Desrisking the Cytotoxicity of a Mitochondriotropic Antioxidant Based on Caffeic Acid by a PEGylated Strategy

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Fernandes, C (Author) Other; Benfeito, S (Author) Other; Amorim, R (Author) Other; Teixeira, J (Author) Other; Oliveira, PJ (Author) Other; Fernando Remiao (Author) FFUP; Fernanda Borges (Author) FCUP

Journal

Title: Bioconjugate Chemistry

Vol. 29

Pages: 2723-2733

ISSN: 1043-1802

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 14 Citations

Scopus - 13 Citations

Other information

Authenticus ID: P-00P-HG7

DOI: 10.1021/acs.bioconjchem.8b00383

Abstract (EN): Mitochondrial oxidative damage is related to diverse pathologies, including cancer and neurodegenerative diseases. Shielding mitochondria from oxidative damage with mitochondriotropic antioxidants is by now considered an effective therapeutic strategy. Despite the success of the approach, some concerns related with cytotoxicity have been reported. For instance, AntiOxCIN(6) is a mitochondriotropic antioxidant based on caffeic acid (CAF) that is cytotoxic in hepatocarcinoma (HepG2) cell lines. PEGylation, often used to enhance drug pharmacologic and pharmaceutical properties, was herein applied to modulate AntiOxCIN(6) toxicity drawbacks. So, a dual-functionalization of polyethylene glycol (PEG) with TPP+ and CAF as targeting and antioxidant arms, respectively, was performed by a two-step amidation strategy using ethyl chloroformate and EDC/NHS as coupling reagents. The data showed that the antioxidant properties related with CAF moiety were maintained in the CAF-PEG-TPP conjugate (CPTPP) and that PEGylation process reverted the loss of ability to chelate iron observed with AntiOxCIN(6). In cellular studies, CPTPP was nontoxic to human HepG2 and neuronal (SH-SY5Y) cells, while both CAF and AntiOxCIN(6) demonstrated harmful effects in the same cell lines. The lack of cytotoxic events linked to oxidative stress levels observed with CPTPP suggested that PEGylation process somehow modulates the putative toxicity related with the presence of a catechol moiety and/or the TPP+ cation. In addition, the mitochondrial oxygen consumption was not significantly affected by CPTPP treatment in SH-SY5Y cells when compared with nontreated cells. CPTPP showed remarkable antioxidant effects in cell-based assays against several oxidative stress-induced agents (H2O2, t-BHP, and FeNTA). From the data it can be concluded that PEGylation technology can modulate the toxicity of mitochondriotropic antioxidants without disturbing the antioxidant profile of the core antioxidant. PEGylation can be considered a relevant tool to hasten the difficulties related to the design and development of mitochondrial nontoxic and operative drug candidates.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11