Modular AND Gate-Controlled Delivery Platform for Tumor Microenvironment Specific Activation of Protein Activity

Article abstract of DOI:10.1002/chem.202000219

Protein therapeutics have inspired intensive research interest in a variety of realms. It is still urgently required to avoid premature or unexpected activation of therapeutic proteins to achieve great specificity for therapy. Herein, we reported a modula

Full text of DOI:10.1002/chem.202000219

A Journal of
Accepted Article
Title: Modular AND Gate Controlled Delivery Platform for Tumor
Microenvironment Specific Activation of Protein Activity
Authors: Jinsong Ren, Enguo Ju, Faming Wang, Zhenzhen Wang,
Chaoying Liu, Kai Dong, Fang Pu, and Xiaogang Qu
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To be cited as: Chem. Eur. J. 10.1002/chem.202000219
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10.1002/chem.202000219
Chemistry - A European Journal
COMMUNICATION
Modular AND Gate Controlled Delivery Platform for Tumor
Microenvironment Specific Activation of Protein Activity
Enguo Ju,a Faming Wang,a Zhenzhen Wang,a Chaoying Liu,* b Kai Dong,a Fang Pu,a Jinsong Ren,* a
and Xiaogang Qu a
Abstract: Protein therapeutics has inspired intensive research
interest in a variety of realms. It is still urgently required to avoid
premature or unexpected activation of therapeutic proteins to
achieve great specificity for therapy. Herein, we reported a modular
AND gate-controlled delivery platform for tumor microenvironment
specific activation of therapeutic protein activity based on
biomineralization of molecular glue adhered protein enzyme. The
AND gate integrates the specific microenvironment of tumor tissues
(acidic pH and a certain concentration of ATP) as inputs and
activates the therapeutic activity of protein only when both inputs are
active. More importantly, the activity of therapeutic protein would not
be activated either at acidic pH or in the presence of ATP, which
could greatly avoid the deleterious effect on normal tissues. Besides,
this AND gate can be modular design and suitable for a variety of
therapeutic proteins and nucleic acids.
responsive delivery systems to release the therapeutic protein in
a spatially, temporally and dosage-controlled manner. Typical
biological stimuli include vascular abnormalities, hypoxia, acidic
pH, redox potential, and altered metabolic states.[6] Of these
stimuli, adenosine-5’-triphosphate (ATP) has attracted extensive
attention as the growing evidence of increased levels of ATP in
many pathological processes.[7] It has been reported that
intratumoral ATP concentrations are up to 104 times higher than
those of interstitial ATP in normal tissues.[8] Based on this finding,
DNA aptamers,[9] phenylboronic acid,[10] and metallic complex[11]
have been previously reported to construct ATP-responsive
delivery systems for enhanced therapeutic efficiency. Though
promising, they still face challenges considering the
ubiquity of ATP in plasma and normal tissues. In other words,
even small amounts of ATP could also activate the biological
activity of protein drugs, which would be inevitably deleterious to
normal tissues.
Since the groundbreaking discovery of insulin as the first
recombinant protein in diabetes treatment, protein therapeutics
has inspired intensive research interest in a variety of realms,
including vaccination, cancer therapy, regenerative medicine,
and loss-of-function genetic diseases.[1] Most protein
pharmaceuticals elicit their biological activity by targeting cell
surface ligands or extracellular domains.[2] Nevertheless, the
efficiency of protein therapeutics was limited by the intrinsic
shortcomings of protein including low stability and high
immunogenicity. Their biological activity would be compromised
when they were exposed to a proteolytic environment or
recognized by the host immune system.[3] Additionally, they also
suffered from the lack of capability of targeting disease tissue
with high therapeutic margins of safety while sparing normal
tissue the side effects.[4] Therefore, the development of delivery
systems capable of protecting the active agents from proteolytic
degradation and decreasing the related toxicity to normal tissues
is of great importance.
The aforementioned concerns encourage us to create a
programmable delivery system for activating the biological
activity of the therapeutic protein by ATP in tumors tissues other
than normal tissues or blood. As one of the basic Boolean logic
gate, AND gate can increase the sensing specificity by
integrating multiple signals to identify a specific environment.
Various biomolecules, such as aptamers,[12] deoxyribozyme,[13]
proteins,[14] transcriptional effectors,[15] and nanoenzyme[16] have
been successfully applied for building functional logic AND gates.
