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

Abstract

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-g-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. In vivo 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.

Indomethacin-based stimuli-responsive micelles combined with paclitaxel to overcome multidrug resistance

“…Internalization of DEX-SS-IND/PTX micelles by MCF-7 and MCF-7/PTX cells was quantitatively investigated via determining intracellular PTX concentration by HPLC method [ 19 ]. 5 × 10 4 cells/well of cells were cultured in a 24-well plate and kept at 37°C for 24 h. Then, PTX, PTX + IND, DEX-IND/PTX, and DEX-SS-IND/PTX micelles were added and incubated for 6 and 24 h, respectively.…”

“…Intracellular PTX content was expressed as the amount (nmol) of PTX associated with a unit weight (1 mg) of cellular protein. Protein contents of cell lysate were measured using BCA protein assay reagent kit [ 19 ].…”

“…The concentration of PTX was determined using high performance liquid chromatography (HPLC) on an Agilent C18 (250 mm × 4.6 mm, 5 μm) column with a linear range from 1 to 20 μg/mL. Acetonitrile/water (45:55, v/v) was used as the mobile phase, and the detection wavelength was set as 240 nm with flow rate at 1.0 mL/min at 30°C [ 19 ]. The DL% and EE% of PTX were calculated as following formula: DL% = (weight of PTX in micelles/Total weight of micelles) × 100% EE% = (weight of PTX in micelles/Feeding amount of PTX) × 100% …”

Orally active Epac inhibitor reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy

“…in different dosing schedules. It should be noted, however, that the cumulative dose of paclitaxel used here is in the range of what is used to treat tumors in mice [14; 32; 34]. In addition to general analysis of potential toxic side effects, the potential interference of ESI-09 treatment with the anti-cancer effect of treatment needs to be examined.…”

Lipid Formulations and Bioconjugation Strategies for Indomethacin Therapeutic Advances

“…It has also been reported that indomethacin can effectively restore TRIAL sensitivity in melanoma cells and act by upregulation of death receptor 5 (DR5) and/or downregulation of survivin [ 28 ]. In the last few years, intensive research has also been conducted on the possibilities of using indomethacin in the treatment of castration-resistant prostate cancer [ 29 ] and its formulations in hormone-refractory breast cancer [ 30 , 31 ].…”