Amphiphilic Cyanine-Platinum Conjugates as Fluorescent Nanodrugs

Article abstract of DOI:10.1002/asia.201501163

Two fluorescent nanomedicines based on small molecular cyanine-platinum conjugates have been prepared via a nanoprecipitation method and characterized by transmission electron microscopy (TEM) as well as dynamic light scattering (DLS). The conjugates exhibited an enhanced fluorescence in their nanoparticle formulation compared to that in solution. The nanomedicines could be endocytosed by cancer cells as revealed by confocal laser scanning microscopy (CLSM) and showed high cellular proliferation inhibition. Fluorescent platinum nanomedicines prepared directly from small molecules could be an alternative strategy for developing new drugs with simultaneous cellular imaging and cancer therapy functions.

Full text of DOI:10.1002/asia.201501163

DOI: 10.1002/asia.201501163
Communication
Drug Design
Amphiphilic Cyanine–Platinum Conjugates as Fluorescent
Nanodrugs
Tingting Sun,[a, b] Zhensheng Li,[a] Zhigang Xie,*[a] and Xiabin Jing[a]
Compared with free drugs, nanomedicines offer an opportu-
Abstract: Two fluorescent nanomedicines based on small
molecular cyanine–platinum conjugates have been pre-
pared via a nanoprecipitation method and characterized
by transmission electron microscopy (TEM) as well as dy-
namic light scattering (DLS). The conjugates exhibited an
enhanced fluorescence in their nanoparticle formulation
compared to that in solution. The nanomedicines could
be endocytosed by cancer cells as revealed by confocal
laser scanning microscopy (CLSM) and showed high cellu-
lar proliferation inhibition. Fluorescent platinum nanome-
dicines prepared directly from small molecules could be
an alternative strategy for developing new drugs with si-
multaneous cellular imaging and cancer therapy func-
tions.
nity to increase the water solubility and to accumulate within
solid tumors preferentially due to the enhanced permeability
and retention (EPR) effect, thus reducing off-target toxicity and
improving the therapeutic index.[12–19] Among various forms of
nanomedicines, polymeric micellar nanoparticles made from
amphiphilic copolymer materials such as poly(ethylene glycol)-
block-poly(D,L-lactic acid) (PEG-PLA) are one of the most
widely used drug-delivery platforms.[15,20–24] However, the low
drug loading and the potential toxicity of carriers are major
drawbacks in translational medicine.[25] On the other hand,
many chemotherapeutic agents are often incompatible with
the carriers, such as platinum drugs, resulting in limited en-
trapment efficiency and suboptimal release kinetics.[12] Even so,
more and more multifunctional delivery materials have been
developed,[26–28] but little attention has been paid to fine-
tuning the chemical structures of these drugs to make them
compatible with ideal polymeric nanocarriers or to even make
nanomedicines by themselves.[29–32]
Platinum compounds have emerged as powerful anticancer
drugs for decades against many solid malignancies, like ovari-
an, bladder, head and neck, testicular and lung cancers.[1–5]
Platinum drugs, cisplatin and carboplatin, alone or in combina-
tion with other drugs, are used to treat 40–80% of cancer pa-
tients.[6,7] These drugs have severe side effects, such as hepato-
toxicity, nephrotoxicity, cardiotoxicity, gastrointestinal dysfunc-
tion, and ototoxicity.[1] Therefore, there is a growing demand
for balancing toxicity and efficacy issues of platinum drug. Fur-
thermore, it is difficult to image the distribution and metabo-
lism of platinum drugs in living cells because most of them are
not fluorescent and cannot be easily detected. Although fluo-
rescent platinum compounds have been previously reported
by using fluorescein derivatives as the fluorophore[8–10] or by
using BODIPY (1,3,5,7-tetramethyl-8-(4-pyridyl)-4,4’-difluorobora
diazaindacene) as the fluorescent reporter,[11] they are still
unable to avoid the side effects of free drugs, such as rapid
clearance in vivo.
