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

Abstract

α-Tocopheryl succinate (α-TOS) is a well-known mitochondrially targeted anticancer compound. However, the major factor limiting the use of α-TOS is its low solubility in physiological media. To overcome this problem, the aim of this work is the preparation of new polymeric and active α-TOS-based nanovehicle with a precise control over its macromolecular architecture. Reversible addition-fragmentation chain transfer polymerization (RAFT) is used to synthesize an α-TOS amphiphilic block copolymer with highly homogeneous molecular weight and relatively narrow dispersity. Macro-chain transfer agents (macro-CTA) based on poly(ethylene glycol) (PEG) of different molecular weights (MW, ranging from 4.6 to 20 kDa) are used to obtain block copolymers with different hydrophilic/hydrophobic ratios with PEG being the hydrophilic block and a methacrylic derivative of α-tocopheryl succinate (MTOS) being the monomer that formed the hydrophobic block. PEG-b-poly(MTOS) form spherical nanoparticles (NPs) by self-organized precipitation (SORP) or solvent exchange in aqueous media enabling to encapsulate and deliver hydrophobic molecules in their core. The resulting NPs are rapidly endocytosed by cancer cells. The biological activity of the synthesized NPs are found to depend on the MW of PEG, with NP comprised of the higher MW copolymer resulting in the lower bioactivity due to PEG shielding inhibiting cellular uptake by endocytosis. Moreover, the biological activity also depends on the MTOS content, as the biological activity increases as a function of MTOS concentration.

Photothermal and photodynamic activity of polymeric nanoparticles based on α-tocopheryl succinate-RAFT block copolymers conjugated to IR-780

“…After purification by dialysis, structural characteristics of synthesized block copolymer were determined (Table 1). The composition of the different block copolymers was elucidated by 1 H-NMR spectroscopy, using the methodology previously described by our group[27] (Figure 3). The MTOS molar composition into the copolymeric system was 30 %-mol with a number average molecular weight higher than 65 kDa and low Ð of 1.40 that confirming the good control of the polymerization, obtaining well-defined amphiphilic block copolymer.…”

“…These bioactive block copolymers present the ability to self-assemble in aqueous media forming micellar nanoaggregates with a hydrophilic shell and a hydrophobic core capable of encapsulating and transport other hydrophobic molecules. Due to its high MTOS content, PEG- b -polyMTOS (71:29) exhibited significant cytotoxic activity [27]. …”

“…MTOS and CTA-PEG 8 were obtained as previously described[27, 38]. 4-dimethylaminopyridine (DMAP, Sigma-Aldrich), triethylamine (Et 3 N, Scharlau) and succinic anhydride (SA, Sigma- Aldrich) were used without further purification in the modification of PEG macro-CTA agent.…”

“…Using reversible addition–fragmentation chain transfer polymerization (RAFT), we have recently synthesized block copolymers based on PEG 8000 and MTOS, a methacrylic derivative of α-tocopheryl succinate (α-TOS), forming bioactive self-assembled NPs[27]. Both the PEG-block and an appropriate MW of the block copolymer favored the cytotoxic activity of α-TOS, a mitocan that selectively induces apoptosis of malignant cells by targeting mitochondria while exerting minimal toxicity towards normal cells and tissues[28].…”

Enhanced Bioactivity of α‐Tocopheryl Succinate Based Block Copolymer Nanoparticles by Reduced Hydrophobicity

“…Our group has recently described new bioactive self‐assembled NPs based on amphiphilic copolymers bearing α‐TOS with antiproliferative and antiangiogenic properties, and able to encapsulate hydrophobic molecules in the core. These copolymers were obtained by free radical polymerization of monomers with different hydrophilicity and reactivity or by RAFT . In this sense, RAFT is considered one of the most versatile living/controlled radical polymerization as it allows the design and synthesis of functional polymers with a well‐defined architecture and controlled molecular weight (MW) with relatively low polydispersity ( Ð ) .…”