Chain-shattering polymeric therapeutics with on-demand drug-release capability

Article abstract of DOI:10.1002/anie.201300497

Trigger happy: Trigger-responsive chain-shattering polymeric therapeutics (CSPTs) were prepared by condensation polymerization of a UV- or hydrogen peroxide-responsive domain and a drug as co-monomers. Drug release can be started and stopped by starting and stopping the trigger treatment. Chemotherapeutic-containing CSPTs showed trigger-responsive in vitro and in vivo antitumor efficacy. Copyright

Full text of DOI:10.1002/anie.201300497

Angewandte
Chemie
DOI: 10.1002/anie.201300497
Polymer–Drug Conjugates
Chain-Shattering Polymeric Therapeutics with
On-Demand Drug-Release Capability**
Yanfeng Zhang, Qian Yin, Lichen Yin, Liang Ma, Li Tang, and Jianjun Cheng*
Polymer–drug conjugates are an important polymeric ther-
apeutic (PT) platform[1] with drug molecules being attached
by cleavable linkages to the pendant functional groups of
linear, branched, brushed polymers[2] that are typically
synthesized prior to drug conjugation.[3] The synthesis and
conjugation processes developed to date, however, may not
provide precise control over the composition and the
structure of the conjugates.[4] When a polymer with a large
number of conjugation-amenable, functional side groups is
used, for example, the site of conjugation usually cannot be
controlled.[5] As such, batch-to-batch variations of
drug loading and release profiles are often observed
with polymer–drug conjugates, and these variations
may present a key bottleneck to the clinical trans-
lation of PTs.[6]
resulting PT would have specific repeating units, and there-
fore specific molecular structure and composition. Drug
release would be precisely controlled by the TRD. Applica-
tion of an external trigger would activate the TRD, which
would subsequently induce a chain-shattering type of degra-
dation of the polymer and release of the neighboring drug
molecules (Scheme 1). Herein, we report the use of this
approach for the design of chain-shattering polymeric ther-
apeutics (CSPTs) and demonstrate the trigger-induced anti-
cancer activity of CSPTs in vitro and in vivo.
To address these challenges, we recently
reported drug-initiated ring-opening polymeri-
zation of lactide and other cyclic esters in the
presence of a zinc catalyst, a technique that can
Scheme 1. Chain-shattering polymeric therapeutics.
provide excellent control over drug loading.[7]
Hydroxy-group-containing drugs are conjugated to
polyesters or polycarbonates by an ester linkage, and drug
loading can be controlled by tuning the monomer/initiator
ratio. Although this technique provides excellent control over
drug loading and affords polymer–drug conjugates with
controlled structures and compositions, the ability to control
drug release from the resulting conjugates is limited: drug
molecules are released by means of hydrolysis or enzymatic
cleavage of the ester linkage.[7a] Incorporating a linker that
allows trigger-responsive, active release of the terminally
conjugated drug remains synthetically challenging.
To develop a new PT with precise control over both drug
loading and release, we attempted to incorporate a trigger-
responsive domain (TRD) into PTs, aiming to achieve
a specific PT structure and to use the TRD to precisely
control drug release. One feasible approach would be using
multiple drug and TRD molecules as monomers to construct
an A/B (TRD/drug) type of condensation polymer. The
The TRD needs to meet two requirements. First, it should
be difunctional and allow for the formation of TRD–drug
linkages that are stable under untreated conditions but
instantly become unstable when the trigger is applied.
Second, the TRD–drug linkage should degrade rapidly on
both sides of the TRD to facilitate chain-shattering type of
depolymerization and release of drug molecules in their
original form. Because (4-aminophenyl)methanol has been
used in the design of trigger-responsive carbonate or urethane
linkages that can release the conjugated drug molecules by
a 1,6-elimination reaction once the protecting group is
removed from the aniline moiety (Scheme 2a), we reasoned
that 2,6-bis(hydroxymethyl)aniline (1, Scheme 2b)[8] would
likely be condensed with a diol drug to form a PTwith trigger-
responsive carbonate bonds. Once the protecting group was
removed from 1, the PT (two repeating units shown in
Scheme 2b) should undergo a 1,4-elimination followed by
a 1,8-elimination, leading to chain shattering and the release
of the constituent drug molecules.
