Tuned Cationic Dendronized Polymer: Molecular Scavenger for Rheumatoid Arthritis Treatment

Article abstract of DOI:10.1002/anie.201813362

Cell-free deoxyribonucleic acid (cfDNA) released from either dead or damaged cells serves as a key autoantigen in rheumatoid arthritis (RA). They can be recognized by nucleic acid (NA) sensors such as the toll-like receptor (TLR), leading to activation of

Full text of DOI:10.1002/anie.201813362

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Accepted Article
Title: Tuned Cationic Dendronized Polymer as a Molecular Scavenger
for Rheumatoid Arthritis Treatment
Authors: Bo Peng, Huiyi Liang, Yuyian Li, Cong Dong, Jun Shen, Hai-
quan Mao, Kam W Leong, Yongming Chen, and Lixin Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813362
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10.1002/anie.201813362
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Screening low toxicity of cationic dendronized polymer with high NA affinity as an inflammation inhibitor
from constructed library.
Tuned Cationic Dendronized Polymer as a Molecular Scavenger
for Rheumatoid Arthritis Treatment
Bo Peng[a, b], Huiyi Liang[a], Yuyan Li[a], Cong Dong[a], Jun Shen[c], Hai-Quan Mao[d], Kam W. Leong[b],
Yongming Chen[a], Lixin Liu[a] *
cationic molecular scavengers of cfDNA because they serve
different purposes. Firstly, the molecular scavenger needs to bind
with NA as tight as possible to prevent their recognition by TLRs
in the endosome.[5] Secondly, molecular scavengers must have
sound biocompatibility because the autoimmune diseases are
mostly chronic ones which require long time and repeated
medication administration. Thirdly, desired pharmacokinetics and
biodistribution profiles of cationic polymer itself are needed for NA
scavenging at certain organs or locations. Systematic study of the
structure-property relationship of cationic polymers is crucial to
find the suitable candidates for inflammatory disease treatment.
Abstract: Cell free deoxyribonucleic acid (cfDNA) released from dead
or damaged cells serves as a key autoantigen in rheumatoid arthritis
(RA). They could be recognized by nucleic acid (NA) sensors like toll-
like receptor (TLR), leading to activation of the innate immune system
and chronic inflammation. Herein, we develop a cationic molecular
scavenger through a screening of cationic dendronized polymers,
which could eliminate the cfDNA and inhibit the TLR recognition and
nucleic acid-induced inflammation. The structure-property study
demonstrates that toxicity, NA binding capacity and biodistribution
could be balanced to achieve maximum therapeutic effect with
exquisite control of molecular structure. In addition, the optimized
cationic polymer effectively inhibited the joint swelling, synovial
hyperplasia and bone destruction in collagen-induced arthritis (CIA)
rat model. The results supported that the synthetic polymers offer new
paradigm for autoimmune disease treatment.
Herein, we target at the most common autoimmune disease,
rheumatoid arthritis (RA), which affects over 0.5% population
worldwide. RA is a systemic illness characterized by diffuse joint
inflammation and destruction. Although the factors that drove
persistent cellular activation in RA remain elusive, the data from
animal model and clinical study suggested that cfDNA played a
key role in driving inflammation for RA.[6] By scavenging the
cfDNAs, recently we have shown that the polycationic
nanoparticles can inhibit the persistent inflammation in RA to
achieve significant symptom relieve.[7] Here we designed and
synthesized a series of cationic dendronized polymers (cDenpols)
to demonstrate that toxicity, NA binding capacity and
biodistribution could be balanced to achieve maximum
therapeutic effect with exquisite control of molecular structure.
The mechanism is showed in Fig. 1a. A Denpol possesses a
linear polymer backbone and high-densely grafted dendrons.[8]
The length of the Denpol could be precisely tuned by the
controlled polymerization and the charge density could be
controlled by the generation of dendron grafts.[9] The
polycaprolactone (PCL) was chosen to be the biodegradable
backbone, which may reduce the toxicity of the Denpols. Different
generations of cationic polyamidoamine (PAMAM) dendrons were
used as the side chain because they showed great anti-
inflammation efficacy in the previous study.[3]
The cfDNA released from the damaging or dead cells serves as
an important damage-associated molecular pattern (DAMP).
