JOURNAL OF
POLYMER SCIENCE
ORIGINAL ARTICLE
REFERENCES AND NOTES
only 14% of NR was released from PV1 nanoparticles within 10 min
and 34% was released after 4 h at pH 7.4, while the PF1 nano-
particles released 28% of NR within 10 min and 38% after 4 h under
the same conditions. This difference becomes pronounced at pH 6.0.
PV1 nanoparticles released 23% of NR within 10 min and 56% after
4 h. For PF1 nanoparticles, approximately 70% of NR was released
within 10 min and 91% was released after 4 h. The larger difference
can be due to the increasing number of protonated amine groups of
reduced PF1 at pH 6.0. As the hydrophobic block length of PF and
PV copolymers increases, the release of NR from nanoparticles
becomes slower due to the less reduction sensitivity of larger
nanoparticles, which is in agreement with the results from the
UV–vis studies. The decomposition of pNBC moieties leads to
unmask the primary amine groups of the linkers, thus converting the
reduction-responsive block copolymer to pH-responsive copolymer.
The simultaneous application of reduction and pH stimuli induces a
rapid disruption of nanoparticles. Therefore, the release of NR from
these reduction-responsive block nanoparticles can be modulated by
altering the structure of amino acid-derived linker, the length of
stimuli-responsive polymer segment and the pH of milieu.
1 M. C. Stuart, W. Huck, J. Genzer, M. Müller, C. Ober, M. Stamm,
G. B. Sukhorukov, L. Szleifer, V. V. Tsukruk, M. Urban, F. Winnik,
S. Zauscher, L. Luzinov, S. Minko, Nat. Mater. 2010, 9, 101.
2 Z. Ge, S. Liu, Chem. Soc. Rev. 2013, 42, 7289.
3 S. Mura, J. Nicolas, Nat. Mater. 2013, 12, 991.
4 E. Fleige, M. A. Quadir, R. Haag, Adv. Drug Deliv. Rev. 2012,
64, 866.
5 J. F. Quinn, M. R. Whittaker, T. P. Davis, Polym. Chem. 2017, 8, 97.
6 G. L. Semenza, Nat. Rev. Cancer 2003, 3, 721.
7 A. L. Harris, Nat. Rev. Cancer 2002, 2, 38.
8 J. M. Brown, W. R. William, Nat. Rev. Cancer 2004, 4, 437.
9 M. Takasawa, R. R. Moustafa, J. C. Baron, Stroke 2008, 39, 1629.
10 J. H. Crawford, T. S. Isbell, Z. Huang, S. Shiva, B. K. Chacko,
A. N. Schechter, V. M. Darley-Usmar, J. D. Kerby, J. D. Lang,
D. Hypoxia Kraus, Blood 2006, 107, 566.
11 C. Murdoch, M. Muthana, C. E. Lewis, J. Immunol. 2005, 175,
6257.
12 H. K. Eltzschig, D. L. Bratton, S. P. Colgan, Nat. Rev. Drug
Discov. 2014, 13, 852.
13 X. Zheng, X. Wang, H. Mao, W. Wu, B. Liu, X. Jiang, Nat.
Commun. 2015, 6, 5834.
CONCLUSIONS
14 W. R. Wilson, M. P. Hay, Nat. Rev. Cancer 2011, 11, 393.
15 S. Y. Sharp, L. R. Kelland, M. R. Valenti, L. A. Brunton,
S. Hobbs, P. Workman, Mol. Pharmacol. 2000, 58, 1146.
In summary, methacrylate monomers from pNBC-caged phenylala-
nine and valine were utilized to prepare amphiphilic block copoly-
mers consisting of hydrophilic PEG block and hydrophobic block
containing pendent reduction-trigger-caped amino acid-derived
linkers. In the aqueous solution, the block copolymers self-
assembled into spherical micelles and vesicles as the length of
hydrophobic block increased. Upon reduced by a chemical reduc-
tant, Na2S2O4, the pNBC moieties were decomposed through a cas-
cade 1,6-elimination and decarboxylation reactions to liberate free
primary amine groups of the linkers, resulting in the disruption of
assemblies. The reduction rate of assemblies decreased as the
hydrophobic block length became longer. It was also found that the
assemblies of the block copolymers containing valine-derived
linkers were less responsive to reduction, compared with those of
the block copolymers containing phenylalanine-derived linkers.
