Floxuridine Homomeric Oligonucleotides “Hitchhike” with Albumin In Situ for Cancer Chemotherapy

Article abstract of DOI:10.1002/anie.201804156

Automated attachment of chemotherapeutic drugs to oligonucleotides through phosphoramidite chemistry and DNA synthesis has emerged as a powerful technology in constructing structure-defined and payload-tunable oligonucleotide–drug conjugates. In practice,

Full text of DOI:10.1002/anie.201804156

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201804156
German Edition: DOI: 10.1002/ange.201804156
Drug Delivery Hot Paper
Floxuridine Homomeric Oligonucleotides “Hitchhike” with Albumin
In Situ for Cancer Chemotherapy
+
+
Cheng Jin , Hui Zhang , Jianmei Zou, Yan Liu, Lin Zhang, Fengjie Li, Ruowen Wang,
Wenjing Xuan, Mao Ye,* and Weihong Tan*
Abstract: Automated attachment of chemotherapeutic drugs to
oligonucleotides through phosphoramidite chemistry and
DNA synthesis has emerged as a powerful technology in
constructing structure-defined and payload-tunable oligonu-
cleotide–drug conjugates. In practice, however, in vivo delivery
of these oligonucleotides remains a challenge. Inspired by the
systemic transport of hydrophobic payloads by serum albumin
in nature, we report the development of a lipid-conjugated
floxuridine homomeric oligonucleotide (LFU20) that “hitch-
hikes” with endogenous serum albumin for cancer chemo-
therapy. Upon intravenous injection, LFU20 immediately
inserts into the hydrophobic cave of albumin to form an
LFU20/albumin complex, which accumulates in the tumor by
the enhanced permeability and retention (EPR) effect and
internalizes into the lysosomes of cancer cells. After degrada-
tion, cytotoxic floxuridine monophosphate is released to inhibit
cell proliferation.
stable during DNA synthesis and subsequent treatment.
Based on these principles, various molecular drugs have
been engineered as building blocks to synthesize therapeutic
oligonucleotides with well-defined molecular structure and
[
2]
tunable payload. Among these drug modules, therapeutic
nucleoside and nucleobase analogues show advantages
[3]
because of their excellent stability during DNA synthesis.
Fluorouracil, one of the most notable therapeutic nucle-
obase analogues, has been approved as an antimetabolite
[4]
drug in the treatment of cancers and other diseases.
Recently, floxuridine was employed to construct fluoropyr-
imidine polymer (F10) and to pair with guanosine in a DNA
[3c,5]
polyhedral nanosystem for cancer therapy.
However, in
spite of these advances, drug-incorporated oligonucleotides
[
6]
face challenges in systemic delivery. Conventional methods
focus on chemical modifications with active targeting ligands
and conjugation with nanoparticles, which accumulate in the
tumor by the EPR effect. However, these technologies have
their limitations, such as complicated preparation and poor
S
olid-phase synthesis of nucleic acids is an example of
[
1]
[7]
automated and modular molecular synthesis. This technol-
ogy can generate oligonucleotides from nucleoside phosphor-
amidites with high yields. As such, almost any small molecule
can be incorporated into oligonucleotides to generate
advanced nucleic acids with novel properties, but only
under the following conditions: 1) The corresponding phos-
phoramidites are available, and 2) the small molecules are
safety profiles. Therefore, facile and effective carriers for
in vivo delivery of drug-incorporated oligonucleotides are still
[
8]
needed.
Serum albumin is the most abundant serum protein
À1 [9]
(about 40 mgmL ) and has an attractive circulation half-
[
10]
time (t ) of about twenty days. It is also well-known as
1
/2
a natural transporter of poorly water-soluble molecules (for
[
3d,11]
example, lipids and cholesterol) in plasma.
Remarkably,
[
+]
[+]
as a delivery carrier for chemotherapy, the biological safety of
serum albumin outperforms that of most other carriers.