Recently, nanomedicines prepared directly from small organ-
ic molecules without using of drug carriers have drawn much
more attentions. Amphiphilic constructs were realized by cou-
pling a hydrophobic compound with hydrophilic antitumor
drugs such as gemcitabine[33] and doxorubicin[34] or by conju-
gating hydrophobic drugs with oligo(ethylene glycol).[35–37]
High drug loading contents and nanoscale particles could be
obtained simultaneously. To the best of our knowledge, no
small molecular platinum drug has been reported to directly
form nanomedicine.
Cyanine lead structures are very useful as fluorescence sens-
ing or imaging probes because of their fluorescence enhance-
ment property upon being bound or enclosed in a hydropho-
bic environment, which is due to the reduction in nonradiative
decay caused by restricted torsional rotation in the excited
state.[38–41] In this work, two cyanine–platinum conjugates
(CPCs) were synthesized, and fluorescent platinum nanomedi-
cines (FPNMs) were prepared by the self-assembly of CPCs in
aqueous solution. CPCs exhibited distinct absorption and pho-
toluminescence (PL) properties in solution and in assembled
states. FPNMs could be internalized by cancer cells and
showed high cellular proliferation inhibition against human
cervical carcinoma (HeLa) and human breast cancer (MCF-7)
cells.
[a] Dr. T. Sun, Dr. Z. Li, Prof. Z. Xie, Prof. X. Jing
State Key Laboratory of Polymer Physics and Chemistry
Changchun Institute of Applied Chemistry
Chinese Academy of Sciences
Changchun 130022 (China)
E-mail: xiez@ciac.ac.cn
[b] Dr. T. Sun
University of Chinese Academy of Sciences
Beijing 100049 (China)
The synthetic route of (E)-4-(2-(1H-indol-3-yl)vinyl)-pyridine
(HIP)–platinum conjugate (HIP-Pt) and (E)-4-(2-(1-methyl-1H-
indol-3-yl)vinyl)-pyridine (MIP)–platinum conjugate (MIP-Pt) is
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201501163.
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Figure 1. TEM images of HIP-Pt NPs (a) and MIP-Pt NPs (b). Inset: Size and
size distribution of HIP-Pt NPs and MIP-Pt NPs.
Scheme 1. The synthetic route of HIP-Pt and MIP-Pt. Reagents and condi-
tions: (a) i) 4-Pyridineacetic acid hydrochloride, triethylamine, 1,4-dioxane,
room temperature, 10 min; ii) Piperidine, reflux, 8 days; (b) Cisplatin, silver ni-
trate, N,N-dimethyl formamide, 24 h; (c) i) Sodium hydride, tetrahydrofuran,
reflux, 30 min; ii) Iodomethane, reflux, overnight.
stability in physiological environment as evidenced by the neg-
ligible changes of particle sizes after being incubated in phos-
phate-buffered saline (PBS, pH 7.4) containing 10% fetal
bovine serum (FBS) for 24 h (Figure S6, Supporting Informa-
tion).
The optical properties of HIP-Pt and MIP-Pt were investigat-
ed as shown in Figure 2. The UV/Vis absorption spectra of HIP-
Pt in EtOH solution, HIP-Pt NPs and HIP-Pt solid exhibited ab-
sorption maxima at 391, 380 and 389 nm, respectively (Fig-
ure 2a). The blue-shifted absorption maxima of HIP-Pt NPs and
HIP-Pt solid are associated with their aggregated states. Fig-
ure 2b shows the PL spectra of HIP-Pt. A dramatical red-shift
of the maximum emission wavelength from 472 to 490 and to
531 nm for HIP-Pt in EtOH to HIP-Pt NPs and HIP-Pt solid was
observed. The UV/Vis absorption (Figure 2c) and PL (Figure 2d)
spectra of MIP-Pt were similar to those of HIP-Pt with the
maximum absorption at 395, 386, and 393 nm, and the maxi-
mum emission at 475, 495, and 529 nm, respectively for MIP-
Pt in EtOH, MIP-Pt NPs and MIP-Pt solid.
More interestingly, HIP-Pt NPs and MIP-Pt NPs displayed an
increased fluorescence intensity relative to small molecular
HIP-Pt and MIP-Pt at the same concentration. To examine the
fluorescence enhancement property of HIP-Pt and MIP-Pt,
their PL properties were investigated by using solvent mixtures
of EtOH and water. As shown in Figure 3a and 3c, with in-
creasing the water fraction (fw) in EtOH/water mixtures from 0
to 90 vol%, the fluorescence intensity of HIP-Pt and MIP-Pt in-
creases gradually, and the emission wavelength is red-shifted.
