Contents lists available at ScienceDirect Catalysis Today journal homepage: www.elsevier.com/locate/cattod Biocatalytic synthesis of poly[ε-caprolactone-co-(12-hydroxystearate)] copolymer for sorafenib nanoformulation useful in drug delivery Izolda Kántor a,c , Diana Aparaschivei b , Anamaria Todea b , Emese Biró a, *, György Babos a,c , Dóra Szerényi c , Balázs Kakasi c , Francisc Péter b, *, Eugen Şişu d , Tivadar Feczkó a,c a Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117, Budapest, Hungary b University Politehnica of Timişoara, Faculty of Industrial Chemistry and Environmental Engineering, Carol Telbisz 6, 300001, Timişoara, Romania c Research Institute of Biomolecular and Chemical Engineering, University of Pannonia, Egyetem u. 10, H-8200, Veszprém, Hungary d “Victor Babes” University of Medicine and Pharmacy Timisoara, 2 Eftimie Murgu Sq., 300041, Timişoara, Romania ARTICLE INFO Keywords: poly[ε-caprolactone-co-(12-hydroxystearate)] biocatalysis hydrolases sorafenib nanoparticles drug delivery ABSTRACT Nanoformulations can play an important role in the improvement of anticancer drug therapies. The bioavail- ability of sorafenib, which is the exclusively applied drug in the treatment of unresectable hepatocellular car- cinoma, may be increased by its incorporation in a biocompatible nanoparticulate matrix that is capable of targeting and controlling the drug release. The copolymers of ε-caprolactone are emerging biodegradable compounds for drug delivery applications. In this work, an immobilized lipase and three native hydrolases, a lipase, an esterase and a protease (two of them not previously used as polyesterification catalysts) have been studied as biocatalysts for the synthesis of oligomers of ε-caprolactone and 12-hydroxystearic acid, proving different selectivity regarding the polymerization degree, ratio of linear and cyclic oligomers, and insertion of the fatty acid units in the polymeric chain. The synthesized poly[ε-caprolactone-co-(12-hydroxystearate)] was used as a novel encapsulating copolymer for preparation of sorafenib-loaded polymeric nanocomposites. The nanoparticle formulation by emulsion-solvent evaporation method was optimized for particle size and en- capsulation efficiency. The developed nanotherapeutics showed promising drug release profile and cytotoxic effect in vitro in HepG2 hepatocellular cells. 1. Introduction Hepatocellular carcinoma (HCC) is a life-threatening disease and, according to global cancer statistics from 2012, the second leading cause of cancer-related deaths in men and the sixth in women, world- wide [1]. Sorafenib is an anti-angiogenic multikinase inhibitor with cytostatic effects. At present, sorafenib is the only drug which is capable to prolong the life of patients suffered from HCC. However, the non- specific uptake of the drug into healthy tissues leads to a high toxicity and a variety of critical side effects. However, the pronounced lipophilicity of the drug molecule is re- sponsible for poor bioavailability and distribution into healthy tissues [2], thus, resulting in a requirement of high doses to be administered. To overcome these drawbacks in current cancer therapy nanocarrier- based delivery of sorafenib and the controlled release of the compound have been approached. Nanomedicine is one of the most growing fields of pharmaceutics. Synthetic copolymers are versatile and tunable devices for producing drug delivery systems such as nanoparticles, micelles, vesicular poly- mersomes, polyplexes, polymer-drug conjugates, and dendrimers [3]. Poly(ε-caprolactone) (PCL) is one of the biodegradable polyesters widely utilized in biomedical applications like tissue engineering (processed as films, mats, or scaffolds) and controlled drug delivery (processed as nanoparticles, microparticles, electro spun mats, or scaf- folds). However, these applications are still restricted due to its high hydrophobicity, slow degradation rate and slow drug release proper- ties. [4]. To overcome these drawbacks, various macromolecular ar- chitectures and compositions were proposed, including copolymers of ε- caprolactone (ECL) with various co-monomers [5], or grafted PCL co- polymers [6]. Although the production of PCL and PCL copolymers is performed mainly by chemical catalysis, using catalysts as stannous octanoate [7], biocatalysis emerged as a valuable alternative in the last decades [8,9]. Lipases are by far the most important enzymes used for the synthesis of green polymers, particularly aliphatic polyesters, including PCL and copolymers of ECL [10,11]. However, other enzymes like cutinases also https://doi.org/10.1016/j.cattod.2020.05.005 Received 18 November 2019; Received in revised form 18 February 2020; Accepted 2 May 2020 ⁎ Corresponding authors. E-mail addresses: emese.biro@gmail.com (E. Biró), francisc.peter@upt.ro (F. Péter). Catalysis Today xxx (xxxx) xxx–xxx 0920-5861/ © 2020 Elsevier B.V. All rights reserved. Please cite this article as: Izolda Kántor, et al., Catalysis Today, https://doi.org/10.1016/j.cattod.2020.05.005