[
*] C. Jin, H. Zhang, J. Zou, Y. Liu, L. Zhang, F. Li, W. Xuan,
[11]
Prof. M. Ye, Prof. W. Tan
Molecular Science and Biomedicine Laboratory, State Key Laboratory
of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, College of Life Sciences, Aptamer Engineering
Center of Hunan Province, Hunan University
Changsha, Hunan, 410082 (China)
Therefore, various hydrophobic payloads, for instance, pacli-
taxel (Abraxane) and perflutren (Optison), have been
designed to bond with albumin for cancer therapy and for
contrast enhancement during ultrasound imaging, respec-
[
12]
tively. Apart from hydrophobic payloads, Levemir (insulin
detemir), a man-made human insulin analogue with a hydro-
phobic alkyl chain at the terminus, was designed to bond with
E-mail: yemaocsu@hotmail.com
tan@chem.ufl.edu
Prof. R. Wang, Prof. W. Tan
[13]
endogenous serum albumin for longer circulation time.
Institute of Molecular Medicine, Renji Hospital, Shanghai Jiao Tong
University School of Medicine, and College of Chemistry and
Chemical Engineering, Shanghai Jiao Tong University, Shanghai,
Following the concept of these examples, we developed
a LFU20 able to “hitchhike” with endogenous albumin for
cancer therapy (Scheme 1). A lipid tail with two octadecyl
(
China)
Prof. R. Wang, Prof. W. Tan
chains inserts into the hydrophobic core of albumin by
Department of Chemistry and Department of Physiology and
Functional Genomics, Center for Research at the Bio/Nano Interface,
Health Cancer Center, UF Genetics Institute and McKnight Brain
Institute, University of Florida
[6,8a,14]
hydrophobic interactions.
As such, upon intravenous
injection, LFU20 noncovalently bonds with albumin in situ to
form an LFU20/albumin complex. LFU20/albumin accumu-
lates in the tumor by the EPR effect and internalizes into the
lysosomes of cancer cells by the Gp18/Gp30-mediated path-
way. After enzymatic degradation, floxuridine monophos-
Gainesville, FL 32611-7200 (USA)
+
[
] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201804156.
[5,15]
phate is released to inhibit cell proliferation.
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terminus, has no obvious interaction with BSA (lanes 1 and
), demonstrating that the lipid tail is essential for the
2
noncovalent interaction between LFU20 and BSA.
To further investigate the kinetics of LFU20 interaction
with albumin, pyrene molecules, which have excimer fluores-
cence in the aggregated state and monomer fluorescence in
the dissociated state, were used to monitor the formation of
the LFU20/albumin complex. As shown in Figure 1c and the
Supporting Information, Figure S13, upon the addition of
BSA, almost all Py-LFU20 micelles had dissociated within
one minute to form Py-LFU20/albumin. Py-G8-LFU12
micelles, which have intermolecular G-quadruplexes in the
[14]
micellar corona to stabilize the micellar structure, showed
only 48% formation of Py-G8-LFU12/albumin, even after
one hour of incubation (Figure S13 f). Apart from BSA,
Scheme 1. Illustration of the solid-phase synthesis of LFU20, self-
assembly of LFU20 to a micellar nanostructure, noncovalent interac-
tion of LFU20 with endogenous albumin after intravenous injection,
and the subsequent cancer therapy of LFU20.
0
.5 mm human serum albumin (HSA) and 10% mice blood
also induce effective formation of LFU20/albumin complex
(
Supporting Information, Figures S14 and S15). Since the
[16]
concentration of albumin in blood is about 0.52–0.75 mm,
which is greater than 0.5 mm, we can conclude that the
intravenous injection of LFU20 DNA micelles into the body
will result in their complete and immediate conversion to
LFU20/albumin complex.
Having confirmed the noncovalent interaction of LFU20
DNA with serum albumin in vitro, we further investigated the
cellular endocytosis of the LFU20/albumin complex. As
a negatively charged biomacromolecule, FU20 (without
lipid tail) cannot internalize into cytoplasm individually
(Figure 2a). LFU20 DNA anchors onto the cell membrane
in DPBS solution (without serum albumin), even after two
hours of incubation (Figures 2a and S16). However, in
LFU20 was generated by iterative synthesis of one lipid
and twenty floxuridine phosphoramidites on a DNA synthe-
sizer (Supporting Information, Figure S7). After deprotection
and purification, LFU20 was obtained with acceptable yields
(> 70%) and high purity (97%) (Supporting Information,
Figures S8 and S10). In DPBS buffer, LFU20 was self-
assembled into amphiphilic polymeric micelles (Figure S12).
