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. 2017 Jul 4:13:1316-1324.
doi: 10.3762/bjoc.13.128. eCollection 2017.

BODIPY-based fluorescent liposomes with sesquiterpene lactone trilobolide

Affiliations

BODIPY-based fluorescent liposomes with sesquiterpene lactone trilobolide

Ludmila Škorpilová et al. Beilstein J Org Chem. .

Abstract

Like thapsigargin, which is undergoing clinical trials, trilobolide is a natural product with promising anticancer and anti-inflammatory properties. Similar to thapsigargin, it has limited aqueous solubility that strongly reduces its potential medicinal applications. The targeted delivery of hydrophobic drugs can be achieved using liposome-based carriers. Therefore, we designed a traceable liposomal drug delivery system for trilobolide. The fluorescent green-emitting dye BODIPY, cholesterol and trilobolide were used to create construct 6. The liposomes were composed of dipalmitoyl-3-trimethylammoniumpropane and phosphatidylethanolamine. The whole system was characterized by atomic force microscopy, the average size of the liposomes was 150 nm in width and 30 nm in height. We evaluated the biological activity of construct 6 and its liposomal formulation, both of which showed immunomodulatory properties in primary rat macrophages. The uptake and intracellular distribution of construct 6 and its liposomal formulation was monitored by means of live-cell fluorescence microscopy in two cancer cell lines. The encapsulation of construct 6 into the liposomes improved the drug distribution in cancer cells and was followed by cell death. This new liposomal trilobolide derivative not only retains the biological properties of pure trilobolide, but also enhances the bioavailability, and thus has potential for the use in theranostic applications.

Keywords: BODIPY conjugates; cancer targeting; drug delivery; liposomes; natural compounds; sesquiterpene lactone trilobolide.

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Figures

Figure 1
Figure 1
Chemical structures of the basic compounds used in this study.
Scheme 1
Scheme 1
Synthesis of the BODIPY building block (part A) and construct 6 (part B).
Figure 2
Figure 2
Absorbance and fluorescence spectra of compounds 36. UV spectra (part A) were recorded with a concentration of 10 μM in DCM and fluorescence spectra (part B) with a concentration of 0.1 μM in DCM using an excitation wavelength of 475 nm. A typical Stokes shift (10 nm) is demonstrated for construct 6 (part C).
Figure 3
Figure 3
NO production in primary rat macrophages. The cells were treated with Tb, compounds 4, 5, and Tb-construct 6 for 24 h with or without lipopolysaccharide (LPS, 100 pg·mL−1). The results represent the mean ± SEM of 2 independent experiments, n = 4. Statistical significance: *P < 0.05, **P < 0.01, ***P < 0.001; black*: compounds are significantly different from untreated cells, red*: the compound is significantly different from LPS-treated cells.
Figure 4
Figure 4
Atomic force microscopy images of liposomes, 5 µm area: A) 2D image, B) 3D image (Ra = 2.4 nm); 2 µm area: C) 2D image, D) 3D image (Ra = 2.6 nm). Ra represents the arithmetic average of the deviations from the centre plane of the sample.
Figure 5
Figure 5
Panel of images from live-cell fluorescence microscopy: intracellular localization of construct 6 in U-2 OS cells after 48 h of incubation: A) 200 nM; C) 500 nM concentration of construct 6; B) and D) merges of A and C with bright field images of U-2 OS cells, respectively.
Figure 6
Figure 6
Panel of images from live-cell fluorescence microscopy: intracellular localization of liposomes with construct 6 (250 nM) in U-2 OS cells after 2 h of incubation: A, D) bright field; B, E) construct 6 in liposomes; C, F) merged images of A and B and D and E.

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