Coordination responsive tellurium-containing multilayer film for controlled delivery

Article abstract of DOI:10.1039/c4cc08588d

A coordination-responsive tellurium containing film was fabricated for controlled release. The coordination chemistry between telluride molecules and cisplatin was utilized for the loading of cisplatin, while competitive ligands were used for triggered release. This work could enrich the coordination responsive system and further tune the release kinetics of cisplatin. This journal is

Full text of DOI:10.1039/c4cc08588d

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Coordination responsive tellurium-containing
multilayer film for controlled delivery†
Cite this: Chem. Commun., 2015,
51, 5520
Wei Cao, Lu Wang and Huaping Xu*
Received 30th October 2014,
Accepted 20th November 2014
DOI: 10.1039/c4cc08588d
www.rsc.org/chemcomm
A coordination-responsive tellurium containing film was fabricated for effects. However, the loading capacities of the abovementioned
controlled release. The coordination chemistry between telluride systems are not satisfactory. Therefore, we seek to develop
molecules and cisplatin was utilized for the loading of cisplatin, various systems to enrich the coordination responsive system
while competitive ligands were used for triggered release. This work and optimize the loading capacity.
could enrich the coordination responsive system and further tune
the release kinetics of cisplatin.
In this study, we fabricated a competitive-coordination-responsive
multilayer film for controlled release through layer-by-layer (LbL)
deposition of telluride-molecule–cisplatin complex and diazo resin
(DAR, structure is shown in Scheme 1). LbL assembly is an attractive
and powerful strategy for fabricating functional materials because of
its simplicity, versatility and systematic control over the thickness
and structure of the layers.21–24 The tellurium-containing small
molecules were employed to coordinate with cisplatin as delivery
vehicles with an increased loading capacity of up to 40%. As small
molecules are not suitable for LbL assembly, the self-assembled
aggregates were employed as polyvalent negatively-charged building
blocks for the LbL film.25,26 Under physiologically relevant condi-
tions, competitive-ligands, such as spermine or spermidine, could
trigger the release of cisplatin from the films. The release kinetics
could be further modulated to a great extent due to the different
nature of the film compared with the previously-reported
Smart materials that are capable of responding to specific stimuli
have been an emerging research topic in the basic science and
material areas due to the possibility of providing efficient drug or
gene carriers for the treatment of diseases such as cancer.1–3 To
achieve a better control of the drug carriers, the delivery systems
have been up to now endowed with pH-,4 redox-,5–7 radiation-,8–10
and enzyme-responsiveness.11,12 Among these systems, we consider
the systems with responses to the unique intracellular stimuli of
cancer cells to be of great interest because they could improve their
intracellular trafficking as well as the release efficiency.3,13,14 How-
ever, developing release systems that are adaptable to physiological
environments of human body is still a big challenge.
Organotellurium compounds have been investigated as promising
pharmacological agents in view of their unique biological properties
such as glutathione peroxidase mimic, antioxidant activity, and
thioredoxin reductase inhibition.15,16 However, compared with sulfur,
the possibility of using tellurium-containing molecules for controlled
delivery systems is still poorly explored. Based on the unique
chemical properties of tellurium,17,18 we had previously reported
the coordination-responsive systems based on the tellurium-
containing polymers for controlled delivery.19,20 The coordina-
tion chemistry of platinum and tellurium enabled the loading of
platinum drugs, whereas under mild conditions competitive
coordination of other ligands could be utilized to trigger the
release of platinum. A tellurium-containing polymer may provide
not only regulated release kinetics but also beneficial biological
Key Lab of Organic Optoelectronics and Molecular Engineering, Department of Chemistry,
Tsinghua University, Beijing 100084, China. E-mail: xuhuaping@mail.tsinghua.edu.cn
† Electronic supplementary information (ESI) available: Details of materials, measure-
ment, synthesis, characterization and self-assembly behaviours of m-TeCOOH. See
DOI: 10.1039/c4cc08588d
Scheme 1 Schematic representation for the coordination responsive
tellurium-containing film for controlled delivery of cisplatin.