However, LFU20 DNA micelles can be disrupted by serum
albumin, which has strong binding affinity for the hydro-
phobic lipid tail (Figure 1a). As shown in Figure 1b, 0.5 mm
bovine serum albumin (BSA) induces the complete conver-
sion of 10 mm LFU20 micelles to LFU20/albumin complex
(
lanes 4 and 5). In contrast, FU20, without a lipid tail at the 5’-
Figure 1. a) Illustration of LFU20 self-assembly into DNA micellar
structure and noncovalent interaction with serum albumin. b) 2%
agarose gel electrophoresis analysis of noncovalent interaction
between 10 mm FU20 or LFU20 with 0.5 mm BSA. Lane 1, FU20;
lane 2, FU20+BSA; lane 3, BSA; lane 4, LFU20 micelles; and lane 5,
LFU20 micelles+BSA. Because of their large particle size (about
Figure 2. a) Confocal microscopy fluorescence images of HeLa cells
treated with 1 mm Cy5-labeled FU20 or LFU20 in DMEM culture
medium (10% FBS) or DPBS buffer at 378C. Lysosome was stained by
DND-99. b) Colocalization investigation of HeLa cells treated with
1 mm FITC-labeled BSA and Cy5-labeled LFU20 in DMEM culture
medium (10% FBS) for 2 h at 378C.
4
3 nm), LFU20 micelles exhibit a tailed band in lane 4. LFU20/albumin
migrates faster than albumin in lane 5, which can be explained by the
presence of negatively charged LFU20. c) Time-dependent analysis of
the percentage of Py-LFU20 in the albumin-bound state after incuba-
tion with 0.5 mm BSA.
2
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DMEM culture medium (10% fetal bovine serum (FBS)), an
standardized IC50 value of LFU20 after calculation is 31.6 mm,
obvious and time-dependent internalization of LFU20 into
HeLa cells was observed (Figure 2a). The lipid tail plays an
important role in the interaction between LFU20 and living
cells. In DPBS solution, LFU20 inserts into the hydrophobic
area of the cell membrane by hydrophobic interactions.
However, in DMEM culture medium (10% FBS), LFU20
bonds with serum albumin to form an LFU20/albumin
complex, resulting in cellular endocytosis (Supporting Infor-
mation, Figure S19). This phenomenon also indicates that
LFU20 binds more strongly to serum albumin than to the cell
membrane. Fluorescence colocalization with Lysotracker red
which is somewhat greater than that of free floxuridine.
Compared to LFU20/albumin, which is a negatively charged
macromolecular complex (molecular weight > 70 kDa), small
molecular floxuridine has a stronger ability to internalize into
cells; therefore, it is reasonable that LFU20 would show lower
in vitro inhibition ratios than those of free floxuridine.
Additionally, compared to FU20, LFU20 also exhibits more
efficient inhibition of the cell proliferation of HepG2 and U-2
OS cells (Supporting Information, Figure S22).
Next, in vivo fluorescence imaging of tumor-implanted
nude mice intravenously injected with Cy5-FU20 or Cy5-
LFU20 was studied. In vivo distribution plays a critical role in
the anticancer efficacy of drug-incorporated oligonucleotides.
As shown in Figure 4, Cy5-FU20 was quickly eliminated from
(
DND-99) demonstrated the transport of internalized
LFU20/albumin to the lysosomes (Pearson correlation
factor: 0.81; Figure 2a).
To further assess whether LFU20/albumin shares an
endocytosis pathway in common with serum albumin, a fluo-
rescence colocalization assay of Cy5-labeled LFU20/albumin
and FITC-labeled BSA was performed. As shown in Fig-
ure 2b, fluorescence of the two channels shows a high overlap
ratio with a Pearson correlation factor of 0.83. Previous
literature has reported that dye-modified BSA internalizes
[17]
into cells by the Gp18/Gp30-associated pathway. Consis-
tent with these findings, our results suggest that the formation
of the LFU20/albumin complex avoids membrane anchoring
based on the blocking of the lipid tail into albumin, instead
favoring cellular internalization by the Gp18/Gp30-mediated
pathway (Figure S19, Supporting Information).