Especially, the stepwise logic AND gate can avoid premature or
unexpected activation of therapeutic proteins, which greatly
increases the specificity to improve the therapeutic efficiency
and decrease the side effects.[17] Herein, we reported the
biomineralization of molecular glue adhered enzyme as an
acidic pH “AND” ATP logic gate for selective and controlled
activation of therapeutic protein in the tumor microenvironment.
As shown in Figure 1, the activity of the therapeutic protein
(trypsin as an example in this study) was temporarily
suppressed by molecular glues through multiple salt bridges
between guanidinium ion and oxyanionic groups. The formed
agglomerates were further surface engineered with pH-sensitive
calcium phosphate. Benefiting from unique properties of the
tumor microenvironment, the intrinsic activity could only be
retrieved upon decomposition of CaP shell at acidic pH and
liberation of protein from molecular glue in the presence of ATP
with concentration as much as that in the tumor tissue. More
importantly, the activity of therapeutic protein would not be
activated either at acidic pH or in the presence of ATP, which
could greatly avoid the deleterious effect on normal tissues.
Therefore, the limited control of specificity and efficacy for
protein therapy can be overcome by constructing a logic gate,
which integrates the specific microenvironment of tumor tissue
as inputs and activates the therapeutic activity of protein only in
the tumor tissue. Besides, this AND gate is based on the
multiple salt bridges between guanidinium and oxyanionic
Recently, a number of synthetic nanomaterials, including
liposomes, polymers, and inorganic nanoparticles, have been
designed for affording protein therapeutics with maximized
efficacy and minimized side effects.[5] Especially, exploiting the
physiological and biochemical differences between normal and
pathological conditions allows researchers to elaborate stimuli-
[a]
E. Ju, F. Wang, Z. Wang, K. Dong, F. Pu, Prof. J. Ren, Prof. X.
Qu
Laboratory of Chemical Biology and State Key Laboratory of Rare
Earth Resource Utilization
Changchun Institute of Applied Chemistry
Chinese Academy of Science, Changchun, Jilin 130022, P.R
E-mail: jren@ciac.ac.cn;
E. Ju and F. Wang contribute equally to this work.
C. Liu
[b]
Department of Respiratory Medicine, First Affiliated Hospital,
Jilin University, Changchun 130021, P. R. China
Supporting information for this article is given via a link at the end
of the document.
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10.1002/chem.202000219
Chemistry - A European Journal
COMMUNICATION
Figure 2. (a) Fluorescence titration experiments to measure the binding
affinity between TRP (0.5 μM) and molecular glue. The TRP was labeled
with sulforhodamine B for monitoring the fluorescence changes. (b) The
relationship between fluorescence intensity at 580 nm and the
concentration of molecular glue. (c) Dynamic light scattering measurement
of the size of TRP (0.5 μM) with increased amount of molecular glue(0, 0.5
μM, 1 μM, and 5 μM). (d) Fluorescence intensity of the mixture of
sulforhodamine B-labeled TRP (0.5 μM) and molecular glue (1 μM) with
the titration of ATP. (e) The associate constants between ATP and
TRP/Glue could be calculated from the the fluorescence changes against
ATP concentrations based on competitive binding model.
Figure 1. Schematic illustration of the modulation of therapeutic protein
with molecular glue and ATP. (a) The molecular glue can adhere to the
surface of protein to form aggregates, leading to suppressed enzyme
activity. Addition of ATP leads a competitive binding of ATP to molecular
gel, which liberates the protein and restore its activity. (b) Design of
biomineralized molecular glue adhered protein for acidic pH and ATP dual-
stimuli-responsive activation of therapeutic protein. (c) Construction of AND
gate delivery system for tumor tissue specific protein therapy.
groups, which can be modular design and suitable for many
therapeutic proteins and nucleic acids.
molecular glue could yield bigger agglomerates. We then chose
the ratio of trypsin to molecular glue as 1:2 with a hydrodynamic
size of 60 nm for the following biomineralization.
