Reduction-sensitive N, N'-Bis(acryloyl) cystinamide-polymerized Nanohydrogel as a Potential Nanocarrier for Paclitaxel Delivery

Abstract

Novel monomer, N, N'-bis(acryloyl) cystinamide (NBACA), was designed and synthesized with L-cystine as row material. By using this NBACA both as the monomer and crosslinker, reduction-sensitive nanohydrogel was prepared in ethanol via distillation-precipitation polymerization. The obtained nanohydrogel can provide a relatively hydrophobic environment and hydrogen-bonding sites inside the gel; therefore, it is suitable for loading hydrophobic drug. When paclitaxel that possess poor water-solubility was used as a model drug, the nanohydrogel represented a high drug-loading capacity, and dispersed well in aqueous solutions. Furthermore, the disulfide-group-containing nanohydrogel exhibited good reduction-sensitive drug-release behavior. The nanohydrogel biodegraded rapidly in a reducing environment, and released approximately 80% of the PTX within 24 h. Cytotoxicity assays showed that the PTX-loaded nanohydrogel exhibited high cytotoxicity against MCF-7 breast cancer cells, while blank nanohydrogels displayed a negligible cytotoxicity.

Keywords: Paclitaxel; biomaterials; drug delivery; nanohydrogel; redox stimuli.

Scheme 1.

Synthesis of N, N’- bis(acryloyl) cystinamide monomer

Figure 1.

FTIR spectra of NBACA monomer (black), blank nanohydrogel (red) and PTX-loaded nanohydrogel (blue)

Figure 2.

¹H NMR spectrum of N, N’-bis(acryloyl) cystinamide in DMSO-d₆

Figure 3.

¹³C NMR spectrum of N, N’-bis(acryloyl) cystinamide in DMSO-d_6.

Figure 4.

(a) Optical image of NBACA nanohydrogels suspension in ultrapure water. (b) SEM image and (c) particle size distribution of NBACA nanohydrogels

Figure 5.

Reduction-sensitive degradation of nanohydrogels in PBS buffer (pH = 7.4) at 37°C under different reducing conditions (10 mM DTT: black line, 10 mM GSH: red line and no reductant: blue line)

Figure 6.

Cumulative release of PTX from nanohydrogels in PBS buffer (pH = 7.4) at 37°C under different reducing conditions (10 mM DTT: black line, 10 mM GSH: red line and no reductant: blue line)

Figure 7.

MTT assays for MCF-7 cells treated with blank nanohydrogel, PTX-loaded nanohydrogel, and free PTX, respectively, for 72 h. The same PTX-loaded nanohydrogel (DLC: 22%) was used to compare with blank nanohydrogel (a) and free PTX (b) respectively