Cell-Selective Delivery of MicroRNA with a MicroRNA–Peptide Conjugate Nanocomplex

Article abstract of DOI:10.1002/asia.201801396

Targeted delivery of microRNA (miRNA) into specific cells has been regarded as an efficient strategy to enhance miRNA-targeted therapeutics. However, concurrent delivery of therapeutic miRNAs into different target cells that is conducive to multi-target t

Full text of DOI:10.1002/asia.201801396

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Cell-selective delivery of microRNA with microRNA-peptide
conjugate nanocomplex
Authors: Xiao Xiao, Xingxing Wang, Haidong Gao, Xi Chen, Jinbo Li,
and Yan Zhang
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To be cited as: Chem. Asian J. 10.1002/asia.201801396
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10.1002/asia.201801396
Chemistry - An Asian Journal
COMMUNICATION
Cell-selective delivery of microRNA with microRNA-peptide
conjugate nanocomplex
Xiao Xiao,[a] Xingxing Wang,[a] Haidong Gao,[b] Xi Chen,[b] Jinbo Li*[a,b] and Yan Zhang*[a,b]
Abstract: Targeted delivery of microRNA (miRNA) into specific cells
has been regarded as an efficient strategy to enhance miRNA-
targeted therapeutics. However, concurrent delivery of therapeutic
miRNAs into different target cells that is conducive to multi-target
therapy is still underdeveloped. Here, we report a novel strategy for
cell-selective delivery of miRNA into different target cells through
using miRNA nanocomplexes (MINRCs) formed by miRNA with
peptide conjugates. The peptide conjugates comprised a cationic cell-
penetrating peptide nona-arginine and a targeting ligand that is cyclic
RGD or folic acid. Upon mixing in buffer, the peptide conjugates and
miR-34a readily formed two MINRCs, respectively. These two
MINRCs facilitated the targeted delivery of miR-34a into RGD
receptor-positive U87MG cells or folate receptor-positive HeLa cells
via ligand-receptor interaction. We also demonstrated that co-
incubation of these two MINRCs with U87MG and HeLa cells led to
cell-selective delivery of miR-34a.
as biocompatible and efficient carriers for nucleic acid delivery
and gene therapy.[9] Targeted delivery of nucleic acids into
specific cells is also achievable through using peptide conjugates
by linking cationic peptides with cell-targeting ligands. For
example, several peptide conjugates that are cationic nona-
arginine (R9) modified with cell-binding ligands were used to
transport small-interfering RNA (siRNA) into specific target cells
through nanocomplexes formed by these peptide conjugates with
siRNA.[10] Recently, we developed a multi-functional peptide
conjugate that comprised R9,
a targeting ligand and an
activatable fluorescence probe for monitoring miRNA function.[11]
The multi-functional peptide conjugate readily formed miRNA
nanocomplex (MIRNC) upon mixing with miRNA for targeted
miRNA delivery as well as real-time imaging of miRNA function.
Therefore, it is possible to use different peptide conjugates to form
MIRNCs with miRNAs and accomplish cell-selective delivery of
miRNA into different target cells through using these MIRNCs.
Here, we report a novel strategy for cell-selective and
concurrent delivery of miRNA into two different target cells by
using MIRNCs (Scheme 1). In this method, R9 is respectively
modified with two different targeting ligands, and the resulted
peptide conjugates are used to form two MIRNCs with miRNA for
selective delivery of miRNA into target cells expressing
corresponding receptors.
MicroRNAs (miRNAs) are endogenous small non-coding RNAs
that function by negatively regulating gene expression at the post-
transcriptional level.[1] Since approximately 60% of human genes
are their targets,[2] miRNAs extensively involve in not only normal
physiologies but also pathologies.[3] Aberrantly expressed
miRNAs have close links with the development and progress of
various human diseases, including cancers.[4] Regulation of
endogenous abnormal miRNAs has therefore been confirmed as
an efficient therapeutic strategy.[5] Synthetic miRNA mimics that
replenish tumor-suppressive miRNAs upon proper delivery into
cells appear as promising drug candidates.[6] The demand of
strategies for targeted delivery of miRNA that can enhance
miRNA-targeted therapeutics is thus tremendously high.[7]
However, cell-selective delivery of miRNA into different target
cells in a multicellular context, which is conducive to multi-target
therapy, still remains challenging.
Scheme 1. Schematic illustration of cell-selective delivery of miRNA with
different miRNA nanocomplexes formed by targeting ligands-modified R9 and
miRNA.
