Redox-responsive tetraphenylethylene-buried crosslinked vesicles for enhanced drug loading and efficient drug delivery monitoring

Article abstract of DOI:10.1039/c9tb01639b

Liposomes have been applied extensively as nanocarriers in the clinic (e.g., to deliver anticancer drugs) due to their biocompatibility and internal cavity structures. However, their low drug-loading capacity (DLC; <10%) and uncontrolled release reduce th

Full text of DOI:10.1039/c9tb01639b

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Redox-responsive tetraphenylethylene-buried
crosslinked vesicles for enhanced drug loading
and efficient drug delivery monitoring†
Cite this: J. Mater. Chem. B, 2019,
7, 7540
Yunlong Yu,a Yun Chen,a Jingsheng Huang,a Liang Wang,a Zhongwei Gub and
a
Shiyong Zhang
*
Liposomes have been applied extensively as nanocarriers in the clinic (e.g., to deliver anticancer drugs)
due to their biocompatibility and internal cavity structures. However, their low drug-loading capacity
(DLC; o10%) and uncontrolled release reduce their efficacy in cancer treatment. To improve the DLC
and monitor release of drugs in cells in real-time, stimuli-responsive vesicles must be developed. We
present various amphiphilic tetraphenylethylene (TPE)-containing compounds designed to self-assemble
into liposome-like vesicles that can load both hydrophilic and hydrophobic drugs. The highest DLC for
doxorubicin (DOX) was r26% for vesicles (diameter = 105 nm) that could encapsulate hydrophilic DOX
in the interior water pool and hydrophobic DOX via p–p stacking interactions between DOX and the TPE
moiety. The stable vesicles could respond rapidly to overexpressed glutathione in the tumor micro-
environment to release loaded DOX for cancer therapy. Vesicles modified by active targeting groups
showed more efficacious tumor treatment compared with unmodified vesicles and free DOX in vitro
and in vivo. Simultaneously we observed, spatiotemporally, the subcellular location of the delivery
system and release process of DOX. Our work provides a novel nano-engineering technology to integrate
the desired properties for anticancer theranostics: high DLC, stability, stimuli-responsiveness to the cancer
environment, drug-delivery monitoring, active targeting, and suppression of tumor growth. These novel
vesicles could be employed as multifunctional drug-delivery systems for cancer therapy.
Received 3rd August 2019,
Accepted 25th October 2019
DOI: 10.1039/c9tb01639b
rsc.li/materials-b
monitor in real-time drug release during delivery.10 In addition, the
uncontrolled release of liposomes may also cause toxicity to normal
1. Introduction
Driven by developments in nanotechnology in recent decades, cells and even induce drug resistance.11 Therefore, designing
there have been great breakthroughs in biomedical treatment stimuli-responsive liposome-like nanocarrier systems for enhancing
for the simultaneous diagnosis and therapy of cancers or other therapeutic drug loading, controlled release, and monitoring drug
diseases.1–3 Notably, nano-based drug-delivery vesicles have localization and the process of release is important.
been applied to deliver various components due to the existence
Fluorescent dyes have been applied extensively for opto-
of specific structures.2,4,5 Thus, they play crucial parts in theranostic electronics, cell imaging, diagnostic sensors, and targeted drug
applications. Liposome vesicles with lipid bilayer-like structures delivery.12–14 However, luminescence can be quenched by the
have been approved as doxorubicin (DOX) carriers in anticancer integration or encapsulation of fluorescent dyes in nanostruc-
treatment to reduce the toxicity of the free drug in vivo, and include tures because of the notorious aggregation-caused quenching
Doxil/Caelyx, DaunoXome, Myocet and EVACET.6,7 However, as (ACQ) effect.15 To overcome these drawbacks, aggregation-
reported, the low drug-loading capacity (o10%) restricts the drug induced emission (AIE) molecules have been employed for
content and true therapeutic effect considerably.8,9 Moreover, with biosensing and bioimaging due to their special ability to aggre-
liposomes, just as vehicles carrying hydrophilic drugs, one cannot gate and luminesce.12,16,17 If they are well dispersed, only weak
luminescence can be obtained. Once aggregation occurs or a
a National Engineering Research Center for Biomaterials, College of Chemistry,
Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
E-mail: szhang@scu.edu.cn; Fax: +86-28-85411109; Tel: +86-28-85411109
b College of Materials Science and Engineering, Nanjing Tech University,
Nanjing, Jiangsu 210009, China
solid state is formed, high emission occurs. As reported pre-
viously, AIE materials show great potential application in cell
imaging and disease detection.17,18 For example, Liang et al.18
directly mixed AIE molecules with DOX to form nanoparticles
(NPs) for drug-delivery monitoring and cancer treatment. How-
ever, the NP morphology was determined by the DOX molar ratio
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9tb01639b
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Scheme 1 Preparation of DOX@TPE@CLVs I–III and T-DOX@TPE@CLVs III for efficacious anticancer therapy (schematic).
