Anticancer and Antiangiogenic Activity of Surfactant-Free Nanoparticles Based on Self-Assembled Polymeric Derivatives of Vitamin E: Structure–Activity Relationship

Abstract

α-Tocopheryl succinate (α-TOS) is a well-known mitochondrially targeted anticancer compound, however, it is highly hydrophobic and toxic. In order to improve its activity and reduce its toxicity, new surfactant-free biologically active nanoparticles (NP) were synthesized. A methacrylic derivative of α-TOS (MTOS) was prepared and incorporated in amphiphilic pseudoblock copolymers when copolymerized with N-vinylpyrrolidone (VP) by free radical polymerization (poly(VP-co-MTOS)). The selected poly(VP-co-MTOS) copolymers formed surfactant-free NP by nanoprecipitation with sizes between 96 and 220 nm and narrow size distribution, and the in vitro biological activity was tested. In order to understand the structure-activity relationship three other methacrylic monomers were synthesized and characterized: MVE did not have the succinate group, SPHY did not have the chromanol ring, and MPHY did not have both the succinate group and the chromanol ring. The corresponding families of copolymers (poly(VP-co-MVE), poly(VP-co-SPHY), and poly(VP-co-MPHY)) were synthesized and characterized, and their biological activity was compared to poly(VP-co-MTOS). Both poly(VP-co-MTOS) and poly(VP-co-MVE) presented triple action: reduced cell viability of cancer cells with little or no harm to normal cells (anticancer), reduced viability of proliferating endothelial cells with little or no harm to quiescent endothelial cells (antiangiogenic), and efficiently encapsulated hydrophobic molecules (nanocarrier). The anticancer and antiangiogenic activity of the synthesized copolymers is demonstrated as the active compound (vitamin E or α-tocopheryl succinate) do not need to be cleaved to trigger the biological action targeting ubiquinone binding sites of complex II. Poly(VP-co-SPHY) and poly(VP-co-MPHY) also formed surfactant-free NP that were also endocyted by the assayed cells; however, these NP did not selectively reduce cell viability of cancer cells. Therefore, the chromanol ring of the vitamin E analogues has an important role in the biological activity of the copolymers. Moreover, when succinate moiety is substituted and vitamin E is directly linked to the macromolecular chain through an ester bond, the biological activity is maintained.

α-TOS-based RAFT block copolymers and their NPs for the treatment of cancer

“…In this case, control over the microstructure was only possible due to the different reactivity of the amphiphilic monomers. As a result, nanoparticles presented PDI values higher than 0.1 and higher distribution width in comparison to these block copolymers 38 .…”

“…These changes would not be possible if other polymerization techniques had been used, such as conventional radical polymerization. Recently, our group described the preparation of amphiphilic NPs based on MTOS that were copolymerized with VP by free radical polymerization (poly(VP- co -MTOS)) 38 . In this case, control over the microstructure was only possible due to the different reactivity of the amphiphilic monomers.…”

“…Our group recently described the anticancer activity of MTOS-based NP based on poly(VP- co -MTOS) pseudo-block copolymer 38 . The most active NP from this family of copolymer only presented 11 mol% of MTOS in its structure and therefore it was remarkable that PEG-b-PMTOS copolymers with higher content on MTOS were less active 38 .…”

“…In fact, we recently described the preparation of amphiphilic copolymers of N -vinyl pyrrolidone (VP) and a methacrylate derivative of α-TOS (MTOS) by free radical polymerization 38 . However, the development of self-assembling systems based on α-TOS with precise control over the macromolecular architecture has not been achieved.…”

Otoprotective properties of 6α-methylprednisolone-loaded nanoparticles against cisplatin: In vitro and in vivo correlation

“…Our group has recently described the preparation, characterization and biological activity of surfactant-free NPs based on amphiphilic copolymeric drugs that selfassembled in aqueous media during nanoprecipitation giving rise to multimicellar nanoaggregates. 31 The hydrophilic segment of the copolymers was mainly based on N-vinyl pyrrolidone (VP), which was selected because of its hydrophilicity, biocompatibility and capability to avoid the reticuloendothelial system. 32 The hydrophobic segment was mainly formed by amethacrylic derivative of vitamin E (MVE) or a methacrylic derivative of α-tocopheryl succinate (MTOS).…”