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. 2009 Jun 10;131(22):7567-9.
doi: 10.1021/ja902039y.

Electrostatically Mediated Liposome Fusion and Lipid Exchange With a Nanoparticle-Supported Bilayer for Control of Surface Charge, Drug Containment, and Delivery

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Electrostatically Mediated Liposome Fusion and Lipid Exchange With a Nanoparticle-Supported Bilayer for Control of Surface Charge, Drug Containment, and Delivery

Juewen Liu et al. J Am Chem Soc. .
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Abstract

The loading and containment of cargo within nanoparticles and their efficient delivery to cells represent a primary challenge in nanomedicine. We report lipid exchange between free and mesoporous silica nanoparticle-supported lipid bilayers as an effective means of containing cargo, controlling charge, and directing delivery to mammalian cells. The delivery of a membrane-impermeable dye (calcein) and a chemotherapeutic drug (doxorubicin) are demonstrated. Exchanged lipid bilayers minimized premature drug release, and an overall positive charge on the supported lipid bilayer effected enhanced delivery.

Figures

Figure 1
Figure 1
(A) A negatively charged drug (green dots) is adsorbed into the pores of a cationic mesoporous silica nanoparticle. Other anions that are adsorbed more strongly (red dots) can displace the loaded drugs (pathway 1). Fusion with a negatively charged liposome reduces the displacement (pathway 2), and further lipid exchange/fusion with cationic liposomes reduces it even more (pathway 3). (B) Photograph of samples after mixing (left) anionic and (right) cationic mesoporous silica particles with calcein followed by centrifugation. (C) Confocal fluorescence microscopy images of a large (15 µm) anionic mesoporous silica particle fused first with Texas Red-DHPE-labeled DOTAP (red) and then mixed with NBD-PC-labeled DOPS liposome (green). The merged image shows colocalization of the red- and green-labeled lipids. (D–F) Representative TEM images of bare anionic mesoporous silica cores (D) and protocells with single (E) or dual (F) supported bilayers formed after successive DOTAP and DOPS fusion/ exchange steps (lipid-fixed and negative-stained).
Figure 2
Figure 2
(A) Fraction of calcein release into the F-12K medium after mixing and centrifugation of calcein-loaded cationic silica cores and of cores (1) fused or (2–4) fused and successively exchanged with liposomes of opposite charges, as determined by fluorimetry. The x axis indicates the last liposome added, and the number of lipid fusion/exchange steps is shown in the parentheses. (B) Flow cytometry histogram of CHO cells incubated with different particles/ protocells. Higher intensity along the x axis (FL1-H) indicates more calcein delivery. (C, E–H) Fluorescence microscopy studies of CHO cells incubated with calcein-loaded cationic silica core or protocells after successive lipid fusion/ exchange with oppositely charged liposomes. Stronger green emission indicates a higher level of calcein delivery. (D) Uptake of cationic silica with covalently linked FITC. Cell nuclei were stained by Hoechst 33342 (blue).
Figure 3
Figure 3
(A) Doxorubicin fluorescence spectra of the supernatant after mixing of the F-12K medium with doxorubicin-loaded anionic silica cores or cores mixed successively with three liposomes (DOTAP/DOPS/DOTAP) for 20 min, followed by centrifugation. (B) Flow cytometry histogram (doxorubicin fluorescence) of CHO cells incubated with different particles. (C, D) Fluorescence microscopy studies of CHO cells incubated with (C) doxorubicin-loaded silica cores or (D) cores mixed with the three liposomes. Intense red dots in (D) indicate endocytosis instead of nonspecific uptake. Cell nuclei were stained by Hoechst 33342 (blue).
Figure 4
Figure 4
(A) ζ potentials of cationic mesoporous silica core protocells (black dots), free liposome in the supernatant (red and blue squares) after successive lipid exchange/fusion steps, and pure DOTAP and DOPS liposomes (in 10 mM MOPS, pH 7.0, 60 mM NaCl). (B) ζ potential of protocells made by adding different concentrations of DOTAP liposomes to cationic silica nanoparticle-supported DOPS bilayers.

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