In addition to conventional carriers such as lipids and
nanovectors,[8] cationic cell-penetrating peptides have emerged
We chose cyclic (Arg-Gly-Asp-Phe-Lys) c(RGDfK) and folic
acid (FA) as the targeting ligands to modify R9. c(RGDfK) and FA
are the ligands of αvβ3 integrin that overexpresses on the
membrane of U87MG cells[12] and folate receptor that is highly
expressed on the membrane of HeLa cells,[13] respectively. To
connect R9 with c(RGDfK) or FA, we used click chemistry[14] as
the conjugation method. Briefly, alkyne-functionalized R9 was
prepared via solid-phase peptide synthesis, and c(RGDfK) or FA
were pre-installed with azide functionality. c(RGDfK)-R9 and FA-
R9 peptide conjugates (Scheme 2) were then obtained through
Cu(I)-catalyzed click reaction between alkyne-functionalized R9
and azide-functionalized c(RGDfK) or azide-functionalized FA.
Following purification of c(RGDfK)-R9 and FA-R9 with high-
performance liquid chromatography (HPLC), we verified these
[a]
[b]
X. Xiao, X. Wang, Prof. Dr. J. Li, Prof. Dr. Y. Zhang
State Key Laboratory of Analytical Chemistry for Life Sciences,
Jiangsu Key Laboratory of Advanced Organic Materials, School of
Chemistry and Chemical Engineering, Nanjing University
163 Xianlin Avenue, Nanjing 210023, China
E-mail: jinboli@nju.edu.cn (J. L.); njuzy@nju.edu.cn (Y. Z.)
H. Gao, Prof. Dr. X. Chen
State Key Laboratory of Pharmaceutical Biotechnology,
Collaborative Innovation Center of Chemistry for Life Sciences,
Jiangsu Engineering Research Center for MicroRNA Biology and
Biotechnology, Nanjing Advanced Institute for Life Sciences
(NAILS), School of Life Sciences, Nanjing University
Institution
163 Xianlin Avenue, Nanjing 210023, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/asia.201801396
Chemistry - An Asian Journal
COMMUNICATION
two peptide conjugates by mass spectrometry (MS) (supporting
information).
Intracellular delivery efficiency of the formed nanocomplexes
was further tested. Since only a few of free miR-34a was left after
self-assembly with c(RGDfK)-R9 or FA-R9, we directly used the
formed nanocomplexes without purification. Nanocomplexes
formed by c(RGDfK)-R9/miR-34a at different molar ratios were
then incubated with U87MG cells that express high level of αvβ3
integrin on the membrane.[12] After incubation for 24 h, the
endogenous miR-34a levels in U87MG cells were measured by
real-time quantitative PCR (RT-qPCR). As shown in Figure 2a,
endogenous miR-34a levels significantly increased when the
c(RGDfK)-R9/miR-34a ratio was larger than 10/1, and it reached
maximum when the molar ratio was 50/1. To test the delivery
efficiency of nanocomplexes formed by FA-R9/miR-34a, folate
receptor-positive HeLa cells[13] were used. Endogenous miR-34a
levels inside HeLa cells were also determined by RT-qPCR after
the nanocomplexes were incubated with HeLa cells for 24 h.
Figure 2b shows the RT-qPCR analysis results. The miR-34a
levels remarkably increased along with the increase of FA-
R9/miR-34a ratio and also reached plateau when the ratio was
50/1. We therefore used the nanocomplexes formed by
c(RGDfK)-R9/miR-34a 50/1 and FA-R9/miR-34a 50/1 for further
investigations, which were respectively dubbed as RGD-MIRNC-
34a and FA-MIRNC-34a. It is worth noting that c(RGDfK)-R9 or
FA-R9 peptide conjugates did not modulate endogenous miR-34a
levels (Figure S2) and the delivery efficiency of these two
nanocomplexes was comparable to that of the commercial
transfection agent Lipofectamine 2000 (Figure S3).
OH
O
H
N
O
O
NH
HN
O
HN
R =
NH
O
HN
O
O
O
H
N
c(RGDfK)-R9
NH
N
N
R
NH2
O
N
3
H2N
NH
O
9
HN
HO
O
H2
N
NH
O
H
N
R =
N
H
O
N
O
N
N
N
H
NH
NH2
FA-R9
Scheme 2. Chemical structures of c(RGDfK)-R9 and FA-R9 peptide conjugates.
Next, we first investigated whether c(RGDfK)-R9 and FA-R9
could self-assemble with miRNA to form nanocomplexes. Tumor-
suppressive miR-34a[5a] was selected as the model miRNA for
further studies. c(RGDfK)-R9 or FA-R9 were mixed with miR-34a
in phosphate buffer saline (PBS) with molar ratios ranging from
0/1 to 70/1. The mixtures were allowed to stand at room
temperature for 30 minutes and further subject to gel
electrophoresis. Figure 1a shows the gel-shift analysis results.