To determine whether 1 underwent the anticipated
elimination reactions, we prepared CPT-1a-CPT (Sche-
me 2c), a conjugate consisting of 1 protected with a UV-
sensitive O-nitrobenzyloxy-l-carbonyl group and attached to
two camptothecin (CPT) molecules by carbonate linkages
(Scheme 2c, Figure S7 and S8). When CPT-1a-CPT was
dissolved in acetonitrile/water (9:1, v/v), CPT release was
found to be negligible. However, when the conjugate solution
was irradiated with UV light (365 nm, 40 mWcmÀ2) for only
2 min, more than 93 Æ5% of CPT was released (Figure 1a
[*] Y. Zhang, Q. Yin, L. Yin, L. Ma, L. Tang, Prof. Dr. J. Cheng
Department of Materials Science and Engineering, University of
Illinois at Urbana-Champaign
1304 West Green Street, Urbana, IL, 61801 (USA)
E-mail: jianjunc@illinois.edu
[**] This work is supported by Dow Chemical Company. We thank Dr.
Liang Hong and Dr. Keith Harris for helpful discussion. Q.Y. was
funded at UIUC from NIH National Cancer Institute Alliance for
Nanotechnology in Cancer “Midwest Cancer Nanotechnology
Training Center” Grant R25 CA154015A.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300497.
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UV light for just 2 min, 40% of the
HCPT was burst-released in its original
form (Figure 1c, S12, and S13). Up to
92% of HCPTwas released from CSPT-
(1a/HCPT) when the CSPT(1a/HCPT)
solution was exposed to UV light for an
additional 13 min. The drastic decrease
in the Mn of CSPT(1a/HCPT) and the
rapid release of HCPT suggested that
the polymer was degraded by means of
a chain-shattering mechanism.
Degradation of the CSPT(1a/
HCPT) backbone should occur only at
1a residues from which the O-nitro-
benzyloxyl-1-carbonyl protecting group
has been removed. Once the UV irradi-
ation is stopped, depletion of the pro-
tecting group should also stop immedi-
ately, resulting in a pause in backbone
degradation and HCPT release. The
degradation and release should not
resume until the trigger (UV light) is
reapplied. To verify this expected
release behavior, we monitored the
release of HCPT from CSPT(1a/
HCPT) in DMF/water (9:1, v/v) in
response to periodic UV irradiation.
As expected, when irradiation was
turned on for 1 min and then off for
60 min, pulsatile release of HCPT was
observed during the 1 min UV-on peri-
ods, and minimal drug release was
observed during the 60 min UV-off
periods (Figure 1d). This pulsatile
HCPT release pattern in response to
periodic UV irradiation further substan-
tiates the remarkable responsiveness of
this class of CSPT.
Scheme 2. a) Degradation of (4-aminophenyl)methanol carbonates and carbamates. b) Degrada-
tion of 2,6-bis(hydroxymethyl)aniline (1) carbonate units in a CSPT by 1,4- and 1,8-elimination
reactions (two repeating units shown in the scheme). c) Synthesis of UV-responsive model drug
conjugate CPT-1a-CPT.
Because the amine group is another
and S10), substantiating the expected 1,4- and 1,8-elimination
reactions and the feasibility of using 1 and related analogues
for the design of CSPTs.
common functional group amenable to conjugation in natural
product-based therapeutics, we next determined whether we
could apply the CSPT design strategy to amine-containing
therapeutics. We selected 9-aminocamptothecin (ACPT) as
the monomer for the synthesis of CSPT(1a/ACPT), and
studied its UV responsiveness (Scheme 3, Figure S5, S15, and
S16). ACPT was incorporated to the CSPT(1a/ACPT) back-
bone by one carbonate bond and one urethane bond. The UV
responsiveness of and drug release from CSPT(1a/ACPT)
were similar to those of CSPT(1a/HCPT) in DMF/water (9:1,
v/v; Figure 1c,d, S14, and S15). Without UV irradiation,
ACPT was released from CSPT(1a/ACPT) very slowly (Fig-
ure 1c). In contrast, when CSPT(1a/ACPT) was irradiated
with UV light (365 nm, 40 mWcmÀ2) for 2 min, 30% of the
ACPT underwent burst release. Up to 88% of ACPT was
released when the CSPT(1a/ACPT) solution was exposed to
UV light for 15 min (Figure 1c). A pulsatile ACPT release
pattern was also observed in response to periodic UV
irradiation (Figure 1d).
We used 10-hydroxycamptothecin (HCPT) as a model
diol drug and synthesized CSPT(1a/HCPT) with a molecular
weight (Mn) of 4200 gmolÀ1 and a polydispersity index (PDI)
of 1.48 through condensation polymerization (Scheme 3a).