so that only a small DOX loading content (10%) would be
achieved. Our research team has long-term experience of the
2. Results and discussion
design and synthesis of crosslinked small-molecule vesicles, The synthetic details of tetraphenylethylene-buried amphi-
which contain hydrophilic water pools and hydrophobic philes 1–3 are described in ESI.† After self-assembly in water,
bilayers and have great potential to improve the drug-loading vesicles were formed directly. As shown in Fig. 1, the hydro-
capacity.19–21 Also, these vesicles can be designed with func- dynamic sizes of TPE@LVs I–III vesicles varied from 58 nm to
tional groups for control of sizes, zeta potential, cell targets and 105 nm with extension of the alkyl length, which was detected
stimulus response to tumor microenvironments. Therefore, our by dynamic light scattering (DLS). Notably, the sizes from
small-molecule vesicles hold great potential to work as drug- transmission electron microscopy (TEM) were smaller than
delivery systems for cancer therapy.
obtained by DLS because the vesicles shrank after being dried
We report the synthesis of a series of amphiphilic tetraphenyl- for TEM. The vesicle structures of TPE@LVs I–III were con-
ethylene (TPE)-buried compounds 1–3 which can self-assemble into firmed by an assay measuring carboxyfluorescein (CF) leakage
different-sized vesicles TPE@LVs I, II and III (58, 78 and 105 nm, (Fig. S2, ESI†). Due to their lipid bilayer-like structure, the
respectively) (Scheme 1). The new drug-delivery system could vesicles could encapsulate hydrophilic drugs in the hydrophilic
encapsulate hydrophilic and hydrophobic DOX by hydrophilic water pool and hydrophobic drugs in the hydrophobic shell
cavities and hydrophobic bilayers via p–p stacking. The highest layer. Here, we used hydrophilic DOX and deacidified DOX
drug-loading content (DLC) could be r26% using TPE@LVs III. (hydrophobic) as drug models. TPE@LVs I–III vesicles could
After crosslinking, the resulting DOX@TPE@CLVs III displayed deliver both types of DOX simultaneously. As shown in Fig. 1e,
good stability in various environments and during long circulation the DLC increased from 21% to 26% along with different sizes
times in blood. Being responsive to the tumor microenvironment, via p–p stacking interactions between DOX and the TPE
the vesicles could be broken to release the encapsulated DOX. After moiety;18 the DLC was much higher than that of general
modification with active targeting glucose, T-DOX@TPE@CLVs III liposomes (o10%). The encapsulation efficiency (EE) increased
showed good targeting and chemotherapy to suppress the growth from 77% to 87% for the three vesicles. As reported, NP sizes of
of HepG2 cancer cells in vitro and in vivo. As an ideal nano- B100 nm have the lowest plasma clearance rate and long
platform, utilization of the vesicles also enabled real-time monitor- circulation lifetimes.8 For subsequent experiments, we selected
ing of drug localization during the entire process of drug delivery. TPE@LVs III vesicle as an optimal nanocarrier due to the
Therefore, a smart redox-responsive drug-delivery system was highest DLC achieved and potential longest circulation time.
fabricated for fluorescent vesicles which could provide new oppor-
Crosslinking is a reliable strategy to stabilize nanocarriers for
tunities for delivery of chemotherapeutic agents for multifunctional drug delivery. Here, linker 4 was used as a crosslinker to covalently
applications in the clinic.
bond the vesicles (TPE@CLVs III) to enhance the stability.
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Fig. 1 Characterization of the self-assembly of TPE-buried amphiphile 1–3 in water. (a) Distribution of the hydrodynamic diameters of compound 1–3-
fabricated TPE@LVs I–III in water, respectively. (b–d) TEM images of TPE@LVs I–III in sequence. (e) The drug-loading content (DLC) and encapsulation
efficiency (EE) of nanoparticles TPE@LVs I–III to load DOX are summarized in the table.