The amount of free miR-34a significantly decreased when the
c(RGDfK)-R9/miR-34a and FA-R9/miR-34a ratios increased.
Most of the free miR-34a was packaged in nanocomplexes when
c(RGDfK)-R9/miRNA ratio was larger than 30/1. Free miR-34a
completely disappeared when FA-R9/miR-34a ratio reached 30/1,
indicating that miR-34a is totally encapsulated in the
nanocomplexes. We then measured the sizes of formed
nanocomplexes by dynamic light scattering (DLS). Continued
decrease in the sizes, which ranged from 1200 to 100 nm or 200
to 100 nm, was observed for nanocomplexes formed by
c(RGDfK)-R9/miR-34a or FA-R9/miR-34a (Figures 1b and 1c).
Transmission electron microscope images of the formed
nanocomplexes (Figure S1) showed that the diameter sizes of
nanocomplexes formed by c(RGDfK)-R9/miR-34a 50/1 or FA-
R9/miR-34a 50/1 were ~80 nm or ~50 nm, respectively. These
results confirm that c(RGDfK)-R9 or FA-R9 peptide conjugates
are able to form nanocomplexes with miRNA and also suggest
that targeting ligands can affect the self-assembly ability of R9
toward miRNA.
Figure 2. RT-qPCR analysis of endogenous miR-34a levels in (a) U87MG cells
and (b) HeLa cells after incubation with free miR-34a or nanocomplexes formed
by c(RGDfK)-R9/miR-34a or FA-R9/miR-34a with molar ratios at 10/1, 30/1,
50/1 and 70/1. The final concentration of miR-34a was 100 nM. Data are shown
as mean ± SEM (n=3). *P < 0.05, relative to blank control.
We have previously demonstrated that MIRNC could
distinguish receptor-positive cells from receptor-negative cells
and deliver miRNA into target cells through receptor-mediated
endocytosis.[11] We speculate that RGD-MIRNC-34a and FA-
MIRNC-34a may have the capability to find target cells in a
mixture of co-cultured cells and deliver miRNA into their target
cells in a cell-selective manner. To demonstrate this hypothesis,
we first validated whether RGD-MIRNC-34a and FA-MIRNC-34a
could recognize their target cells. We used αvβ3 integrin-positive
U87MG and HUVEC cells, folate receptor-positive HeLa and KB
cells, and RAW264.7 cells that are both αvβ3 integrin-negative and
folate receptor-negative (Figure S4). These cells were then
respectively incubated with RGD-MIRNC-34a or FA-MIRNC-34a
for 24 h, followed by analysis of endogenous miR-34a levels via
RT-qPCR. As shown in Figures 3a and 3b, in comparison with
Figure 1. (a) Gel-shift analysis of free miR-34a in the mixtures of c(RGDfK)-R9
or FA-R9 and miR-34a with molar ratios at 10/1, 30/1, 50/1 and 70/1. (b, c)
Hydrodynamic sizes of the nanocomplexes formed (b) c(RGDfK)-R9 or (c) FA-
R9 with miR-34a. The molar ratios were 10/1, 30/1, 50/1 and 70/1. Data are
shown as mean ± SEM (n=3).
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that induced by RGD-MIRNC-34a, the endogenous miR-34a
levels in U87MG and HUVEC cells after treatment with FA-
MIRNC-34a were much lower. Similarly, the endogenous miR-
34a levels in HeLa and KB cells remarkably up-regulated only
after treatment with FA-MIRNC-34a but not RGD-MIRNC-34a
(Figures 3c and 3d). It is noteworthy that no significant uptake of
both FA-MIRNC-34a and RGD-MIRNC-34a in RAW264.7 cells
was observed (Figure 3e). To further validate these results, we
used R9 without targeting ligands to self-assemble with miR-34a
to deliver miR-34a into these cells, resulting in only a slight
increase in endogenous miR-34a levels (Figure 3). Moreover, we
also used c(RDDfK) that cannot bind to αvβ3 integrin to modify R9
and prepared the nanocomplex RDD-MIRNC-34a through
incubation of c(RDDfK)-R9 with miR-34a (50/1). When using
RDD-MIRNC-34a to treat U87MG or HUVEC cells, we detected
only a slight increase in endogenous miR-34a levels (Figure S5).
These results demonstrate that MIRNCs are able to recognize
target cells and deliver miRNA with high specificity and efficiency.
