Engineering folate-targeting diselenide-containing triblock copolymer as a redox-responsive shell-sheddable micelle for antitumor therapy in vivo

Behroozi, F ; Sharif University of Technology | 2018

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  1. Type of Document: Article
  2. DOI: 10.1016/j.actbio.2018.05.031
  3. Publisher: Acta Materialia Inc , 2018
  4. Abstract:
  5. The oxidation-reduction (redox)–responsive micelle system is based on a diselenide-containing triblock copolymer, poly(ε-caprolactone)-bis(diselenide-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate) [PCL-(SeSe-mPEG/PEG-FA)2]. This has helped in the development of tumor-targeted delivery for hydrophobic anticancer drugs. The diselenide bond, as a redox-sensitive linkage, was designed in such a manner that it is located at the hydrophilic–hydrophobic hinge to allow complete collapse of the micelle and thus efficient drug release in redox environments. The amphiphilic block copolymers self-assembled into micelles at concentrations higher than the critical micelle concentration (CMC) in an aqueous environment. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses showed that the micelles were spherical with an average diameter of 120 nm. The insoluble anticancer drug paclitaxel (PTX) was loaded into micelles, and its triggered release behavior under different redox conditions was verified. Folate-targeting micelles showed an enhanced uptake in 4T1 breast cancer cells and in vitro cytotoxicity by flow cytometry and (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay, respectively. Delayed tumor growth was confirmed in the subcutaneously implanted 4T1 breast cancer in mice after intraperitoneal injection. The proposed redox-responsive copolymer offers a new type of biomaterial for drug delivery into cancer cells in vivo. Statement of Significance: On-demand drug actuation is highly desired. Redox-responsive polymeric DDSs have been shown to be able to respond and release their cargo in a selective manner when encountering a significant change in the potential difference, such as that present between cancerous and healthy tissues. This study offers an added advantage to the field of redox-responsive polymers by reporting a new type of shell-sheddable micelle based on an amphiphilic triblock co-polymer, containing diselenide as a redox-sensitive linkage. The linkage was smartly located at the hydrophilic-hydrophilic bridge in the co-polymer offering complete collapse of the micelle when exposed to the right trigger. The system was able to delay tumor growth and reduce toxicity in a breast cancer tumor model following intraperitoneal injection in mice. © 2018 Acta Materialia Inc
  6. Keywords:
  7. Breast cancer ; Diselenide ; Drug delivery ; Micelle ; Redox-sensitive ; Copolymer ; Coumarin derivative ; Folic acid ; Glutathione ; Hydrogen peroxide ; Organoselenium derivative ; Paclitaxel ; Poly(epsilon caprolactone) bis[diselenide methoxy poly(ethylene glycol)/poly(ethylene glycol) folate] ; Unclassified drug ; 4T1 cell line ; Animal cell ; Animal experiment ; Animal model ; Animal tissue ; Article ; Bone marrow suppression ; Cancer therapy ; Cellular distribution ; Controlled study ; Dispersity ; Drug cytotoxicity ; Drug delivery system ; Drug efficacy ; Echography ; Enzyme activity ; Female ; Flow cytometry ; IC50 ; In vitro study ; Internalization ; Liver toxicity ; Micellization ; Mouse ; Nonhuman ; Oxidation reduction reaction ; Photon correlation spectroscopy ; Priority journal ; Sustained drug release ; Transmission electron microscopy ; Tumor volume ; X-ray computed tomography
  8. Source: Acta Biomaterialia ; Volume 76 , 2018 , Pages 239-256 ; 17427061 (ISSN)
  9. URL: https://www.sciencedirect.com/science/article/pii/S1742706118303076?via%3Dihub