After crosslinking, the size and spherical morphology of the measured on the vesicles changed from positive to approximately
vesicles did not change much, as observed from DLS and TEM in neutral after crosslinking, which provided further evidence of the
Fig. 2a. Proton nuclear magnetic resonance (1H NMR) spectroscopy formation of TPE@CLVs III. The low zeta potential worked aided
before and after crosslinking (Fig. S3, ESI†) showed that the long circulation times because it reduced the clearance by macro-
characteristic peak of acrylate at 6.0–6.8 ppm disappeared, indicating phages in blood during drug delivery. The dilution and FBS stability
successful conjugation with linker 4 (0.5 equiv.). The zeta potential of TPE@CLVs III was evaluated using uncrosslinked (TPE@LVs)
Fig. 2 Physicochemical properties of crosslinked TPE@CLVs III. (a) DLS and TEM of TPE@CLVs III. (b) Zeta potentials of uncrosslinked TPE@LVs III
and crosslinked TPE@CLVs III. (c) Particle sizes of TPE@LVs III and TPE@CLVs III after incubation with 10% FBS at 37 1C over time ([3] = 200 mg mLÀ1).
(d) Particle sizes of TPE@LVs III and TPE@CLVs III at various dilutions at 37 1C.
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Fig. 3 (a) UV-vis absorption spectra of free DOX and DOX@TPE@CLVs III. (b) Fluorescence spectra of DOX@TPE@CLVs III and UV-vis absorption spectra
of free DOX. (c) Fluorescence spectra of free DOX, TPE@CLVs III and DOX@TPE@CLVs III (TPE lex = 373 nm, DOX lex = 480 nm, [TPE] = 50 mM, [DOX] =
10 mg mLÀ1).
as a comparison (Fig. 2c and d). The dimension of TPE@CLVs time (Fig. S4, ESI†). Therefore, DOX@TPE@CLVs III could be
was unchanged even at a concentration below the critical vesicle applied to realize real-time monitoring of the localization and
concentration (CVC) whereas TPE@LVs disassembled during release of drugs upon internalization into cancer cells.
dilution. TPE@CLVs also showed good stability in 10% FBS
Next, the stimuli-responsive release of DOX@TPE@CLVs III
for Z24 h.
was evaluated under various environments (Fig. 4). At pH = 7.4,
To characterize the interior composition of TPE@LVs III there was only 19% release of DOX, and a slight increase in
vesicles, fluorescence spectroscopy and UV-vis absorption DOX release at pH = 5.0, which might have occurred because
spectroscopy were undertaken to explore the p–p interactions the acidic environment changed part of the hydrophobic DOX
between DOX and TPE.11,18 An absorption peak at 480 nm for to acidified DOX (hydrophilic). Only in the presence of gluta-
free DOX in water was noted (Fig. 3a). After encapsulation in thione (GSH) could 460% of DOX be released in 35 h, whereas
crosslinked vesicles, the formed DOX@TPE@CLVs III showed 80% release could be achieved under acidic conditions. The
a red shift of the absorption peak to 506 nm, which was DOX@TPE@CLVs III system was designed to respond to the over-
attributed to the ground-state electron donor–electron acceptor expressed GSH (2–10 mM) in the tumor microenvironment.22,23
interaction and p–p stacking between TPE and DOX.18 The Thus, redox-labile DOX@TPE@CLVs III could be broken down by
overlap of the emission spectrum of TPE and the absorption removal of disulfide bonds by GSH to release the loaded DOX.
¨
spectrum of DOX (Fig. 3b) indicated a Forster resonance energy Vesicle damage could be detected through size variation by DLS
transfer (FRET) effect. After loading DOX in TPE@CLVs III, the (Fig. 4b). These results implied that DOX@TPE@CLVs III were
emission of DOX@TPE@CLVs III decreased markedly at practical and favorable for stimuli-responsive release of anti-
475 nm and 556 nm compared with that of TPE@LVs III and cancer drugs in vitro.
free DOX respectively due to the FRET effect and self-quenching
For efficacious anticancer treatment, specific targeting of
of DOX aggregation.18 However, once DOX had been released tumor cells is important.20,24,25 Here, DOX@TPE@CLVs III was
from the vesicles, TPE fluorescence recovered gradually with modified with 20 mol% glucose by a one-step reaction with
Fig. 4 (a) In vitro DOX release of crosslinked DOX@TPE@CLVs III at pH = 7.4 (PBS buffer) and pH = 5.0 (acetate buffer) at 37 1C over time. (b) Variation in
particle size of TPE@CLVs III before and after incubation at pH = 5.0 (acetate buffer) and 10 mM glutathione (GSH) at 37 1C.