It is also worth noting that miR-34a upon delivery into U87MG or
HeLa cells by RGD-MIRNC-34a or FA-MIRNC-34a was able to
repress target gene expression (Figure S6), which was
demonstrated by using luciferase reporter systems as we
reported before.[11, 15]
Figures 4a and 4e show the image for nucleus staining and bright
field image of co-cultured cells, respectively. In the view, we could
easily recognize HeLa and U87MG cells. Fluorescence signals
from Cy3-miR-34a and Cy5-miR-34a inside co-cultured cells were
then acquired to indicate the location of miR-34a delivered by
RGD-MIRNC-34a or FA-MIRNC-34a. We found that Cy3-miR-
34a mainly located in the cytoplasm of U87MG cells (Figures 4b
and 4d). In comparison, Cy5-miR-34a was mainly detected in the
cytoplasm of HeLa cells (Figures 4c and 4d). Moreover, RGD-
MIRNC-34a and FA-MIRNC-34a could also selectively deliver
miR-34a into U87MG cells and HeLa cells, respectively, when
U87MG cells or HeLa cells were co-cultured with RAW264.7 cells
(Figures S9 and S10). These results confirm that RGD-MIRNC-
34a and FA-MIRNC-34a are able to deliver miRNA into their
target cells when incubation with co-cultured cells. Therefore, cell-
selective delivery of miRNA in complex multicellular systems is
achievable through using MIRNCs.
Figure 4. Bright field and confocal fluorescence images of co-cultured U87MG
cells and HeLa cells (1/1) after incubation with RGD-MIRNC-34aCy3 and FA-
MIRNC-34aCy5 for 24 h. The final concentration of Cy3/Cy5-labeled miR-34a
was 100 nM. (a) Hoechst 33342 channel, nucleus staining of HeLa cells; (b)
Cy3 channel; (c) Cy5 channel; (d) Merged image; (e) Bright field image. Scale
bar: 75 µm.
In summary, we developed a novel strategy for cell-selective
delivery of miRNA in a multicellular context. In this strategy,
c(RGDfK)-R9 and FA-R9 peptide conjugates were the only
necessary reagents, which were constructed by conjugating
c(RGDfK) or FA with R9 through click chemistry. These two
peptide conjugates readily formed two MIRNCs with miR-34a.
RGD-MIRNC-34a and FA-MIRNC-34a were able to deliver miR-
34a into corresponding target cells with high specificity and
efficiency. Upon incubation with co-cultured target cells, RGD-
MIRNC-34a and FA-MIRNC-34a delivered miR-34a into their
target cells in a cell-selective manner. Therefore, this strategy
offers a practical way to realize cell-selective delivery of miRNA
in multicellular context. Further exploration of this strategy in
multi-miRNA delivery and multi-target therapy in living animals is
now underway in our group.
Figure 3. RT-qPCR analysis of endogenous miR-34a levels in (a) U87MG cells,
(b) HUVEC cells, (c) HeLa cells, (d) KB cells and (e) RAW264.7 cells after
incubation with nanocomplex formed by R9 and miR-34a (peptide/miRNA 50/1),
RGD-MIRNC-34a, or FA-MIRNC-34a for 24 h. The final concentration of miR-
34a was 100 nM. Data are shown as mean ± SEM (n=3). *P < 0.05.
Finally, we demonstrated the hypothesis that cell-selective
delivery of miRNA in a mixture of co-cultured cells could be
achieved through using different MIRNCs. To directly view the
selective delivery, we used Cy3/Cy5-labled miR-34a for
fluorescence tracking. The nanocomplexes were prepared by
respectively mixing c(RGDfK)-R9 with Cy3-miR-34a (50/1) or FA-
R9 with Cy5-miR-34a (50/1). Time-dependent fluorescence
imaging results confirmed that RGD-MIRNC-34aCy3 or FA-
MIRNC-34aCy5 could respectively deliver miR-34a into their target
cells through endocytosis (Figures S7 and S8). We then co-
cultured U87MG and HeLa cells, followed by co-incubation with
RGD-MIRNC-34aCy3 and FA-MIRNC-34aCy5 for 24 h. To
distinguish HeLa cells from U87MG cells, HeLa cells were pre-
stained with Hoechst 33342 prior to co-culture with U87MG cells.
Acknowledgements
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We would like to acknowledge the financial support from the
National Natural Science Foundation of China (21672103,
21572102, 91753116, 21372115) and the Fundamental Research
Funds for Central Universities (020514380133, 020514380137).
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Keywords: microRNA
•
peptide conjugate
•
microRNA
nanocomplex • targeted delivery • cell-selective delivery
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Chemistry - An Asian Journal
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Entry for the Table of Contents (Please choose one layout)
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We report a novel strategy for
cell-selective delivery of
microRNA into different target
cells through using microRNA
nanocomplexes formed by
microRNA with peptide
conjugates.
Xiao Xiao, Xingxing Wang,
Haidong Gao, Xi Chen, Jinbo Li*
and Yan Zhang*
Page No. – Page No.
Cell-selective delivery of
microRNA with microRNA-
peptide conjugate nanocomplex
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Author(s), Corresponding Author(s)*
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Title
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