To study its UV-triggered degradation, we monitored the
change of its Mn value in dimethylformamide (DMF) by
means of gel permeation chromatography (GPC). In the
absence of UV irradiation, the Mn of CSPT(1a/HCPT)
remained unchanged in DMF over a long period of time. In
contrast, when CSPT(1a/HCPT) was irradiated with UV light
(365 nm, 40 mWcmÀ2) for 20 min, its Mn changed drastically
(from 4200 to 800 gmolÀ1), and CSPT(1a/HCPT) was almost
completely degraded (Figure 1b). We then investigated the
release of HCPT from CSPT(1a/HCPT) in DMF/water (9:1,
v/v). Without UV irradiation, the proportion of HCPT
released from CSPT(1a/HCPT) was negligible (Figure 1c).
In comparison, when CSPT(1a/HCPT) was irradiated with
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Figure 2. a) Preparation of CSPT/PEL NPs by nanoprecipitation, dis-
assembly of the NPs in response to trigger-induced CSPT degradation,
and drug release from the NPs. b) Release of HCPT and ACPT from
CSPT(1a/HCPT)/PEL and CSPT(1a/ACPT)/PEL NPs, respectively, with
continuous UV irradiation (+UV) or without UV (ÀUV) irradiation.
c) Pulsatile release of HCPT and ACPT from CSPT(1a/HCPT)/PEL and
CSPT(1a/ACPT)/PEL NPs in response to periodic UV irradiation for
1 min every 60 min.
Figure 1. a) Release of CPT from CPT-1a-CPT with or without UV
irradiation. b) Gel permeation chromatographic analysis of CSPT(1a/
HCPT) 1) before and 2) after UV irradiation (365 nm, 40 mWcmÀ2
,
20 min). c) Release of HCPT and ACPT from CSPT(1a/HCPT) and
CSPT(1a/ACPT), respectively, with continuous UV irradiation (+UV)
for 15 min or without UV irradiation (ÀUV). d) Pulsatile release of
HCPT and ACPT from CSPT(1a/HCPT) and CSPT(1a/
ACPT), respectively, in response to periodic UV irradiation
for 1 min every 60 min.
We next determined whether other triggers
could be used to control the degradation of CSPTs
and the release of the constituent drug molecules.
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)benzyl-(2,6-bis(hydroxylmethyl)phenyl)carba-
mate (1b, Scheme 3), an analogue of 1 with
a redox-sensitive protecting group, was synthe-
sized and co-condensed with ACPT (Figure S6).
CSPT(1b/ACPT) showed the expected H2O2-
triggered degradation and rapid ACPT release in
DMF/water (9:1, v/v; Scheme S9, Figure S17 and
S18).
We further investigated whether CSPTs could
be used for formulation of nanoparticle (NP)-
based delivery systems with on-demand release
profiles. By co-precipitating CSPTs with poly(eth-
ylene glycol)-block-poly(l-lactide) (PEG113-b-
PLLA18 or PEL) in water (Figure 2a), we
obtained the CSPTs/PEL NPs with diameter
below 150 nm, very high drug loading (over
48 wt%) and very high loading efficiency (over
92%) (Table S1). CSPTs/PEL NPs showed appro-
priate particle size and drug loading for drug
delivery applications. On the contrary, CPT,
HCPT, ACPT, and CPT-1a-CPT loaded NPs
prepared similarly by co-precipitating with PEL degradation and release of drugs from UV-responsive CSPTs upon UV irradiation.
Scheme 3. a) Synthesis of UV- and H2O2-responsive CSPTs. b) Proposed chain-shattering
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in water afforded particles with very large
particle size (over 1 mm), low drug loading
and very low loading efficiency (under
10%; Table S1). CSPT(1a/HCPT)/PEL
NPs showed excellent responsiveness to
triggered-induced drug release. Without
UV irradiation, the proportion of HCPT
released from the NPs in phosphate buf-
fered saline (PBS) solution was nearly
negligible (Figure 2b). However, when the
NPs were irradiated with UV light for
10 min, 59% of the HCPT was released
(Figure 2b). Pulsatile release of HCPT
from CSPT(1a/HCPT)/PEL NPs was also
observed with periodic UV irradiation
(Figure 2c). UV-responsive CSPT(1a/
ACPT)/PEL NPs were similarly prepared,
and they also showed burst release and
pulsatile release of ACPT in response to
UV irradiation (Figure 2b,c).
