A pH‐sensitive nano drug delivery system derived from pullulan/doxorubicin conjugate

Abstract

A novel pH-sensitive nanoparticle drug delivery system for doxorubicin (DOX) is prepared. Pullulan, a natural biocompatible polysaccharide, was partly carboxymethylized; hydrazine hydrate was condensed with the carboxyl groups forming hydrazide. The hydrazide was coupled with DOX through the formation of hydrazone bond. The chemical structure of the conjugate was determined by FTIR and (1)H NMR. The pullulan/DOX conjugate nanoparticles were formed through the aggregation of hydrophobic DOX. The size and morphology of prepared nanoparticles were characterized using dynamic light scattering and transmission electron microscope. The results showed that the nanoparticles were spherical and their size was less than 100 nm. The content of DOX in conjugate was 3.18 wt %. The investigation of the release behavior in vitro indicated that the DOX was released from nanoparticles faster at pH 5.0 (62% DOX released within 24 h) than at pH 7.4 (29% DOX released within 24 h). The in vitro cytotoxicity of pullulan/DOX conjugate nanoparticles was tested by the MTT assay.

Micellar Nanocarriers Assembled from Doxorubicin‐Conjugated Amphiphilic Macromolecules (DOX–AM)

“…The in vitro release of DOX from DOX–AM conjugates was analyzed at two different buffered solutions (pH 5.0 and 7.4) to evaluate pH‐sensitivity of the hydrazone linker. Figure 6 shows that DOX released faster at pH 5.0 (lysosomal pH) compared to pH 7.4 (physiological pH), similar to data reported elsewhere 27, 41, 45, 46, 48. Statistical analysis of data ( p < 0.05) showed significant differences in DOX release between pH 5.0 and 7.4 at all time points.…”

Micellar Nanocarriers Assembled from Doxorubicin‐Conjugated Amphiphilic Macromolecules (DOX–AM)

“…The in vitro release of DOX from DOX–AM conjugates was analyzed at two different buffered solutions (pH 5.0 and 7.4) to evaluate pH‐sensitivity of the hydrazone linker. Figure 6 shows that DOX released faster at pH 5.0 (lysosomal pH) compared to pH 7.4 (physiological pH), similar to data reported elsewhere 27, 41, 45, 46, 48. Statistical analysis of data ( p < 0.05) showed significant differences in DOX release between pH 5.0 and 7.4 at all time points.…”

Preparation, Drug Release, and Cell Growth Inhibition of a Gelatin: Doxorubicin Conjugate

“…A DOX content of 5.0 % w/w, or 7% of the gelatin carboxyl sites, represents about a 15% DOX addition yield on the hydrazide sites. The DOX load is comparable to levels reported in similar conjugates ranging from 3.2% w/w in a pullulan – DOX conjugate (8) to 8.6% w/w in a HPMA – DOX conjugate (27). …”

“…The pH dependent DOX release profiles of G-DOX in Fig 3 are similar to release profiles in other hydrazone macromolecular DOX conjugates (4, 8, 37). The limited DOX release at pH 7.4 and in growth medium is intended to produce few drug interactions with healthy tissue within the systemic circulation, in particular the myocardial cells.…”

Galactosylated pullulan–curcumin conjugate micelles for site specific anticancer activity to hepatocarcinoma cells

“…Zhang et al reported the synthesis of folate-decorated maleilated pullulan-doxorubicin conjugate effective in ovarian carcinoma A2780 cells than free doxorubicin [16]. Amphiphilic pullulan conjugates with pH sensitivity have also been reported for the delivery of doxorubicin [27]. In this study, The presence of aldehyde in oxidized pullulan is confirmed by FT-IR spectroscopy (Fig.…”

Micellar Nanocarriers Assembled from Doxorubicin‐Conjugated Amphiphilic Macromolecules (DOX–AM)

“…The in vitro release of DOX from DOX–AM conjugates was analyzed at two different buffered solutions (pH 5.0 and 7.4) to evaluate pH‐sensitivity of the hydrazone linker. Figure 6 shows that DOX released faster at pH 5.0 (lysosomal pH) compared to pH 7.4 (physiological pH), similar to data reported elsewhere 27, 41, 45, 46, 48. Statistical analysis of data ( p < 0.05) showed significant differences in DOX release between pH 5.0 and 7.4 at all time points.…”

Preparation, Drug Release, and Cell Growth Inhibition of a Gelatin: Doxorubicin Conjugate

“…A DOX content of 5.0 % w/w, or 7% of the gelatin carboxyl sites, represents about a 15% DOX addition yield on the hydrazide sites. The DOX load is comparable to levels reported in similar conjugates ranging from 3.2% w/w in a pullulan – DOX conjugate (8) to 8.6% w/w in a HPMA – DOX conjugate (27). …”

“…The pH dependent DOX release profiles of G-DOX in Fig 3 are similar to release profiles in other hydrazone macromolecular DOX conjugates (4, 8, 37). The limited DOX release at pH 7.4 and in growth medium is intended to produce few drug interactions with healthy tissue within the systemic circulation, in particular the myocardial cells.…”

Galactosylated pullulan–curcumin conjugate micelles for site specific anticancer activity to hepatocarcinoma cells

“…Zhang et al reported the synthesis of folate-decorated maleilated pullulan-doxorubicin conjugate effective in ovarian carcinoma A2780 cells than free doxorubicin [16]. Amphiphilic pullulan conjugates with pH sensitivity have also been reported for the delivery of doxorubicin [27]. In this study, The presence of aldehyde in oxidized pullulan is confirmed by FT-IR spectroscopy (Fig.…”

Micellar Nanocarriers Assembled from Doxorubicin‐Conjugated Amphiphilic Macromolecules (DOX–AM)

“…The in vitro release of DOX from DOX–AM conjugates was analyzed at two different buffered solutions (pH 5.0 and 7.4) to evaluate pH‐sensitivity of the hydrazone linker. Figure 6 shows that DOX released faster at pH 5.0 (lysosomal pH) compared to pH 7.4 (physiological pH), similar to data reported elsewhere 27, 41, 45, 46, 48. Statistical analysis of data ( p < 0.05) showed significant differences in DOX release between pH 5.0 and 7.4 at all time points.…”

Preparation, Drug Release, and Cell Growth Inhibition of a Gelatin: Doxorubicin Conjugate

“…A DOX content of 5.0 % w/w, or 7% of the gelatin carboxyl sites, represents about a 15% DOX addition yield on the hydrazide sites. The DOX load is comparable to levels reported in similar conjugates ranging from 3.2% w/w in a pullulan – DOX conjugate (8) to 8.6% w/w in a HPMA – DOX conjugate (27). …”

“…The pH dependent DOX release profiles of G-DOX in Fig 3 are similar to release profiles in other hydrazone macromolecular DOX conjugates (4, 8, 37). The limited DOX release at pH 7.4 and in growth medium is intended to produce few drug interactions with healthy tissue within the systemic circulation, in particular the myocardial cells.…”

Galactosylated pullulan–curcumin conjugate micelles for site specific anticancer activity to hepatocarcinoma cells

“…Zhang et al reported the synthesis of folate-decorated maleilated pullulan-doxorubicin conjugate effective in ovarian carcinoma A2780 cells than free doxorubicin [16]. Amphiphilic pullulan conjugates with pH sensitivity have also been reported for the delivery of doxorubicin [27]. In this study, The presence of aldehyde in oxidized pullulan is confirmed by FT-IR spectroscopy (Fig.…”