5520 | Chem. Commun., 2015, 51, 5520--5522
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micelles. Because spermine and spermidine are biomolecules at 2.70 ppm and the formation of a new broad peak (3.6–3.2 ppm),
existing ubiquitously in the human body, it is highly anticipated suggesting that platinum coordinated with Te atoms. The observa-
that the new coordination responsive system may be adaptable tion that the chemical shift of H1 remained unchanged after the
to the physiological environment.
coordination confirms that cisplatin coordinated with Te atoms on
The telluride-containing small molecules were designed and m-TeCOOH instead of the carboxylic acid moiety. In addition, 125Te
synthesized. The design was based on the following considerations. NMR spectra provide more direct evidence for the coordination.
We first devised a telluride compound 11,110-tellurodiundecanoic As shown in Fig. 1b, the chemical shift of tellurium downshifted
acid (denoted as m-Te11COOH) with long alkyl chains to increase from 191 ppm to 283 ppm as a result of the deshielding effects of
the stability and simultaneously decrease the toxicity caused by the platinum. To further support the formation of coordination
volatility. The carboxylic acid groups were utilized to increase the species, ESI-mass analysis was conducted; it revealed that the
hydrophilicity. Yet the solubility of m-Te11COOH was poor even in molecular ion peaks {Pt(m-TeCOOH)(NH3)2Cl}+ (m/z = 679.11)
the buffer of pH 9.4. Then, the alkyl chain was shortened by and {Pt(m-TeCOONa)(NH3)2Cl}+ (m/z = 723.06) were the predominant
employing 8-bromooctanoic acid to react with disodium telluride species (Fig. S5, ESI†), indicating that m-TeCOOH and cisplatin
to obtain 8,80-tellurodioctanoic acid (denoted as m-TeCOOH) with could coordinate with 1 : 1 stoichiometry. Thus, the NMR and MS
desired amphiphilicity (for details, please see the ESI†). The solubility data supported the formation of cisplatin/m-TeCOOH coordina-
of the compound m-TeCOOH proved to be satisfying at neutral pH. tion species.
We assumed that m-TeCOOH could coordinate with cisplatin and
The self-assembly behavior of the coordination complex was
work as a delivery vehicle with enhanced loading capacity. However, studied in pH 4.0 sodium borate buffer. The CAC of the coordination
we were concerned about the coordination site of platinum because complex was determined to be approximately 3.2 mM by recording
it may also coordinate with the carboxylic acid groups present on the concentration-dependent count rates in the DLS measurement of
both ends.
the aggregates suspension (Fig. 1c). The aggregates are spherical with
To have an exact view of its coordination mode with cisplatin, a diameter of about 2 mm (Fig. 1d), as revealed by the SEM and TEM
different characterizations for m-TeCOOH and the complex were images (for details, please see Fig. S6, ESI†). With the ratio of
examined and compared. As shown in the 1H NMR spectra of cisplatin to m-TeCOOH as 1 : 1, the loading capacity of cisplatin
Fig. 1a, the peaks for the key protons (H1, H2) are well resolved, could reach 40%, which is a dramatic increase compared with the
making it convenient to identify the complexation mode. When previous tellurium-containing polymer micelles. The zeta potential of
compared with m-TeCOOH, the complex exhibited significant the aggregates was determined to be about ꢀ22.7 mV, indicating
variation in 1H NMR spectra including the disappearance of peaks that the carboxylic acid groups were partially deprotonated and that
the tellurium-containing micelles could be incorporated into the LbL
thin films. The optimal polyanion was DAR because DAR could be
used to crosslink the film by UV-mediated photo-reaction.
