Redox-Responsive Polymersomes as Smart Doxorubicin Delivery Systems

Abstract

Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG-PDH-mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120-190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells.

Keywords: doxorubicin hydrochloride; drug release kinetics; polymersome; redox-responsive; smart drug delivery systems; triblock copolymer mPEG–PDH–mPEG.

Figure 1

Schematic representation of the molecular structure of mPEG–PDH–mPEG copolymer and the self-assembly of drug-loaded polymersomes.

Figure 2

Photograph of the drug-loaded (10 wt.% Dox·HCl) polymersome dispersion.

Figure 3

Conventional TEM image of the blank polymersomes formed at pH 7.4 with a polymer concentration of 5 mg·mL⁻¹ (scale bar = 100 nm).

Figure 4

(a) Representative size distribution profile based on intensity and (b) zeta potential of blank polymersomes (measured in PBS at 25 °C).

Figure 5

Variation in average hydrodynamic diameter, PDI and zeta potential of the blank polymersome dispersion in PBS (10 mM, pH 7.4) with time. The measurements were recorded from a fresh dispersion and after storage for four weeks at 4 °C.

Figure 6

Unstained TEM image of drug-loaded (5 wt.% Dox·HCl) polymersomes (scale bar = 100 nm).

Figure 7

TEM images of drug-loaded (10 wt.% Dox·HCl) polymersomes stained with 1.0 wt.% phosphotungstic acid solution (scale bar = left 1 µm, right 0.2 µm).

Figure 8

CLSM image of drug-loaded (10 wt.% Dox·HCl) polymersomes (scale bar = 2 µm).

Figure 9

Photograph of centrifuged samples (10 wt.% Dox·HCl polymersomes dispersion).

Figure 10

Cumulative in vitro release profiles of drug-loaded (10 wt.% Dox·HCl) polymersomes in PBS (10 mM, pH 7.4) with or without 50 mM GSH at 37 °C (mean ± SD, n = 3).