Nanoparticles containing anti-inflammatory agents as chemotherapy adjuvants: optimization and in vitro characterization

Abstract

The pre-administration of dexamethasone (DEX) has previously been shown to enhance the anti-tumor efficacy of chemotherapeutic agents. The delivery of anti-inflammatory agents specifically to tumors via nanoparticle carriers is expected to promote the effectiveness of chemotherapeutic agents while avoiding systemic toxicities. The process for preparing solid lipid nanoparticles containing anti-inflammatory agents using the nanotemplate engineering method was optimized. Due to the solubilization of DEX in the bulk aqueous phase, its more lipophilic palmitate ester was synthesized and incorporated in nanoparticles that included a pegylating agent, PEG6000 mono-stearate, as part of the formulation. The stealth properties of these nanoparticles were demonstrated to be enhanced compared to latex particles by measuring the adsorption of radioiodinated IgG (185 microg vs. 6.7 microg IgG/mg NP). In addition, the uptake of (14)C-labeled nanoparticles by murine macrophages was shown to decrease from 36.6% to 14.7% of the nanoparticles/mg cell protein as the amount of pegylating agent in the formulation increased from 0 to 4 mg/mL. The high loading values and low burst effect observed for these DEX palmitate-containing nanoparticles in addition to their stealth properties are expected to allow for the delivery of sufficient amounts of DEX to tumors to enhance the uptake of chemotherapeutic agents.

Fig. 1

A theoretical model depicting the role of dexamethasone (DEX) delivered via a nanoparticle carrier in blocking immune and cytokine related effects in the tumor microenvironment and in normal tissues

Fig. 2

TEM of pegylated DEX-P-containing nanoparticles

Fig. 3

Particle size of DEX-P nanoparticles following storage at 4°C. Mean (± std. dev.) of 3 measurements per time point

Fig. 4

³H-DEX-P and ¹⁴C-Stearyl alcohol release from NPs in 10% plasma (37°C). Mean (± std. dev.) of 3 measurements per time point

Fig. 5

Uptake of ¹⁴C-labeled DEX-P nanoparticles by murine macrophages. Nanoparticles were formulated with varying amounts of PEG6000 MS and incubated for 15, 30, 60 and 90 min. Mean (± std. dev.) of 5 measurements per time point