Chronic activation of immune cells by the cfDNA through nucleic
acid-sensing pathways like TLR contributes to many sterile
inflammation conditions, including autoimmune diseases.[1]
Although the TLR antagonists could reduce the cfDNA-induced
inflammation,[2] inhibiting function of TLR could result in immune
suppression and adverse side effects, such as increased risk of
infection. Lee et al. [3] demonstrated that cationic polymers could
be applied to scavenge the artificial pro-inflammatory nucleic
acids and rescue mice from liver failure. Holl et al. [4] proved that
introduction of cationic polymers could limit autoimmunity caused
by the endogenous cfDNA in lupus-prone mice. Therefore,
scavenging NAs with cationic polymers may become a new
strategy to treat some immune diseases. However, most of the
current cationic polymers for gene delivery may be not perfect
[a]
Dr. B. Peng, H. Y. Liang, Dr. Y. Y. Li, C. Dong, Prof. L. X. Liu, Prof.
Y. M. Chen,
The cDenpols were prepared through a combination of
controlled ring-opening polymerization and click chemistry (Fig.
1b). Firstly, the PCL backbone with pendant bromine groups was
synthesized by the ring-opening polymerization of bromo-3-
caprolactone.[10] Then the bromine groups were converted into
azide groups by sodium azide. Secondly, di-tert-butyl dicarbonate
(BOC)-protected PAMAMs were introduced into the Denpols by
copper-catalyzed alkyne azido click reaction. Finally, the PCL-g-
PAMAM Denpols were obtained by removal of BOC group. By
grafting different generations of PAMAM onto the different lengths
of PCL, we obtained a small library of Denpols with different
charge number and density (Fig. S1-S11 and Table S1). The
summaries of grafting efficiency, molecular weight and
polydispersity of the PCL-g-PAMAM Denpols are given in Table
S2. The zeta potential test shows the charge density of the
cDenpols increased with the length and generation of side chain
(Fig. S12). Their abbreviation of cDenpols was shown as X-Gn,
School of Materials Science and Engineering, and Center of
Functional Biomaterials, Key Laboratory of Polymeric Composite
Materials and Functional Materials of Ministry of Education, GD
Research Center for Functional Biomaterials Engineering and
Technology, Sun Yat-sen University, Guangzhou 510275, China
E-mail: liulixin@mail.sysu.edu.cn
[b]
Dr. B. Peng, Prof. K. W. Leong
Department of Biomedical Engineering,
Columbia University, New York, NY 10027, USA
Prof. J. Shen, Department of Radiology, Sun Yat-sen Memorial
Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
Prof. H. Q. Mao
Department of Materials Science and Engineering, Johns Hopkins
University, Baltimore, MD 21205, USA
[c]
[d]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201813362
Angewandte Chemie International Edition
COMMUNICATION
binding affinity of cDenpols in presence of FBS and very limited
influence was found (Fig. S16).
The affinity of cationic materials to cfDNA is structurally
related on the molecular level. We investigated the ability of the
materials to block NA biological activation with Ramos BlueTM
reporter cells. Among the TLR family, activation of TLR9 has been
found in RA synovium, which is a mixed cell population including
B cells, monocytes, synovial fibroblasts and macrophages.[13] TLR
signaling in the immune cells culminates to produce inflammatory
cytokines and/or type I IFN. It further leads to T cell activation and
matrix metalloproteinases production, finally result in joint
inflammation, cartilage and bone damage in RA. We used the
CpG ODN to activate TLR9 of Ramos BlueTM reporter cells to
mimic the cfDNA-induced inflammation. The anti-inflammatory
effect of PCL-g-PAMAM increased with both the length and side
dendron generation (Fig. 2d and S17). From 71-G1 to 384-G1,
polymer concentrations resulting in 80% TLR inhibition decreased
from 3.1 to 1.7 μg/mL. From 384-G1 to 384-G3, the concentration
decreased from 1.7 to 1.0 μg/mL. Thus 384-G3 showed the best
anti-inflammatory effect in TLR inhibition from Ramos BlueTM
reporter cells, agreeing with the results of heparin competition
array.
