Drug-interactive mPEG- b-PLA-Phe(Boc) micelles enhance the tolerance and anti-tumor efficacy of docetaxel

Abstract

Docetaxel (DTX) is one of the most promising chemotherapeutic agents for a variety of solid tumors. However, the clinical efficacy of the marketed formulation, Taxotere^®, is limited due to its poor aqueous solubility, side effects caused by the emulsifier, and low selective DTX distribution in vivo. Here a facile, well-defined, and easy-to-scale up DTX-loaded N-(tert-butoxycarbonyl)-_L-phenylalanine end-capped methoxy-poly(ethylene glycol)-block-poly(_D,L-lactide) (mPEG-b-PLA-Phe(Boc)) micelles (DTX-PMs) were prepared in an effort to develop a less toxic and more efficacious docetaxel formulation. The physicochemical properties, pharmacokinetics, biodistribution, and in vivo anti-tumor efficacy were evaluated in comparison to the marketed DTX formulation Taxotere^®. DTX was successfully encapsulated in the hydrophobic micellar core with a high encapsulation efficiency (> 95%) and a high drug loading capacity (4.81 ± 0.08%). DTX-PMs exhibited outstanding stability in the aqueous environment due to the strong interactions between the terminal amino acid residues and docetaxel. The pharmacokinetic study in Sprague-Dawley rats revealed higher DTX concentrations in both whole blood and plasma for the group treated with DTX-PMs than that treated with Taxotere^® due to the improved stability of the micellar formulation. In human non-small cell lung cancer (A549) tumor-bearing Balb/c nude mice, DTX-PMs significantly improved DTX accumulation and stalled DTX elimination in tumors than in bone marrow. Furthermore, only by half of the DTX dosage, our DTX/mPEG-b-PLA-Phe(Boc) micelles can achieve similar therapeutic effects as Taxotere^®. Altogether, DTX-PMs hold great promise as a simple and effective drug delivery system for cancer chemotherapy.

Keywords: Polymeric micelles; anti-tumor efficacy; docetaxel.

Figure 1.

Synthesis route of mPEG-b-PLA-Phe(Boc).

Figure 2.

Appearance of the freeze-dried DTX-PMs (left vial) and reconstituted dispersion in water (right vial) (A); morphology of DTX-PMs observed using TEM (B); size distribution of blank PMs and DTX-PMs determined using DLS (C).

Figure 3.

Storage stability of DTX-micelles. Percentage of DTX solubilized in PBS/Tween-80 (0.01 M/0.2%, pH 7.4) versus incubation time at 4 and 25 °C.

Figure 4.

In vitro DTX release profile.

Figure 5.

In vitro cytotoxicity of the emulsifier of Taxotere^® (50/50 v/v Tween-80 and 13% ethanol), blank PMs, Taxotere^®, and DTX-PMs against NCI-H460 cells.

Figure 6.

DTX distribution of Taxotere^® and DTX-PMs in whole blood (A) and plasma (B) of Sprague–Dawley rats after i.v. administration at a single dose of 10 mg/kg.

Figure 7.

DTX distribution of Taxotere^® and DTX-PMs in tumor (A) and bone marrow (B) of A549 xenograft Balb/c nude mice model after i.v. administration at a single dose of 10 mg/kg.

Figure 8.

In vivo anti-tumor efficacy in A549 xenograft model. G1, saline; G2, blank PMs; G3-5, Taxotere^® at DTX doses of 2.5, 5, and 10 mg/kg; G6–8: DTX-PMs at DTX doses of 2.5, 5, and 10 mg/kg. (A) Tumor growth curves (tumor volume versus time); (B) tumor inhibition rate; (C) body weight; (D) images of mice with A549 tumors. Each data point is mean ± standard deviation (n = 8). **p<.01 versus control (saline); *p<.05 versus control (saline); ^#p<.05 versus Taxotere^®.