Hyaluronan-Cyclodextrin Conjugates as Doxorubicin Delivery Systems

Abstract

In the last years, nanoparticles based on cyclodextrins have been widely investigated for the delivery of anticancer drugs. In this work, we synthesized nanoparticles with a hyaluronic acid backbone functionalized with cyclodextrins under green conditions. We functionalized hyaluronic acid with two different molecular weights (about 11 kDa and 45 kDa) to compare their behavior as doxorubicin delivery systems. We found that the new hyaluronan-cyclodextrin conjugates increased the water solubility of doxorubicin. Moreover, we tested the antiproliferative activity of doxorubicin in the presence of the new cyclodextrin polymers in SK-N-SH and SK-N-SH-PMA (over-expressing CD44 receptor) cancer cells. We found that hyaluronan-cyclodextrin conjugates improved the uptake and antiproliferative activity of doxorubicin in the SK-N-SH-PMA compared to the SK-N-SH cell line at the ratio 8/1 doxorubicin/polymer. Notably, the system based on hyaluronan (45 kDa) was more effective as a drug carrier and significantly reduced the IC₅₀ value of doxorubicin by about 56%. We also found that hyaluronic acid polymers determined an improved antiproliferative activity of doxorubicin (IC₅₀ values are on average reduced by about 70% of free DOXO) in both cell lines at the ratio 16/1 doxorubicin/polymer.

Keywords: CD44; SK-N-SH; cyclodextrins; doxorubicin; hyaluronan-cyclodextrin conjugate; hyaluronic acid; nanomedicine; nanoparticles.

Figure 1

HA β-Cyclodextrin conjugates HAHβCyD and HALβCyD.

Figure 2

¹H NMR spectra of HALβCyD (D₂O, 500 MHz).

Figure 3

DOXO solubility (phosphate buffer, pH 7.4) versus the amount of HAHβCyD (▲) or HALβCyD (●) (reported as CyD cavity concentration).

Figure 4

Correlation between IC₅₀ of DOXO (y = −0.0323X + 5.5905, r² 0.670, n = 10, p < 0.004) either administered as parent drug or as CyD polymer complexes and its uptake into SK-N-SH and SK-N-SH-PMA cells.