Figure 1. a) Scheme of cfDNA elimination and anti-inflammation mechanism
of cDenpol. The cfDNAs released from the dying cell induce the immune cell
activation and joint inflammation (upper panel). cDenpols bind to the
pathogenetic cfDNA, inhibit the activation of immune cells, and lead to joint
protection (lower panel). b) Synthesis of PCL-g-PAMAM. c) Gel permeation
chromatography (GPC) traces of 71-G1 Denpol before (red) and after (black)
storing in the pH = 7.4, 37 ºC, PBS for 24 h.
Then we separated the endogenous cfDNA from the synovial
fluid of RA patients and co-cultured with the primary macrophages
also from the RA patients to induce the inflammation. Both
peripheral blood mononuclear cell (PBMC)-derived macrophage
and synovial fluid-derived resident macrophages were used to
identify the anti-inflammation effect of 384-G3 Denpol, which
showed the best performance in scavenging the inflammatory
CpG. Firstly, these cells from RA patients were activated by the
cfDNA in vitro. Their tumor necrosis factor-α (TNF-α) and
interferon-α (IFN-α) level were dramatically increased after 24 h
co-culture with cfDNA in a dose-dependent manner (Fig. 2e,f).
Then addition of 384-G3 Denpol could effectively inhibit the
activation of macrophages (Fig. 2e,f and S18-19). Therefore,
cationic polymers could also inhibit the activation of clinically
relevant patient-derived primary cells by cfDNA from patients.
where X equals degree of polymerization of PCL, n equals
generation number of PAMAM dendron. cDenpol could be
degraded in the physiological condition (Fig. 1c).
The cytotoxicity of cDenpols was first screened on the
RAW264.7 mice macrophages and they showed the 75%
maximal inhibitory concentration (IC75) of 200 to 300 μg/mL. The
cytotoxicity of PCL-g-PAMAM increased with both the length and
side chain generation (Fig. 2a and S13). From 71-G1 to 384-G1,
the IC75 decreased from 332 to 246 μg/mL. From 384-G1 to 384-
G3, the IC75 decreased from 246 to 163 μg/mL.
The cfDNA level in the synovial fluid is much higher than in
the serum in the RA patients.[14] Favorable biodistribution should
greatly enhance the cfDNA elimination efficiency of the cDenpols
while the rapid clearance by the mononuclear phagocyte system
(MPS) might compromise the therapeutic outcome. As shown in
Fig. 3 and Fig. S20, certain cDenpols preferentially accumulated
to the inflammatory joints of the collagen-induced arthritis (CIA)
model rats and such a passive joint targeting efficiency was
clearly related to the structure of cDenpol. From 71-G3 to 384-G3,
the cDenpols with longer backbone accumulated more in the
inflammatory joint of CIA rats. For the 384-G2 and 384-G3, the
later one with higher charge density showed better passive joint
targeting efficiency. From anatomy images we could also confirm
that the targeting efficiency increased with charge density and
chain length. The structures of the Denpols also influenced their
biodistribution in the internal organs. 9 h after injection (Fig. S20),
all the polymers showed considerable accumulation in the kidney,
The polymer concentration resulting in 70% polymer-DNA
binding was determined by ethidium bromide (EtBr) competition
array[11] to evaluate the DNA binding affinity of cDenpols (Fig. 2b
and S14). All the cDenpols showed strong DNA binding affinity.
From 384-G1 to 384-G3, the polymer concentrations resulting in
70% polymer-DNA binding decreased from 1 to 0.6 μg/mL. It
seems that the binding affinity of the Denpols was more
significantly influenced by the charge density instead of length of
polymer. Then we applied the heparin competition array to give
detail information of binding capacity of the Denpols based on the
EtBr array.[12] The concentration of heparin to disrupt 50% of the
polymer/DNA was used to compare the binding strength of
Denpols. The result showed that the binding affinity depended
upon not only the charge density but also the polymer length (Fig.