The LbL assembling process was carried out and monitored by
UV-Vis spectroscopy. A linear increase of the absorbance at 380 nm
(Fig. 2a), which is the characteristic peak for diazonium groups, was
observed with the growing number of bilayers, indicating a progres-
sive and uniform deposition process. After reaching the desired layer
number, the film was irradiated with UV light for 10 min. Under UV
irradiation, diazonium groups of DAR decomposed to produce
cationic phenyl groups, which reacted with the nucleophilic carboxyl-
ate groups in m-TeCOOH to form esters. As shown in the UV-Vis
spectrum in Fig. 2b, the peak at 380 nm for diazonium disappeared
upon UV irradiation, indicating that the covalently cross-linked
tellurium-containing films were obtained.
Fig. 1 Evidence for the coordination between cisplatin and m-TeCOOH and
1
the self-assembly behavior of the coordination complex. (a) H NMR spectra
and (b) 125Te NMR spectra for m-TeCOOH before and after coordination with
cisplatin. (c) The critical aggregation concentration (CAC) of the coordination
complex determined by recording the concentration-dependent count rates in
the dynamic light scattering (DLS) measurement of the aggregate suspension.
(d) Scanning electron microscopy (SEM) image for the aggregates of the
coordination complex.
Fig. 2 LbL assembly and photo crosslinking process for the fabrication of the
film. (a) UV-vis spectra monitoring the LbL assembly of ten-bilayers of DAR and
m-TeCOOH/cisplatin. (Inset) absorbance at 380 nm vs. the number of bilayers
deposited. (b) UV-Vis spectra of the multilayer film before and after UV irradiation.
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chemistry. The film is endowed with higher loading capacity of
cisplatin and could further tune the competitive ligand triggered
release kinetics of the drug loaded. This approach broadens the
possibility for the design of coordination responsive systems in
therapeutic applications under physiological environments. If an
erasable template is employed, capsules can be fabricated for
delivery vehicles that can be applicable for transportation in blood.
Because the assembly method used can be generalized, other
crosslinkers could also be used to fabricate the film. Furthermore,
functionalization with low-fouling capability and targeting ligand
may also be envisioned.
Fig. 3 Controlled release profiles of cisplatin for the multilayer films.
This work was financially supported by the National Basic
Research Program of China (2013CB834502), the Foundation for
Innovative Research Groups of the National Natural Science Founda-
tion of China (21121004), the Research Project of Chinese Ministry of
Education (113006A), Tsinghua University Initiative Scientific
Research Program (2012Z02131), the NSFC-DFG joint grant
(TRR 61) and The Importation and Development of High-Caliber
Talents Project of Beijing Municipal Institutions.
To obtain more insight into the resulting film, the morphology
was studied by different techniques. AFM analysis revealed a
relatively flat surface with a roughness of about 10 nm (see the
Fig. S7, ESI†). Because one of the building blocks is the aggregates
with diameters of about 2 mm, the smooth surface may suggest the
deformation of the aggregates. Attempts were also made to inves-
tigate the thickness of the films. The corresponding cross-sectional
SEM showed that the 10-bilayer film has an average thickness
of about 80 nm, indicating that the micelles collapsed in the film
(Fig. S8, ESI†). It is reasoned that the deformation of aggregates is
caused by two reasons. On the one hand, the aggregates of telluride
molecules became unstable upon dehydration. Their electrostatic
attractive force with positively-charged DAR might have caused the
structure change when they deposited on a solid surface. On the
other hand, the chemical crosslinking process when irradiated by
UV light might have further induced a force to press the aggregates.
We envisaged that the release of cisplatin from the films could be
triggered by the competitive ligands, for example, spermine and
spermidine, which are ubiquitous polyamines in human bodies with
strong biological activities. To test the hypothesis, we conducted the
systematic release study of the films obtained. Upon incubation in
the presence of competitive ligands, high cumulative drug release
was achieved in a controlled manner. In total, 3.6 ꢁ 103 ng and 4.0 ꢁ
103 ng cisplatin were released for 5 mM spermine and 5 mM
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