16 K. Kiyose, K. Hanaoka, D. Oushiki, T. Nakamura, M. Kajimura,
M. Suematsu, H. Nishimatsu, T. Yamane, T. Terai, Y. Hirata,
T. Nagano, J. Am. Chem. Soc. 2010, 132, 15846.
17 W. Zhang, W. Fan, Z. Zhou, J. Garrison, ACS Med. Chem.
Lett. 2017, 8, 1269.
18 M. P. Hay, W. R. Wilson, W. A. Denny, Bioorg. Med. Chem.
2005, 13, 4043.
19 Y. Ikeda, H. Hisano, Y. Nishikawa, Y. Nagasaki, Mol. Pharm.
2016, 13, 2283.
20 A. Chevalier, Y. Zhang, O. M. Khdour, J. B. Kaye, S. M. Hecht,
J. Am. Chem. Soc. 2016, 138, 12009.
21 W. Piao, S. Tsuda, Y. Tanaka, S. Maeda, F. Liu, S. Takahashi,
Y. Kushida, T. Ueno, T. Komatsu, T. Terai, T. Nakazawa,
M. Uchiyama, K. Morokuma, T. Nagano, K. Hanaoka, Angew.
Chem. Int. Ed. 2013, 52, 13028.
With NR as
a model hydrophobic drug, the NR-loaded
22 O. Kensuke, A. Chiho, H. Takashi, M. Masataka, M. Tadahiko,
Bioconjug. Chem. 2012, 23, 324.
nanoparticles exhibited reduction-triggered release behavior in the
presence of Na2S2O4. Moreover, the decomposition of pNBC moie-
ties also converted the reduction-responsive block copolymer into
pH-responsive copolymer. Due to the protonation of the unmasked
amines of the linkers under mildly acidic conditions, the release of
NR was accelerated by simultaneous application of reduction and
pH stimuli. Since the pNBC trigger can allow potential NTR
-mediated reduction, the incorporation of pNBC moieties into poly-
mers as the reduction-trigger will extend the redox-sensitive func-
tionality from GSH-responsive disulfide to other biomolecule-
responsive polymeric assemblies. Further investigation on the
reduction responsiveness of these pNBC containing block copoly-
mers in NTR and NADH tumor microenvironment is under way.
23 H. Cho, J. Bae, V. K. Garripelli, J. M. Anderson, H. W. Jun,
S. Jo, Chem. Commun. 2012, 48, 6043.
24 H. Mutlu, C. M. Geiselhart, C. B. Kowollik, Mater. Horiz. 2018,
5, 162.
25 J. Y. Rao, A. Khan, J. Am. Chem. Soc. 2013, 135, 14056.
26 J. Y. Rao, C. Hottinger, A. Khan, J. Am. Chem. Soc. 2014, 136, 5872.
27 J. Y. Rao, A. Khan, Polym. Chem. 2015, 6, 686.
28 T. Eom, W. Yoo, Y. D. Lee, J. H. Park, Y. Choe, J. Bang,
S. Kim, A. Khan, J. Mater. Chem. B 2017, 5, 4574.
29 T. Eoma, W. Yoo, S. Kim, A. Khan, Biomaterials 2018, 185, 333.
30 F. Perche, S. Biswas, T. Wang, L. Zhu, V. P. Torchilin, Angew.
Chem. Int. Ed. 2014, 53, 3362.
31 P. Kulkarni, M. K. Haldar, S. You, Y. Choi, S. Mallik, Bio-
macromolecules 2016, 17, 2507.
ACKNOWLEDGMENT
32 T. Thambi, V. G. Deepagan, H. Y. Yoon, H. S. Han, S. -H. Kim,
S. Son, D. -G. Ahn, C. -H. Jo, Y. D. Suh, K. Kim, I. C. Kwon,
D. S. Lee, J. H. Park, Biomaterials 2014, 35, 1735.
This project was financially supported by the National Natural
Science Foundation of China under contract no. 51773100.
10
JOURNAL OF POLYMER SCIENCE, PART A: POLYMER CHEMISTRY 2019