The molecular glue was firstly synthesized through “thio-
yne” click chemistry between alkyne-appended monomers
containing guanidinium ion and boronic acid units, and a dithiol
monomer[10] (Figure S1-S5). The molecular glue was
incorporated with guanidinium ion and boronic acid. The
cooperated effect of guanidinium ion/phosphate ion salt bridge
and covalently bound boronic acid/1,2-diol can result in a high
affinity of molecular glue toward ATP than protein. The number-
average molecular weight of molecular glue was calculated to be
about 8, 000 by quantification of the thiol termini through
Ellman’s assay. To confirm the molecular glues could adhere to
the surface of trypsin to form agglomerates, we labeled trypsin
with a fluorescence probe sulforhodamine B and conducted
titration experiments with molecular glue. As shown in Figure 2a,
the addition of molecular to trypsin could quench the
fluorescence emission at 580 nm, which was attributed to the
aggregation of trypsin caused by the strong adhesion of
molecular glue with proteins. The association constant for the
binding between molecular glues and trypsin was calculated to
be 1.7 × 106 M-1 by fitting fluorescence changes to the quadratic
equilibrium binding equation (Figure 2b). Dynamic light
scattering measurements revealed the addition of molecular
glue in trypsin could result in increased hydrodynamic sizes,
which further supported that molecular glues could result in the
agglomerates of trypsin (Figure 2c). In addition, more amount of
Subsequently, to demonstrate the molecular glue that
adhered to trypsin could be detached by the competitive
interaction of ATP, we monitored the fluorescence intensity
changes of sulforhodamine B labeled TRP/Glue with the addition
of ATP. As shown in Figure 2d, the fluorescence intensity at 580
nm increased along with the increased concentration of ATP.
This result suggested that the adhesion between trypsin and
molecular glue could be detached by the competitive binding of
ATP. By fitting the dissociation profile to the competitive binding
model, the association constant for molecular glue toward ATP
was determined to be 1.2 × 106 M-1 (Figure 2e). Taken together,
the molecular glues could act as an effective tool for ATP-
responsive modulation of the activity of the enzyme, which
provides a foundation for the construction of programmable
protein delivery for cancer therapy.
To construct pH AND ATP logic controlled therapeutic
protein delivery system, we further biomineralized the molecular
glues adhered enzyme by adding sodium hydrogen phosphate
into the solution containing TRP/Glue (ratio of trypsin and
molecular glue as 1:2) and calcium ions. It is well known that the
carboxyl residues of protein could provide active nucleation sites
for CaP nucleation.[18] Therefore, TRP/Glue could be
incorporated into calcium phosphate during the formation of
nanoparticles to obtain the final product designed as
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Figure 4. (a) Absorbance changes at 405 nm of TRP, and TRP/Glue@CaP
at pH 6.5 in the presence of ATP in Tris-HCl buffer containing BAPNA. The
enzymatic activity can be measured by TRP-catalyzed hydrolysis of BAPNA
to p-nitroaniline, which has
a significant absorbance at 405 nm. (b)
Normalized enzymatic activity of TRP/Glue@CaP at pH 6.5 in the presence
of ATP. (c) Absorbance changes at 405 nm of the TRP/Glue@CaP at pH
6.5 or 7.4 in the absence or presence of ATP in the Tris-HCl buffer
containing BAPNA. (d) Absorbance intensity at 405 nm was recorded for the
AND logic gate. (Inset) truth table for the AND gate.
Figure 3. Characterizations of the TRP/Glue@CaP nanoparticles. (a) TEM
image of the TRP/Glue@CaP. (Inset) the amplified TEM image of the
TRP/Glue@CaP. (b) The energy dispersive X-ray elemental mapping
images of Ca-K, P-K, O-K, N-K, and C-K. (c) The diameter distribution of the
TRP/Glue@CaP measured by DLS.
acidic environment could degrade the CaP shell and
subsequently the presence of ATP could competitively bind with
molecular glue to liberate the trypsin. We also proved that ATP
has no influence on the hydrolytic activity of trypsin (Figure S10).
Besides, TRP/Glue@CaP at pH 6.5 without the addition of ATP
also showed nearly very low hydrolytic activity (Figure 4a). This
result indicated that TRP/Glue exposed very few active sites to
the substrate even CaP was degraded. However, the enzymatic
activity of TRP/Glue@CaP at pH 6.5 gradually recovered with
the addition of ATP. The correlation between the enzyme activity
and concentration of ATP showed a distinct difference of activity
at the ATP concentration of 0.1 μM and 100 μM (Figure 4b).
