loaded drugs. The size distribution and morphology of the vesicles were characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) experiments. After staining with phosphotungstic acid, the hollow morphology of the vesicles with a phase-separated inhomogeneous membrane was observed by TEM and SEM. The DLS results showed that the hydrodynamic diameter of the vesicles was 208 nm and the polydispersity was 0.075. The size of the vesicles observed by TEM was between 180 and 200 nm, which was in accordance with that measured by DLS. To verify the drug loading capacity and controlled release ability of the vesicle, a water-soluble antibiotic was encapsulated in the vesicles. The experimental results showed that the drug loading content was 10.4% relative to the vesicles and the drug loading efficiency was approximately 32.7%. For vesicles containing the same amount of antibiotics, the release rate at 25 ℃ was 35% higher than that at 37 ℃ after 12 h in aqueous solution. Overall, this photocrosslinked vesicle with temperature-responsive properties facilitates lowering temperature-triggered drug release during therapeutic hypothermia.

Key words:
• Polymer vesicle
•  /  Temperature-sensitive
•  /  Photocrosslinking
•  /  Controlled drug release
•  /  Reversible addition fragmentation chain transfer (RAFT) polymerization

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