2c and S15). From 71-G1 to 384-G1, the concentration of heparin
to disrupt 50% of the polymer/DNA increased from 0.09 to 0.32
μg/mL. From 384-G1 to 384-G3, the concentration increased from
0.32 to 0.65 μg/mL. The 384-G3 showed highest DNA binding
affinity. To eliminate the influence of plasma proteins which might
compete binding with cationic polymer, we also tested the DNA
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10.1002/anie.201813362
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COMMUNICATION
***
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cfDNA 5 ug/mL
cfDNA 15 ug/mL
384-G3
Figure 2. In vitro evaluation of the structure-property relationship of the cDenpol. a) IC75 of nine PCL-g-PAMAM Denpols by MTT array. b) Polymer
concentrations resulting in 70% polymer-DNA binding by EtBr competition array. c) Heparin concentrations resulting in 50% of polymer/DNA complex
dissociation. d) Polymer concentrations resulting in 80% TLR9 inhibition of Ramos-BlueTM cells. e) and f) The inhibition of 384-G3 on suppressing the TNF-α
and IFN-α secretion from e) synovial fluid-derived macrophages and f) PBMC-derived macrophage from the RA patients treated with the cfDNA by ELISA
array. Error bars represent SD (n=3) and the statistics were determined by t-test. *P < 0.05, **P < 0.01 and ***P < 0.001. The original data was presented in
Fig. S17-18.
implying degradation of polymers into small pieces. And the
accumulation of cDenpols in liver also increased with the polymer
length. It indicated that increase of the charge density might
enhance the clearance of polymers by MPS.[15]
Then we evaluate whether cDenpols could show potency to
treat the CIA rat model, which shares many similarities with the
human RA.[16] As the CIA rats developed joint swelling from day
13 after first immunization, daily intravenous injection of 384-G2
and 384-G3 was performed on the CIA rats from day 13 to
evaluate their anti-inflammatory effects, respectively (Fig. 4a).
The clinical score of hindpaw and forepaw swelling were both
greatly inhibited compared to the control group (Fig. 4b). After 28
days, the rats were sacrificed, and the joints were analyzed by
Hematoxylin-eosin (H&E) staining and micro-CT. H&E staining
showed severe hyperplasia of the synovial membrane and
immune cell infiltration in the multiple joints of CIA model group.
Conversely, the rats treated with 384-G2 and 384-G3 displayed
near-normal synovial membranes in right hindpaws (Fig. 4c) and
in other joints (Fig. S21-23). Just as the RA in human, the small
joints were more seriously affected by synovial hyperplasia and
inflammation in CIA rats (Fig. S23). Although 384-G2 and 384-G3
showed similar anti-inflammatory in ankle joints of hindpaw, 384-
G3 with better in vitro DNA binding affinity displayed better joint
protection in the smaller toe joints.
Figure 3. In vivo imaging of cDenpol in the CIA model rats. a) the evolution of
the fluorescent signals throughout the CIA model rats. b) the distribution of
fluorescent signals in the organs 2 h after injection of 384-G3. ①Thymus; ②
Heart; ③Lung; ④Liver; ⑤⑥Kidney; ⑦Pancreas; ⑧Spleen; ⑨Bladder; ⑩⑪
Forepaw; ⑫⑬Hindpaw.
model group (Fig. 4e and 4f) significantly decreased to 81% and
57% of control group, indicating a serious bone loss of joint
because of arthritis. Bone surface area/bone volume (BSA/BV) of
model rat was also greatly increased to 178% of control group,
demonstrating the severe arthritis-mediate surface bone
corrosion (Fig. S28A). After treatment with 384-G2 and 384-G3,
BMD, BV/TV and BSA/BV were greatly improved. The porous
structure of trabecular bones offers the maximal strength with
minimum mass. In the CIA model group, the trabeculae thickness
decreased to 62% and trabeculae spacing elevated to 289% (Fig
Micro-CT showed that the CIA rats developed severe bone
damage in multiple joints. In contrast, the cDenpols inhibited the
bone destruction (Fig. 4d for the tarsometatarsal joints of left
hindpaws, and Fig. S25-27 for the ankle joints and the
tarsometatarsal joints of the left hindpaws of individual rats). The
quantitative study of micro-CT showed that the bone mineral
density (BMD) and bone volume/total volume (BT/TV) of CIA
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10.1002/anie.201813362
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COMMUNICATION
Figure 4. In vivo anti-inflammatory activity of the cDenpols in the CIA model rats. a) Experimental timeline to evaluate the anti-inflammatory activity. b) The
clinical score of RA model rats, 384-G2 and 384-G3 treated rats (n=6-9) since 13 days after first immunization, the daily dose of polymers was 20 mg/kg by
intravenous injection. c) H&E staining images of the ankle joints of right hindpaws of the control, CIA model, 384-G3 and 384-G2 treated groups. d) Micro-CT
images of the tarsometatarsal joints of left hindpaws of different groups. e), f), and g) The BMD, BT/TV, and trabecular spacing calculated from the micro-CT
images. h) The cfDNA level in serum before and after the experiment. The whole set of data is presented in Supplementary Information.