We evaluated the cytotoxicity of
CSPTs/PEL NPs using microculture tetra-
zolium (MTT, MTT= 3-(4,5-dimethylthia-
zol-2-yl)-2,5-diphenyltetrazolium
bro-
mide)) assay. Without UV treatment,
CSPT(1a/HCPT)/PEL and CSPT(1a/
ACPT)/PEL NPs showed low cytotoxicity
in HeLa cells with IC50 values of 1230 nm
and 1687 nm respectively (Figure 3a, b).
Upon UV treatment, the IC50 values
decreased substantially to 97 nm and
109 nm for CSPT(1a/HCPT)/PEL and
CSPT(1a/ACPT)/PEL NPs, respectively,
suggesting that the cytotoxicity of CSPTs/
PEL NPs can be well controlled by external
stimulations. Similarly, CSPT(1b/ACPT)/
PEL NPs showed significantly higher cyto-
toxicity in the presence of H2O2 (IC50 =
113 nm) than the untreated CSPT(1b/
ACPT)/PEL NPs (IC50 = 1436 nm) (Fig-
ure 3a,b). Degradation species from the
control polymer (poly(1a/3), Scheme S7)
without anticancer drugs showed negligible
cytotoxicity to the same cell lines (Fig-
ure S20).
Figure 3. a, b) Cytotoxicity of CSPTs/PEL NPs in HeLa cells. Triggering conditions: UV
treatment (360 nm, 20 mWcmÀ2, 10 min) for CSPT(1a/HCPT)/PEL NPs and CSPT(1a/
ACPT)/PEL NPs; H2O2 treatment (1 mm) for CSPT(1b/ACPT)/PEL NPs. The half maximal
inhibitory concentration (IC50) values were determined by half-cell viability concentration
from the MTT assay and summarized in the Table. c,d) BALB/c mice bearing subcutaneous
4T1 tumors received a single intratumoral injection of phosphate buffered saline (PBS),
H2O2, ACPT or CSPT(1b/ACPT)/PEL NPs (0.5 mg ACPT equiv/tumor) with or without H2O2
(10 mm, 100 mL/tumor). H2O2 was administered intratumorally 1 h after the injection of
CSPT(1b/ACPT)/PEL NPs. The mice were sacrificed 48 h post injection. The 4T1 tumors
were collected, sectioned, and stained with deoxynucleotidyl transferase-mediated deoxyur-
idine triphosphate nick end (TUNEL) for apoptosis analysis. Representative images (c) and
quantification by ImageJ (d) of TUNEL stains are shown. Scale bar: 50 mm. The apoptosis
index was determined as the ratio of apoptotic cell number (TUNEL, green) to the total cell
number (4’,6-diamidino-2-phenylindole (DAPI), blue) (20 tissue sections were counted per
tumor; n=4; data are represented as average ÆSEM and analyzed by One-way ANOVA
(Fisher) (*p<0.05; n.s.=not significant)).
To further demonstrate the therapeutic
efficacy of the CSPTs in vivo, we evaluated
the triggered cell apoptosis in subcutaneous
4T1 tumors in BALB/c mice treated with the CSPTs/PEL NPs
(Figure 3c,d; Figure S21). Tumors that were treated with
CSPT(1b/ACPT)/PEL NPs intratumorally then treated with
H2O2 showed 2.5-fold higher apoptosis index (69.6 Æ 5.0%)
compared to a control group without H2O2 treatment (27.3 Æ
2.7%). To exclude the possibility that cell apoptosis were
induced by H2O2, mice were treated intratumorally with H2O2
(10 mm, 100 mL/tumor) alone; no significant cell apoptosis
(with apoptosis index of 18.3 Æ 1.7%) was observed as
compared to PBS (1 ꢀ , 100 mL) negative control group
(with apoptosis index of 15.2 Æ 4.8%; Figure 3c,d). Therefore,
the trigger-responsive CSPT(1b/ACPT)/PEL NPs markedly
improved the antitumor efficacy by inducing higher apoptosis
index in tumors with elevated level of reactive oxygen species,
including H2O2, which is one of the characteristics of tumor
tissues.[9]
The development of PTs for personalized medicine
requires precise control over drug release; the payload ideally
is retained in the delivery vehicle during circulation, tissue
distribution, and cellular trafficking processes and then burst
released when the delivery vehicle reaches the target cells or
intracellular compartments. In this study, we designed 2,6-
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periodically applied triggers. The trigger-responsive cytotox-
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strated by applying external stimulations. This class of CSPTs
showed unprecedented, active control over drug release and
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Received: January 20, 2013
Revised: February 19, 2013
Published online: May 6, 2013
Keywords: cancer therapy · controlled release · polymer–
.
drug conjugate · polymers · trigger-responsive polymer
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