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. 2014 Oct 22;136(42):14722-5.
doi: 10.1021/ja5088024. Epub 2014 Oct 13.

Cocoon-like self-degradable DNA nanoclew for anticancer drug delivery

Wujin Sun  1 , Tianyue Jiang, Yue Lu, Margaret Reiff, Ran Mo, Zhen Gu
Affiliations

Cocoon-like self-degradable DNA nanoclew for anticancer drug delivery

Wujin Sun et al. J Am Chem Soc. .

Abstract

A bioinspired cocoon-like anticancer drug delivery system consisting of a deoxyribonuclease (DNase)-degradable DNA nanoclew (NCl) embedded with an acid-responsive DNase I nanocapsule (NCa) was developed for targeted cancer treatment. The NCl was assembled from a long-chain single-stranded DNA synthesized by rolling-circle amplification (RCA). Multiple GC-pair sequences were integrated into the NCl for enhanced loading capacity of the anticancer drug doxorubicin (DOX). Meanwhile, negatively charged DNase I was encapsulated in a positively charged acid-degradable polymeric nanogel to facilitate decoration of DNase I into the NCl by electrostatic interactions. In an acidic environment, the activity of DNase I was activated through the acid-triggered shedding of the polymeric shell of the NCa, resulting in the cocoon-like self-degradation of the NCl and promoting the release of DOX for enhanced therapeutic efficacy.

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Figures

Figure 1
Figure 1
(a) Main components of the cocoon-like self-degradable DNA nanoclew, consisting of DOX/FA-NCl/NCa, and acid-triggered DOX release. (b) Schematic illustration of efficient delivery of DOX by DOX/FA-NCl/NCa to nuclei for cancer therapy: (I) internalization in endosomes; (II) pH-triggered degradation of the NCl for DOX release; (III) accumulation of DOX in cell nuclei.
Figure 2
Figure 2
(a) Hydrodynamic size of NCl as determined by dynamic light scattering (DLS). Inset: atomic force microscopy (AFM) image of NCl. The scale bar is 500 nm. (b) Hydrodynamic size of NCa. Inset: transmission electron microscopy (TEM) image of NCa. The scale bar is 10 nm. (c) Circular dichroism (CD) spectra of native DNase I and NCa. (d) DNA-degrading activities of NCa and cNCa at pH 7.4 and 5.4. Bars represent mean ± standard deviation (n = 3).
Figure 3
Figure 3
(a) Hydrodynamic size of NCl/NCa complexes. Inset: TEM image of an NCl/Au-NCa complex. The scale bar is 100 nm. The arrows indicate Au-NCa adsorbed on the NCl surface. (b) DOX release from DOX/NCl/NCa and DOX/NCl/cNCa at pH 7.4 and 5.4. Bars represent mean ± SD (n = 3). (c) AFM images of NCl/NCa complexes after incubation at pH 7.4 and 5.4 for 2 h. The scale bar is 500 nm.
Figure 4
Figure 4
(a) Relative uptake efficiency of DOX/FA-NCl/NCa by MCF-7 cells. **, P < 0.01 compared with the control. Bars represent mean ± SD (n = 3). (b) Confocal laser scanning microscopy images of MCF-7 cells after incubation with DOX/FA-NCl/NCa for different times. Late endosome and lysosomes were stained with LysoTracker green. Red, DOX; green, endolysosome; blue, Hoechst 33342; yellow, colocalization of red and green pixels; magenta, colocalization of red and blue pixels. The scale bar is 10 μm. (c) In vitro cytotoxicities of DOX/NCl, DOX/NCl/NCa, and DOX/FA-NCl/NCa against MCF-7 cells for 24 h. *, P < 0.05. Bars represent mean ± SD (n = 6). (d) In vitro cytotoxicities of the blank FA-NCl, NCa, and FA-NCl/NCa against MCF-7 cells for 24 h. Bars represent mean ± SD (n = 6).
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