Nanospheres with a smectic hydrophobic core and an amorphous PEG hydrophilic shell: structural changes and implications for drug delivery

Abstract

The structure of nanospheres with a crystalline core and an amorphous diffuse shell was investigated by small-angle neutron scattering (SANS), small-, medium-, and wide-angle X-ray scattering (SAXS, MAXS and WAXS), and differential scanning calorimetry (DSC). Nanospheres, 28 to 35 nm in diameter, were prepared from a triblock copolymer with poly(ethylene glycol) (PEG) hydrophilic end-blocks and oligomers of alternating desaminotyrosyl-tyrosine octyl ester (DTO) and suberic acid (SA) as the central hydrophobic block. In the lyophilized nanospheres, the diffraction patterns show that the PEG shell is ∼10 nm in thickness and crystalline, and the hydrophobic core is ∼10 nm in diameter with a smectic liquid crystalline texture. In aqueous dispersions, the hydrated PEG forms an amorphous shell, but the crystalline phase in the core persists at concentrations down to 1 mg ml^-1 as evidenced by the sharp MAXS diffraction peak at a d-spacing of 24.4 Å and a melting endotherm at 40 °C. As the dispersion is diluted (<1 mg ml^-1), the core becomes less ordered, and its diameter decreases by 50% even though the overall size of the nanosphere remains essentially unchanged. It is likely that below a critical concentration, intermixing of hydrophobic segments with the PEG segments reduces the size and the crystallinity of the core. At these concentrations, the PEG corona forms a eutectic with water. The mechanisms by which the concentration of the dispersion influences the structure of the nanospheres, and consequently their drug-release characteristics, are discussed.

Figure 1

Chemical structure of the triblock copolymers used in this study.

Figure 2

(a) DSC scans of PEG_5k, and from DP20 copolymer and freeze-dried DP20 nanosphere. (b) Wide-angle XRD scans of the samples used for the DSC scans. (c) DSC scan of the 11.6 mg/ml nanodispersion used in Figure 1b. (d) DSC scans of 5 and 30 mg/ml dispersions, different from those used in Figures b and c. The inset shows a segment at 10X y-scale.

Figure 3

(a) Scheme of the XRD measurement. (b) Overlay of the three segments of the XRD scans at two different concentrations. The two sets of curves have been offset vertically for clarity. The inset shows that the MAXS peak is still visible at low concentrations, but is much broader.

Figure 4

(a) I(q)*q vs. q plot to show the interference peak at high concentrations. (b) Guinier plots of the SAXS data for DP20 polymer at high and low concentrations. (c–d) Simulated curves at high and low concentrations.

Figure 5

SANS data from DP20 at two different D₂O concentrations.

Figure 6

(a) A model based on the SAXS data in Table 2. The dimensions shown are for the DP20 polymer-based nanospheres. (b) The structure in freeze-dried nanosphere. (c) Structure of the nanosphere at concentrations > 1mg/ml. (d) Illustration of a diffuse interface between the core and the shell at concentrations < 1 mg/ml.

Figure 7

Effect of concentration on the core structure. (a) Total diameter or the corona diameter. (b) Core diameter. (c) The crystallite size of the core. (d) The d-spacing between the crystalline stems in the core. Top row figures are from SAXS data, and the bottom row from the MAXS data. Curves are drawn free-hand through the data points to show the trend.

Figure 8

WAXD data showing the effect of pH. Left: High concentration. Right: Low concentration.