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. 2018 Jan 23:13:493-504.
doi: 10.2147/IJN.S152474. eCollection 2018.

Pharmacokinetics and in vitro/in vivo antitumor efficacy of aptamer-targeted Ecoflex® nanoparticles for docetaxel delivery in ovarian cancer

Erfaneh Ghassami  1 , Jaleh Varshosaz  1 , Ali Jahanian-Najafabadi  2 , Mohsen Minaiyan  3 , Parvin Rajabi  4 , Effat Hayati  5
Affiliations

Pharmacokinetics and in vitro/in vivo antitumor efficacy of aptamer-targeted Ecoflex® nanoparticles for docetaxel delivery in ovarian cancer

Erfaneh Ghassami et al. Int J Nanomedicine. .

Abstract

Purpose: Epithelixal ovarian cancer is the fourth cause of cancer death in developed countries with 77% of ovarian cancer cases diagnosed with regional or distant metastasis, with poor survival rates. Docetaxel (DTX) is a well-known anticancer agent, with clinically proven efficacy in several malignancies, including ovarian cancer. However, the adverse effects caused by the active ingredient or currently marketed formulations could even deprive the patient of the advantages of treatment. Therefore, in the current study, polymeric nanoparticles (NPs) equipped with aptamer molecules as targeting agents were proposed to minimize the adverse effects and enhance the antitumor efficacy through directing the drug cargo toward its site of action.

Materials and methods: Electrospraying technique was implemented to fabricate poly (butylene adipate-co-butylene terephthalate) (Ecoflex®) NPs loaded with DTX (DTX-NPs). Afterward, aptamer molecules were added to the DTX-NPs, which bound via covalent bonds (Apt-DTX-NPs). The particle size, size distribution, zeta potential, entrapment efficiency, and release profile of the NPs were characterized. Using MTT assay and flow-cytometry analysis, the in vitro cytotoxicity and cellular uptake of the NPs were compared to those of the free drug. Following intravenous administration of Taxotere®, DTX-NPs, and Apt-DTX-NPs (at an equivalent dose of 5 mg/kg of DTX), pharmacokinetic parameters and antitumor efficacy were compared in female Balb/c and HER-2-overexpressing tumor-bearing B6 athymic mice, respectively.

Results: The obtained results demonstrated significantly enhanced in vitro cytotoxicity and cellular uptake of Apt-DTX-NPs in a HER-2-overexpressing cell line, comparing to DTX-NPs and the free drug. The results of in vivo studies indicated significant increment in pharmacokinetic parameters including the area under the plasma concentration-time curve, mean residence time, and elimination half-life. Significant increment in antitumor efficacy was also observed, probably due to the targeted delivery of DTX to the tumor site and enhanced cellular uptake as evaluated in the aforementioned tests.

Conclusion: Hence, the proposed drug delivery system could be considered as an appropriate potential substitute for currently marketed DTX formulations.

Keywords: Ecoflex; aptamer; docetaxel; electrospraying; nanoparticles; ovarian cancer; pharmacokinetic.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
(A) Physicochemical characteristics of the HER-2-specific aptamer-targeted Ecoflex® nanoparticles loaded with DTX in comparison to non-targeted Ecoflex nanoparticles loaded with DTX. (B) Particle size and zeta potential diagrams of non-targeted Ecoflex nanoparticles loaded with DTX. (C) Particle size and zeta potential diagrams of aptamer-targeted Ecoflex nanoparticles loaded with DTX. Abbreviations: DTX, docetaxel; PDI, polydispersity index; Apt-DTX-NPs, aptamer-conjugated nanoparticles loaded with docetaxel; RE30, drug release efficiency in 30 hours.
Figure 2
Figure 2
Micrographs obtained after immunohistochemistry test on cell suspensions of (A) SKOV-3 cells (HER-2-positive) and (B) MDA-MB-468 cells (HER-2-negative) to compare the presence of HER-2 receptors; and (C) micrographs of SKOV-3 tumor tissue, indicating the presence of HER-2 receptors on cell membrane (considered as 3+ score), defined as strong complete membrane staining in more than 30% of tumor cells.
Figure 3
Figure 3
Viability percent after 24 hours incubation of (A) SKOV-3 cells treated with DTX-NPs, Apt-DTX-NPs, and free drug with different concentrations in the range of 100–1,000 ng/mL, and (B) MDA-MB-468 cells treated with DTX-NPs, Apt-DTX-NPs, and free drug with different concentrations in the range of 10–100 ng/mL, and compared to control samples including blank NPs (NPs which were not loaded with DTX) and DMSO (in the maximum concentration used in treatment groups). Note: Significant differences are marked as *p<0.05. Abbreviations: DTX, docetaxel; DTX-NPs, non-targeted nanoparticles loaded with docetaxel; Apt-DTX-NPs, aptamer-conjugated nanoparticles loaded with docetaxel; Blank NPs, nanoparticles not loaded with DTX; DMSO, dimethyl sulfoxide.
Figure 4
Figure 4
Flow-cytomertry diagrams indicating the intensity of fluorescence in SKOV-3 (A) and MDA-MB-468 (B) cells, following 2 hours incubation with 1) blank NPs (NPs which were not loaded with RhB), 2) free RhB, 3) RhB-NPs (non-targeted nanoparticles loaded with RhB), and 4) Apt-RhB-NPs (aptamer-conjugated nanoparticles loaded with RhB). Note: M1 portion represents autofluorescence of the nontreated cells and M2 portion represents any additional intensity of fluorescence caused by uptake of probe. Abbreviations: FL, fluorescence; RhB, Rhodamine B.
Figure 5
Figure 5
Mean plasma concentration–time profile of docetaxel (DTX) in Balb/c mice following intravenous administration of Taxotere®, DTX-NPs (non-targeted nanoparticles loaded with docetaxel), and Apt-DTX-NPs (aptamer-conjugated nanoparticles loaded with docetaxel). The results are indicated as mean ± SD (n=3).
Figure 6
Figure 6
Tumor inhibition effect of different treatments by (A) changes in tumor volume and (B) changes in body weight of mice after treatment with normal saline (control group), Taxotere®, Apt-DTX-NPs (aptamer-conjugated nanoparticles loaded with docetaxel), and DTX-NPs (non-targeted nanoparticles loaded with docetaxel). The results are indicated as mean ± SD (n=3) and significant differences are marked as *p<0.05.
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