PTS micelles for the delivery of hydrophobic methotrexate

Abstract

Polyoxyethanyl-α-tocopheryl sebacate (PTS) is an amphiphilic compound with self-emulsifying properties known to form micelles. In this work, we report the production of PTS micelles for the encapsulation and delivery of a hydrophobic derivative of methotrexate, MTX di-ethylated (MTX-OEt). We optimized the micelles production by testing two different techniques: auxiliary solvent and sonication. Small and homogeneous micelles (≈40 nm) were obtained through the auxiliary solvent method performed at 30°C and using 15 mg/mL of PTS. The produced micelles with the most promising physicochemical properties did not induce cytotoxicity when tested in normal human cells (BJ5ta cells), being considered for the encapsulation of MTX-OEt. This prodrug was achieved by Fisher esterification using ethanol, being isolated in good yield (η = 68%). MTX-OEt was efficiently encapsulated onto the produced micelles which preserved their physicochemical properties. The PTS micelles loaded with MTX-OEt, free MTX-OEt and free unmodified MTX revealed similar biological effect against cancer cells (Caco-2 cells). These results demonstrated that the biological activity of MTX is not altered after modification. The developed PTS micelles revealed a promising intracellular delivery performance with potentiality for cancer therapy.

Poloxamer 407 based-nanoparticles for controlled release of methotrexate

“…The 1 H NMR spectra of the ionic complex showed all the typical peaks of MTX and DODAB. The MTX peaks reveal the same pattern as previously reported (Cerqueira et al, 2019), with small chemical shifts, especially of the protons g, h and j/i, which are close to the complexed carboxylic groups.…”

“…The synthesis of MTX as di-ethylated ester form was performed using the procedure previously reported by us (Cerqueira et al, 2019).…”

“…The size distribution and surface charge of the produced nanoparticles were analysed by dynamic light scattering using the Malvern Zetasizer NS from Malvern Instruments, UK. The measurements were performed using PBS at pH 7.4, at 25°C (Cerqueira et al, 2019). The concentration of P407 was kept constant at 1 mg/mL.…”

“…MTX-OEt was produced as described by Cerqueira et al (Cerqueira et al, 2019) (Scheme 2) and its encapsulation in P407-based nanoparticles was tested without any further modification. We tested the encapsulation of this prodrug due to this hydrophobic nature but also due to its promising biological effect against cancer cells (Caco-2 cell line), previously described by Cerqueira et al (Cerqueira et al, 2019).…”

α-Chymotrypsin catalyses the synthesis of methotrexate oligomers

“…Methotrexate is a commercially available drug for the treatment of several cancers, auto-immune diseases, and rheumatoid arthritis [11]. However, this drug presents several limitations, such as poor solubility in water, low resistance, high toxicity, and diverse side-effects associated to its administration [12]. Due to the presence of both amine and carboxylic acid groups in its composition, it represents an excellent template for peptide bond formation.…”