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Fig. 5 (a) Viability of HepG2 liver cells after incubation with free DOXÁHCl, DOX@TPE@CLVs III or T-DOX@TPE@CLVs III for 24 h at 37 1C at a series
of concentrations (mean Æ SD, n = 5, P1* o 0.05, P2* o 0.05). (b) Quantification of cellular uptake of free DOXÁHCl, DOX@TPE@CLVs III and
T-DOX@TPE@CLVs III after incubation for 3 h ([DOX] = 2 mM) by flow cytometry.
carboxylic-acid groups on vesicles to form T-DOX@TPE@CLVs III.
To observe the subcellular locations of the drug-delivery system
To evaluate cytotoxicity in vitro, free DOXÁHCl, DOX@TPE@CLVs directly, TPE@CLVs III, free DOXÁHCl, DOX@TPE@CLVs III and
III and T-DOX@TPE@CLVs III were incubated separately with T-DOX@TPE@CLVs III were incubated with HepG2 cells for 3, 6
HepG2 liver cancer cells and the Cell Counting Kit (CCK)-8 assay and 12 h, respectively, and observed by confocal laser scanning
carried out (Fig. 5a). After 24 h of treatment, the half-maximal microscopy. Blue fluorescence (480 nm) was attributed to the
inhibitory concentration (IC50) of DOX@TPE@CLVs III was TPE moiety and red fluorescence (576 nm) to DOX molecules
15.35 mg mLÀ1, which was higher than that of free DOXÁHCl (Fig. 6). Free DOXÁHCl could enter cells through diffusion, and
(4.74 mg mLÀ1). The zeta potential for TPE@CLVs III was low strong fluorescence was observed in nuclei after incubation
(Fig. 2), which could affect the endocytosis of cells. Free DOX with HepG2 cells for 6 h. TPE@CLVs III was present only in
could diffuse rapidly into cancer cells to kill them. Encouragingly, the cytoplasm even after 12 h incubation. For DOX@TPE@
for T-DOX@TPE@CLVs III, a low IC50 could be obtained, CLVs III and T-DOX@TPE@CLVs III, weak fluorescence
3.21 mg mLÀ1, which was even lower than that for free DOX. appeared after 3 h incubation with HepG2 cells due to ACQ
T-DOX@TPE@CLVs III could target and enter cells effectively. and the FRET effect. After incubation time for 6 and 12 h,
After the response to GSH and in acidic environment, the vesicles the fluorescence from TPE and DOX recovered gradually as a
ruptured to release DOX to cause cytotoxicity. Subsequently, flow result of the disassembly of NP structure to release DOX.
cytometry was applied to estimate the intracellular DOX concen- T-DOX@TPE@CLVs III could enter cells faster than DOX@
tration after cell uptake. As shown in Fig. 5b, the T-DOX@TPE@ TPE@CLVs III for specific active targeting. In particular, 12 h
CLVs III was more efficient in delivering DOX molecules into cells after incubation, T-DOX@TPE@CLVs III showed stronger fluores-
compared with DOX@TPE@CLVs III, data that were consistent with cence because more DOX was released and entered the cytoplasm
the results of cytotoxicity testing.
and nuclei. These results suggested that this nanocarrier could be
Fig. 6 CLSM images of HepG2 cells treated with free DOXÁHCl, TPE@CLVs III, DOX@TPE@CLVs III or T-DOX@TPE@CLVs III for 3, 6, or 12 h. For each
panel, the fluorescence of TPE in cells (blue), fluorescence of DOX in cells (red) and merged fluorescence (pink) are shown. Scale bar = 10 mm ([DOX] =
4 mM, [1] = 11.6 mM).
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Fig. 7 Ex vivo fluorescence images showing the pharmacokinetics of DOXÁHCl, DOX@TPE@CLVs III and T-DOX@TPE@CLVs III. (a) Pharmacokinetic
profiles after intravenous injection of samples in BALB/c mice (5 mg per kg bodyweight). (b) Ex vivo fluorescence images of tissues of HepG2 tumor-
bearing nude mice 12 h after intravenous injection of DOXÁHCl, DOX@TPE@CLVs III or T-DOX@TPE@CLVs III, respectively. (c) Quantitative analyses of
the fluorescence intensity of tissues 12 h after injection, respectively (mean Æ SD, n = 3).
applied to monitor the entire process of drug release for a drug- As shown in Fig. 8a, the volume of the tumor region on
delivery system.