Figure 3b and 3d show the plots of the relative fluorescence
intensity (I/I0) as a function of fw for HIP-Pt and MIP-Pt, where
I0 is the fluorescence intensity of HIP-Pt or MIP-Pt in pure
EtOH and I is that in EtOH/water mixtures. The fluorescence in-
tensity is nearly 2-times that in pure EtOH solution when the
water content is 90 vol%. Insets in Figure 3b and 3d show
photographs of HIP-Pt and MIP-Pt in EtOH/water mixtures
with water fractions of 0 and 90% taken under room light and
illumination with UV light (365 nm). Different from typical ag-
gregation-induced emission (AIE) fluorogens like tetraphenyl-
ethene (TPE), which is nonemissive in solution and emits inten-
sively only in the aggregated state, HIP-Pt and MIP-Pt display
different emission properties in their solution and aggregated
states. However, the restriction of intramolecular rotation (RIR)
theory for the typical AIE system is capable of explaining such
shown in Scheme 1, and the details of synthesis are outlined in
the Supporting Information. 1-Methyl-1H-indole-3-carbalde-
hyde (1) was prepared according to a reported method,[38] and
then HIP and MIP were obtained with indole-3-carbaldehyde
or compound 1 as reactant.[42] Eventually, HIP-Pt and MIP-Pt
were synthesized according to the procedure described in our
earlier work.[11] The structures of HIP-Pt and MIP-Pt were con-
1
firmed by H NMR spectroscopy (Figures S1 and S2, Supporting
Information) and matrix-assisted laser desorption/ionization
time-of-flight mass spectrometry (MALDI-TOF MS) (Figure S3,
Supporting Information). As shown in Figures S1 and S2, the
peaks k and l around 4.5 ppm with an integral area of about 3
for each peak indicated that cisplatin was conjugated to HIP
and MIP successfully. The signals at 485.4 and 499.4 in Fig-
ure S3 are ascribed to the theoretical molecular weight of
[HIP-Pt]+ and [MIP-Pt]+ respectively. These obtained data ob-
tained are in good agreement with the proposed structures.
As HIP or MIP is a hydrophobic dye and cisplatin is a hydro-
philic drug, we hypothesized that HIP-Pt and MIP-Pt could
self-assemble into nanoparticles (HIP-Pt NPs and MIP-Pt NPs)
in aqueous solutions. To test our hypothesis, the nanoprecipi-
tation method was used. HIP-Pt and MIP-Pt were first dis-
solved in ethanol (EtOH) and then added dropwise to distilled
water under stirring. After evaporation of EtOH, HIP-Pt NPs
and MIP-Pt NPs were obtained. Transmission electron micros-
copy (TEM) and dynamic light scattering (DLS) analyses con-
firmed the formation of HIP-Pt NPs and MIP-Pt NPs (Figure 1).
The critical aggregation concentrations (CAC) of HIP-Pt NPs
and MIP-Pt NPs were 1.47 and 1.92 mm respectively (Figure S4,
Supporting Information). The average hydrodynamic diameter
determined by DLS is about 74 nm for HIP-Pt NPs and 70 nm
for MIP-Pt NPs. The concentrations of HIP-Pt NPs and MIP-Pt
NPs in aqueous solutions were obtained via a standard curve.
The size and size distribution showed negligible changes after
storage for 20 days (Figure S5, Supporting Information), indi-
cating the high stability of HIP-Pt NPs and MIP-Pt NPs in
water. The nanomedicines also exhibited favorable structural
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Figure 2. UV/Vis absorption and PL (excited at the relative maximum absorption wavelength) spectra of HIP-Pt (a, b) and MIP-Pt (c, d) in different forms.