Since LFU20 contains twenty tandem floxuridine mod-
ules, a universal antimetabolite drug used in the treatment of
several cancers, the performance of LFU20 in inhibiting cell
proliferation was examined. Four control groups were used,
FU20, free floxuridine, DNA with twenty repeated thymidine
Figure 4. In vivo fluorescence imaging of tumor-implanted BALB/c
nude mice intravenously injected with Cy5-FU20 or Cy5-LFU20.
the body owing to its small molecular size. Although most
Cy5-LFU20/albumin was also eliminated from the body, an
obvious fluorescence signal in the tumor was still observed,
even after 48 h. Upon injection into mice through the tail
vein, LFU20 micelles dissociated to form LFU20/albumin
complex with longer circulation time and stronger penetra-
[
8a]
(
T20), and lipid-conjugated T20 (LT20). LFU20 clearly
tion through tumor tissue compared to FU20. This resulted
in the better performance of LFU20 in accumulating in tumor
tissue compared to FU20.
decreased cell proliferation with an IC50 value of 1.58 mm.
However, FU20 showed only about 38% inhibition ratios,
even at the concentration of 10 mm (Figure 3). Compared with
FU20, LFU20/albumin showed stronger cellular internaliza-
tion efficacy, indicating more release of drugs in HeLa cells.
Neither T20 nor LT20 had appreciable cytotoxicity, demon-
strating that the therapeutic efficacy of LFU20 could be
attributed to the incorporation of floxuridine, not the lipid
group. Free floxuridine showed an IC50 value of 23.07 mm.
Because LFU20 contains twenty floxuridine modules, the
Encouraged by in vitro therapeutic efficacy and passive
accumulation in tumor, an in vivo evaluation of therapeutic
efficacy was performed. Tumor-implanted BALB/c nude mice
3
with tumor volumes of about 70 mm were intravenously
injected with LFU20, FU20, floxuridine, or PBS. As shown in
Figure 5a,b, LFU20 was the most efficient drug for the
inhibition of tumor growth compared with the others. Free
floxuridine exhibited poorer therapeutic efficacy compared to
that of LFU20, which is an inverse result compared with the
in vitro results. This could be explained by the faster
elimination of the small-molecule floxuridine from the body
[
9]
when compared to albumin-bound LFU20. Finally, hema-
toxylin and eosin (H&E) staining of tumor sections was also
used to evaluate in vivo therapeutic efficacy (Figure 5c).
Cancer cells from the free floxuridine and FU20-treated
groups showed well-defined nuclear structure with features
similar to those of the PBS-treated group. On the other hand,
in the LFU20-treated group, obvious nuclear shrinkage of
cancer cells was apparent, suggesting that LFU20 had induced
efficient cell apoptosis in tumor.
Figure 3. Inhibition ratios of FU20, LFU20, free floxuridine, T20, and
LT20 to HeLa cells. Samples were diluted with DMEM culture medium
(
10% FBS) to the corresponding concentration, followed by addition
In summary, a new strategy for in vivo delivery of
floxuridine homomeric oligonucleotides was accomplished
by incorporating a hydrophobic lipid tail, allowing LFU20 to
to 96-well plates. Cells were cultured for an additional 48 h prior to cell
viability assay. The concentration of free floxuridine is twenty-fold
higher than that of the label on the X axis.
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Keywords: albumin · cancer chemotherapy · drug delivery ·
floxuridine · lipid-conjugated oligonucleotides
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Manuscript received: April 8, 2018
Revised manuscript received: May 8, 2018
Version of record online: && &&, &&&&
4
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Communications
Drug Delivery
Hitchhiker’s guide to the bloodstream: A
new strategy for in vivo delivery of flox-
uridine homomeric oligonucleotides was
accomplished by incorporating a hydro-
phobic lipid tail at the 5’-terminus,
allowing LFU20 to hitchhike with endog-
enous serum albumin. The LFU20/albu-
min complex accumulates in the tumor
by the EPR effect and inhibits tumor
growth.
C. Jin, H. Zhang, J. Zou, Y. Liu, L. Zhang,
F. Li, R. Wang, W. Xuan, M. Ye,*
W. Tan*
&&&& — &&&&
Floxuridine Homomeric
Oligonucleotides “Hitchhike” with
Albumin In Situ for Cancer Chemotherapy
Angew. Chem. Int. Ed. 2018, 57, 1 – 5
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!