T-DOX@TPE@CLVs III-treated mice showed much slower
Furthermore, pharmacokinetic investigation in vivo was growth than that for saline (B9.9 Æ 0.3 fold)-, free DOXÁHCl
conducted using BALB/c mice bearing HepG2 solid tumors. (B7.2 Æ 0.4 fold)- and DOX@TPE@CLVs III (B1.5 Æ 0.4 fold)-
After intravenous injection of DOXÁHCl, DOX@TPE@CLVs III treated mice. Upon killing after 18 days, the typical images and
or T-DOX@TPE@CLVs III, plasma was collected for analyses. As weights of tumors are shown as Fig. 8b and c, respectively.
illustrated in Fig. 7a, blood clearance of DOX@TPE@CLVs Meanwhile, the relative change in bodyweight was also mea-
III and T-DOX@TPE@CLVs III was slower than that for free sured (Fig. 8d). Clearly, the bodyweight of mice treated with free
DOXÁHCl. For free DOX, the area under the curve (AUC) was DOXÁHCl decreased to B66% due to its side effects.8,26 Others
74.30 and half-life (t1/2) was 1.01 h, and DOX@TPE@CLVs III groups showed relatively stable bodyweights of mice. Based
increased the AUC to 727.14 (9.78-fold) and increased t1/2 to 8.86 h on tests in mice, T-DOX@TPE@CLVs III could suppress tumor
(8.77-fold). Moreover, the AUC and t1/2 of T-DOX@TPE@CLVs III growth in vivo, which agreed with the corresponding results
was 924.03 (12.44-fold) and 6.82 h (36.75-fold) compared with free in vitro.
DOXÁHCl. A drug-biodistribution study was carried out in vivo to
estimate the antitumor activity of free DOXÁHCl, DOX@TPE@CLVs
III and T-DOX@TPE@CLVs III. As shown in Fig. 7b, analyses
of fluorescence intensity indicated that the crosslinked NPs
3. Conclusions
targeted the tumors in living mice passively via the enhanced We designed and synthesized amphiphilic TPE-bearing com-
permeability and retention (EPR) effect. According to ex vivo pounds to self-assemble liposome-like vesicles: TPE@LVs. They
images and semiquantitative analyses of DOX content in could be applied to deliver both hydrophilic DOX in the water
different organs and tumors (lex = 480 nm, lem = 580 nm), free pool and hydrophobic DOX in the bilayer via p–p stacking
DOXÁHCl accumulated readily in the liver and kidneys, whereas interactions between DOX and the TPE moiety. The highest
T-DOX@TPE@CLVs III was the predominant delivery system DLC of 26% was achieved using a vesicle diameter of 105 nm,
for active targeting of solid tumors even 12 h after injection which was higher than that of general liposomes (o10%). After
(Fig. 7c).
crosslinking, the formed DOX@TPE@CLVs not only showed
To evaluate the therapeutic efficacy of free DOXÁHCl, robust stability under physiological conditions, but also responded
DOX@TPE@CLVs III and T-DOX@TPE@CLVs III in vivo, nude to the tumor microenvironment to release DOX for cancer
mice bearing HepG2 solid tumors were applied. The volume therapy. After modification with active targeting glucose mole-
of tumor in living mice was measured continuously for 18 days. cules, T-DOX@TPE@CLVs could be effectively applied to monitor
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Fig. 8 In vivo anticancer therapy using free DOXÁHCl, DOX@TPE@CLVs III and T-DOX@TPE@CLVs III and the control (0.9% NaCl) after intravenous
injection through the tail vein of nude mice bearing xenograft HepG2 liver tumors. (a) Relative change in the tumor volume over time (mean Æ SD, n = 5,
P1* o 0.05). (b) Representative image of mice bearing tumors and excised tumors after treatment for 18 days. (c) The excised tumor weights after
treatment with 0.9% saline, free DOX, DOX@TPE@CLVs III or T-DOX@TPE@CLVs III for 18 days (mean Æ SD, n = 5, P2* o 0.05). (d) Relative change in
bodyweight over time (mean Æ SD, n = 5, P3* o 0.05).
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