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W. Wang et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
Fig. 1. Synthetic route of iodinated PLA copolymer.
The functional comonomer and iodination molecule were
synthesized according to the previous reported procedure [9,10].
Detailed experimental procedures are available in Supporting
information. All the prepared small molecules and polymers were
characterized using proton nuclear magnetic resonance (1H NMR)
in Figs. S1 and S2 (Supporting information) and Fig. 1. The data
were listed here:
The molecular weight and thermal properties of these
copolymers were monitored by GPC and DSC, respectively. And
the data were listed in Table 1. As shown in Fig. S3 (Supporting
information), single and symmetric eluting curves could be
observed for all the copolymers. The molecular weight of
copolymers showed a little reduction after deprotection and then
showed a considerable increment after oxime “Click” reaction. The
differences can be explained by a little chain scission during
deprotection process and the increment of hydrodynamic volume
of the molecular chains by anchoring a large volume of contrast
agent, respectively. During thermal analysis, all the copolymers did
not show crystallization and melting peak, and showed a slight
increment of glass transition temperature after deprotection.
The radiopacity intensity directly depends on the content of
iodine within the copolymers. Thus, the iodine contents were
calculated by both 1H NMR (Fig. 2) and EDS (Fig. 3), listed in Table 1.
The iodine contents could be easily regulated by the feedstock. X-ray
imaging of I-P(LA-co-TMC) materials is obtained by using X-ray
radiography and Micro-CT. All these samples were made into strips
with 2 mm thickness, and the X-ray images were obtained by X-
radiographicexaminationunderstandardX-raycondition. Asshown
in Fig. 3a, the four non-iodinated samples exhibited similar low
radiopacity,whereastheother twoiodinatedsamplesexhibitedhigh
radiopacity. Further, Fig. 3b showed the in vivo radiopacity of a little
of iodinated materials implanted into rabbit, which both exhibited
goodradiopacityandX-ray identificationduetothehighcontentsof
iodine atoms. The excellent X-ray visibility indicated a great
potential application as interventional device or implant.
To evaluate the cell cytotoxicty of these new synthesized
copolymers, in vitro biological properties as cytotoxicity against
3T3-Swissalbinowas testedviadirectcontactmethodusingAlamar
blue. The cell viability on tissue culture plate was set as control. The
cellviabilitywasmeasuredonamicroplatereader(VarioskanFLash,
Thermo Fisher) at intervals of 24 h. As shown in Fig. 4a, all the PLA
copolymers showed high values of the relative growth rate (RGR%)
above 75%, demonstrating non-cytotoxicity of synthesized poly-
mers. Furthermore, the cell morphology after incubation for 24 h
and 72 h were shown under fluorescent microscope in Fig. 4b. It can
be seen that the cells proliferated rapidly and spread out on the
surface regardless of the samples with or without iodine atoms.
In conclusion, biodegradable radiopaque iodinated PLA copoly-
mers have been successfully synthesized by in-chain functionaliza-
tion through the combination of ring opening copolymerization and
oxime “Click” reaction. Two different iodine contents copolymers
were carefully characterized to being definite molecular structure,
good X-ray visibility, and low cell cytotoxicty. It is a feasible method
to develop biodegradable biomaterials with inherent radiopacity.
II: 1H NMR (400 MHz, CDCl3):
d 2.35 (1H, OH), 3,7 (2H, CH2), 3.3
(3H, CH3).
III: 1H NMR (400 MHz, CDCl3):
d
d
4.4 (2H, CH2), 3.35 (3H, CH3).
1.45 (3H, LA = CH3), 4.12 (2H,
IV: 1H NMR (400 MHz, CDCl3):
TMC = CH2), 3.18 (3H, TMC = CH3), 5.14 (H, LA = CH).
V: 1H NMR (400 MHz, CDCl3):
d
1.45 (3H, LA = CH3), 4.83 (2H,
TMC = CH2), 5.14 (H, LA = CH).
VII: 1H NMR (400 MHz, CDCl3):
d 7.92 (m, 1H, Ar=H), 7.90 (1H,
phthalimido), 7.78 (1H, phthalimido), 7.61 (1H, Ar=H), 7.48 (1H,
Ar=H), 7.01 (1H, Ar=H), 5.35 (2H, C2H4ICH2-).
VIII: 1H NMR (400 MHz, CDCl3):
d
7.81 (1H, Ar=H), 7.35–7.49
(2H, Ar=H), 7.0 (1H, Ar=H), 6.51 (2H, -ONH2), 4.69 (2H, C6H4ICH2-).
IX: 1H NMR (400 MHz, CDCl3,
): 1.45 (3H, LA = CH3), 4.83 (2H,
d
TMC = CH2), 5.08 (2H, C6H4ICH2-), 5.14 (H, LA = CH), 6.9 (1H, Ar=H),
7.2 (1H, Ar=H), 7.5 (1H, Ar=H), 7.9 (1H, Ar=H).
The chemical structure of these copolymers during the
synthetic processes were traced and confirmed by 1HNMR. As
shown in Fig. 2, the peak c of OCH3 in TMC unit at 3.18 ppm
completely disappeared after deprotection, and the peak b of OCH2
at 4.12 ppm shifted to the peak at 4.83 ppm (b') after deprotection,
indicating the ketal group has been changed into the ketone group.
As a result, it can be concluded that the ketone-containing PLA
copolymer has been successfully prepared. Furthermore, the
appearance of new peaks e + f+g + h (6.9–7.2 ppm, 7.5–7.9 ppm)
originated from the protons of phenyl groups in O-(2-iodobenzyl)
hydroxylamine confirmed that the iodinated hydroxylamine has
been imparted into the target polymers by oxime “Click” reaction.
Therefore, 1HNMR spectra demonstrate the successful synthesis of
iodinated PLA copolymers.
Acknowledgment
The work was financially supported by the National Natural
Science Foundation of China (No. 31500767), the Natural Science
Fig. 2. 1HNMR spectra of pristine, deprotection and iodinated copolymers.
Please cite this article in press as: W. Wang, et al., In-chain functionalization through the combination of ring opening copolymerization and
Wang, Wenhuan