Figure 3. (Left) PL spectra of HIP-Pt (a) and MIP-Pt (c) in EtOH/water mixtures with different water fractions (fw). (Right) Plot of the relative peak intensity (I/I0)
vs. fw for HIP-Pt (b) and MIP-Pt (d). Concentration: 100 mgmLÀ1 each; excitation wavelength: 391 nm for HIP-Pt and 395 nm for MIP-Pt. Insets: Photographs
of HIP-Pt and MIP-Pt in EtOH/water mixtures with different water fractions (0% and 90%) taken under room light (top) and UV light (bottom).
fluorescence enhancement of HIP-Pt and MIP-Pt, as revealed
by the dramatically enhanced fluorescence intensity of HIP-Pt
and MIP-Pt with increasing viscosity of the solution (Figure S7,
Supporting Information).
could be internalized by HeLa cells and showed green fluores-
cence in the cytoplasm as revealed by confocal laser scanning
microscopy (CLSM) imaging (Figure S8, Supporting Informa-
tion). The internalization of HIP-Pt NPs and MIP-Pt NPs by
HeLa cells was also evaluated by CLSM, and fluorescence co-lo-
calization analyses of the nanoparticles and lysosome-specific
Cellular uptake is important for both small molecules and
nanomedicines to exert their functions. HIP-Pt and MIP-Pt
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fluorescent dye (Lyso-Tracker Red) were performed. The cells
were first incubated with the nanoparticles in the culture
media for 1 h and then stained with Lyso-Tracker Red for
45 min at 378C. As can be seen in Figure 4, the fluorescence of
Lyso-Tracker Red superimposes significantly with the fluores-
cence of HIP-Pt NPs and MIP-Pt NPs, which suggests that the
nanoparticles could be internalized by living cells via endocy-
tosis.
seen that cytotoxicities of both nanoparticles are concentra-
tion-dependent. The numbers in red in Figure 5 are the half
maximal inhibitory concentration (IC50) values of HIP-Pt NPs
and MIP-Pt NPs against HeLa and MCF-7 cell lines. As shown
in Figure S9 in the Supporting Information, the anticancer ac-
tivities of HIP-Pt NPs and MIP-Pt NPs are slightly lower than
that of cisplatin, but they exhibit an activity comparable with
cisplatin at a higher concentration of 100 mm, which is accept-
able in view of the merits of nanomedicines. These results
show that HIP-Pt NPs and MIP-Pt NPs can serve as efficient
chemotherapeutic nanomedicines for killing cancer cells.
In summary, fluorescent HIP-Pt NPs and MIP-Pt NPs were
successfully prepared from pure small molecules HIP-Pt and
MIP-Pt. The nanoparticles in water showed an enhanced fluo-
rescence compared to the corresponding small molecules in
EtOH solution. More importantly, HIP-Pt NPs and MIP-Pt NPs
could be internalized by living cells via endocytosis and kill
cancer cells efficiently, that is, they could fulfil cytostatic and
imaging functions simultaneously. The fluorescent platinum
nanomedicines made from pure small molecules provide an
improved alternative for traditional chemotherapeutic plati-
num drugs. These results make the self-assembly of small mo-
lecular drugs with both imaging and therapeutic functions
promising for developing novel nanomedicines in the future.
Figure 4. CLSM images of HeLa cells incubated with HIP-Pt NPs and MIP-Pt
NPs for 1 h at 378C at a concentration of 10 mm. Pictures correspond to
bright field images, the fluorescence of HIP-Pt NPs and MIP-Pt NPs (green),
the fluorescence of Lyso-Tracker Red (red), and merged images from left to
right.
Experimental Section
Subsequently, the anti-proliferative properties of HIP-Pt NPs
and MIP-Pt NPs against HeLa and MCF-7 cells were evaluated
by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium
bromide) assays. Figure 5 shows the cell viabilities of HeLa (Fig-
ure 5a) and MCF-7 (Figure 5b) cells after 48 h culture with HIP-
Pt NPs and MIP-Pt NPs at various concentrations. It can be
Detailed experimental methods and additional data can be found
in the Supporting Information.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Project No. 91227118 and 51522307).
Keywords: conjugates
platinum · self-assembly
· fluorescence · nanomedicines ·
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Manuscript received: October 22, 2015
Revised: November 8, 2015
Accepted Article published: November 11, 2015
Final Article published: December 3, 2015
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