Considering the concentration of extracellular ATP in tumor
tissue is more than 100 μM while that in normal tissue is less
than 0.1 μM, TRP/Glue@CaP can achieve tumor-specific
targeting activation of the enzyme. Based on the above results,
we designed an AND logic gate that employed acidic pH and
ATP (100 μM) as inputs, and the enzymatic activity of
TRP/Glue@CaP as the output.[19] The signal response after
application of a different combination of inputs was shown in
Figure 4c and 4d. In the absence of both or either of the inputs
(0/0, 0/1, 1/0), enzymatic activity was very low and no increase
absorption at 405 nm was observed. Therefore, TRP/Glue@CaP
remained in an OFF state (output 0). However, in the presence
of both inputs (1/1), the enzymatic activity was activated to a
very high level, which was considered as an ON state (output 1).
This AND gate could increase the sensing specificity towards
tumor microenvironment by integrating two signals, each of
which may be too general to identify the tumor tissue. Moreover,
this platform was based on the multiple salt bridges between
guanidinium and oxyanionic groups, which not only suitable for
proteins but also for nucleic acids. Therefore, TRP/Glue@CaP
can be extended to a broad range of applications such as
sensing, imaging, delivery as well as therapy.
TRP/Glue@CaP. Transmission electron microscopy (TEM)
image revealed that the spherical and uniform morphology of
Trp/Glue@CaP with an average diameter of 110 nm (Figure 3a).
The superficial CaP inorganic materials phase facilitates direct
observation without any staining treatment. Moreover, energy
dispersive X-ray elemental (EDX) mapping images further
demonstrated that Ca, P, O, C, N elements were distributed in
the nanoparticles, which indicated that TRP/Glue was
successfully coated by CaP layer (Figure 3b). The result of the
diameter distribution of Trp/Glue@CaP with a polydispersity
index of 0.104 measured by DLS was also in accordance with
TEM images (Figure 3c). Compared with TRP/Glue, the size
increase was evidently due to the precipitated mineral layer.
Besides, the amount of trypsin in Trp/Glue@CaP was calculated
as 4.2 μM in 1 mg/mL TRP/Glue@CaP (Figure S6). Considering
CaP was a pH-sensitive mineral phase, which was stable in
physiology condition while could be degraded at the acidic
environment. Therefore, the above results indicated that
TRP/Glue@CaP had the potential to be a protein delivery
system for pH and ATP logic controlled activation of therapeutic
effect.
We then examined the protein activity of TRP/Glue@CaP
through a trypsin-catalyzed hydrolysis assay. N-α-benzoyl-DL-
arginine 4-nitroanilide (BAPNA) could be hydrolyzed to p-
nitroaniline by active trypsin, which resulted in the characteristic
absorption at 405 nm increase (Figure S7). TRP/Glue@CaP at
pH 7.4 showed nearly no enzymatic activity, which indicated
CaP shell could greatly protect the protein active site from
contacting its substrate (Figure S8). In addition, no enzymatic
activity of TRP/Glue@CaP at pH 7.4 was observed even in the
presence of ATP. As CaP shell was pH-sensitive, the enzymatic
activity of TRP/Glue@CaP in the presence of ATP (100 μM) was
dependent on pH (Figure S9). We assumed the process as that
Finally, to demonstrate the potential of pH and ATP logic
controlled therapeutic protein delivery as an approach for
specific tumor therapy, the capability of TRP/Glue@CaP to
selectively inhibit tumor cell proliferation was studied. It has
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10.1002/chem.202000219
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COMMUNICATION
Keywords: protein therapy • logic gate • molecular glue•
biomineralization • drug delivery
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Acknowledgements
This study was supported by the Natural Science Foundation of
China (grant nos. 21820102009, 21871249, 21533008, and
91856205,) and the Key Program of Frontier of Sciences (CAS
QYZDJ-SSW-SLH052).
Conflict of Interest
The authors declare no conflict of interest.
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COMMUNICATION
COMMUNICATION
Enguo Ju, Faming Wang, Zhenzhen
Wang, Chaoying Liu, * Kai Dong, Fang
Pu, Jinsong Ren,* and Xiaogang Qu
Page No. – Page No.
Modular
Delivery
AND
Platform
Gate
Controlled
Tumor
for
Microenvironment Specific Activation
of Protein Activity
A modular AND gate-controlled delivery platform for tumor microenvironment
specific activation of therapeutic protein activity was constructed based on
biomineralization and molecular glue, which greatly increase the specificity and
efficiency of protein therapy.
This article is protected by copyright. All rights reserved.