4g and S28B,C), indicating trabeculae bone thinning due to the
bone corrosion. Moreover, the three-dimensional trabecular
microarchitecture, defined by trabecular bone pattern factor
(TBPf), was also greatly damaged in the CIA model group. On the
contrary, the cationic polymer treated group showed similar TBPf
level of control group (Fig. S28D). All these micro-CT analyses
showed that the cDenpols have great bone protection effect in the
RA treatment.
preferentially accumulated in the inflammatory joint of CIA rats.
As a result, the cDenpol inhibited the joint swelling, synovial
hyperplasia and bone destruction in CIA rats. Therefore,
cDenpols could be engineered to bind to cfDNAs and interfere
with the cascade inflammation without significant toxicity with
exquisite control of molecular structure, showing potential for
realizing cDenpols with anti-inflammatory effect for RA treatment.
The cfDNA levels in the serum of rats before and after
treatment were tested (Fig. 4h). At day 28, the cfDNA of CIA rats
in the model group raised dramatically. However, the cfDNA of
control group still showed the similar level at day 13. The 384-G2
and 384-G3 treated groups showed lower cfDNA level. And the
384-G3 showed lowest cfDNA level which is similar to the control
group, consisting with the in vitro DNA binding affinity test. By
monitoring the body weight change of rats (Fig. S29A), the treated
rats showed some body weight loss comparing with the model
group but, at the end of the treatment, rats in 384-G2 group
recovered. Furthermore, the H&E staining of internal organs of
both groups did not show any organ damage (Fig. S29B). Thus,
the in vivo toxicity of both cDenpols is not significant while the
384-G2 could be more biocompatible.
Acknowledgements
Financial support from the Guangdong Innovative and
Entrepreneurial Research Team Program (No. 2013S086),
National Natural Science Foundation of China (Grant No.
21875290, 51403243, 51533009, and 5182010500), International
Postdoctorate Exchange Program, the China Postdoctoral
Science Foundation (Grant No. 2014M552262), and Natural
Science
Foundation
of
Guangdong
Province
(No.
2014A030312018) is gratefully acknowledged.
Keywords: Autoimmune diseases • Cationic Polymer • Cell free
DNA • Dendrimer • Rheumatoid Arthritis
In this report, we describe a strategy applying precisely
tailored PCL-g-PAMAM cDenpols with high affinity to cfDNAs, a
key autoantigen in RA. Effective cfDNA elimination with the
optimized cDenpols not only inhibited the activation of TLR
reporter cell line by artificial DNA but also prevented the activation
of patient-derived primary macrophages by patient-derived
cfDNAs in vitro. Biodistribution study showed the cDenpols with
longer backbone and higher charge density were more
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10.1002/anie.201813362
Angewandte Chemie International Edition
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Screening of cationic dendronized
polymers gave cationic molecular
scavengers, which could eliminate
the cell-free DNAs to inhibit the TLR
recognition and nucleic acid-induced
inflammation.
Bo Peng, Huiyi Liang, Yuyan Li, Cong
Dong, Lixin Liu*, Jun Shen, Hai-Quan
Mao, Kam W. Leong, Yongming Chen
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Tuned Cationic Dendronized
Polymer as a Molecular Scavenger
for Rheumatoid Arthritis Treatment
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