Plasma pharmacokinetic parameters of PTX after intravenous administration of Taxol and DEX-IND/PTX micelles in rats (n = 5).

<p>Plasma pharmacokinetic parameters of PTX after intravenous administration of Taxol and DEX-IND/PTX micelles in rats (n = 5).</p

<i>In vitro</i> anti-tumor activity of DEX-IND/PTX micelles.

<p>(A, B) Cytotoxicity of DEX-IND micelles without PTX encapsulation in MCF-7 and MCF-7/ADR cells for 24 h (n = 3). (C, D) The viability of MCF-7/ADR cells after incubation with PTX, PTX + IND and DEX-IND/PTX micelles for 24 h. Data represent mean ± standard deviation (n = 3). *<i>P</i> < 0.05.</p

Chemosensitizing indomethacin-conjugated dextran-based micelles for effective delivery of paclitaxel in resistant breast cancer therapy

<div><p>Multidrug resistance (MDR) against chemotherapeutic agents has become the major obstacle to successful cancer therapy and multidrug resistance-associated proteins (MRPs) mediated drug efflux is the key factor for MDR. Indomethacin (IND), one of the non-steroidal anti-inflammatory agents, has been demonstrated to increase cytotoxic effects of anti-tumor agents as MRP substrates. In this study, dextran-<i>g</i>-indomethacin (DEX-IND) polymeric micelles were designed to delivery paclitaxel (PTX) for the treatment of MDR tumors. The DEX-IND polymer could effectively encapsulate PTX with high loading content and DEX-IND/PTX micelles present a small size distribution. Compared with free PTX, the release of PTX from DEX-IND/PTX micelles could be prolonged to 48 h. Cellular uptake test showed that the internalization of DEX-IND/PTX micelles by drug-sensitive MCF-7/ADR cells was significantly higher than free PTX benefiting from the inhibitory effect of IND on MRPs. In vitro cytotoxicity test further demonstrated that DEX-IND/PTX micelles could enhance the cytotoxicity of PTX against MCF-7/ADR tumor cells. <i>In vivo</i> pharmacokinetic results showed that DEX-IND/PTX micelles had longer systemic circulation time and slower plasma elimination rate in comparison to PTX. The anti-tumor efficacy test showed that DEX-IND/PTX micelles exhibited greater tumor growth-inhibition effects on MDR tumor-bearing mice, with good correlation between in vitro and in vivo. Overall, the cumulative evidence indicates that DEX-IND/PTX micelles hold significant promise for the treatment of MDR tumors.</p></div

<i>In vitro</i> anti-tumor activity of DEX-IND/PTX micelles.

<p>(A, B) Cytotoxicity of DEX-IND micelles without PTX encapsulation in MCF-7 and MCF-7/ADR cells for 24 h (n = 3). (C, D) The viability of MCF-7/ADR cells after incubation with PTX, PTX + IND and DEX-IND/PTX micelles for 24 h. Data represent mean ± standard deviation (n = 3). *<i>P</i> < 0.05.</p

Stability and <i>in vitro</i> release of DEX-IND/PTX micelles.

<p>(A, B) <i>In vitro</i> stability of DEX-IND/PTX micelles at 4°C, including size and PDI. (C) <i>In vitro</i> release profiles of free PTX and DEX-IND/PTX micelles in pH 7.4 PBS, and DEX-IND/PTX micelles in pH 5.0 PBS. Data represent mean ± standard deviation (n = 3).</p

Preparation and characterization of DEX-IND micelles.

<p>(A) Synthetic route of DEX-IND polymer. (B) ^<i>1</i><i>H</i> NMR spectra. (C) Negative-stain transmission electron microscopy of DEX-IND and DEX-IND/PTX micelles. (D) Characteristics of DEX-IND and DEX-IND/PTX micelles.</p

The concentration versus time curve of PTX and DEX-IND/PTX after intravenous administration.

<p>Data represent mean ± standard deviation (n = 5).</p

<i>In vivo</i> antitumor activities of PTX and DEX-IND/PTX after intravenous administration tumor-bearing mice.

<p>(A) Mice tumor volume changes within 48 days. (B) Mice body weight changes within 48 days. Data represent mean ± standard deviation (n = 5).</p