Impact of Secondary Structure of Polypeptides on Glucose

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Impact of the secondary structure of polypeptides on the glucose concentration sensitivity of nanocarriers for insulin delivery Liu Yang, Jingyu Lv, Shirui Li, Yuqiang Li, Jun-Jiao Yang, Bo Zhang, and Jing Yang ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00075 • Publication Date (Web): 04 Jul 2018 Downloaded from http://pubs.acs.org on July 11, 2018

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Impact of the secondary structure of polypeptides on the glucose concentration sensitivity of nanocarriers for insulin delivery

Liu Yang, Jingyu Lv, Shirui Li, Yuqiang Li, Junjiao Yang, Bo Zhang,* Jing Yang *

Liu Yang, Jingyu Lv, Yuqiang Li, Prof. Jing Yang, State Key Laboratory of Chemical Resource, Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. [email protected]; Tel.: +86-10-64427578 Prof. Bo Zhang, Dr. Shirui Li Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China. [email protected]. Prof. Junjiao Yang, College of Science, Beijing University of Chemical Technology, Beijing 100029, China.

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Abstract A reasonably intelligent response to glucose concentration fluctuations is crucial for developing a self-regulated insulin delivery system. Inspired by the relationship between the higher ordered structures of proteins and their versatile functions, the introduction of polypeptides capable of mimicking different secondary structures into the delivery system will be anticipated for adjusting glucose concentration sensitivity. Herein, this work presents the impact of different secondary structural architectures of polypeptide blocks on the stability of glucose-responsive complex nanoparticles (CNPs) in the normal physiological environment and their response to the stimuli of normoglycemic and hyperglycemic conditions in vitro. Results from the conformational investigations of the CNPs carried out using circular dichroism and insulin release under the different stimuli suggested that the stability and glucose sensitivity of the CNPs are closely related to the secondary structure composition of the polypeptide blocks. The CNPs with a dominant α-helix structure exhibit a promising potential to improve normal glycemic control and to reduce the incidences of hyperglycemia and hypoglycemia both in vitro and in vivo.

Keywords: insulin delivery, polypeptide, secondary structure, α-helix, intelligent release

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1. Introduction Due to the versatile functions originating from their higher ordered structures, proteins, as one of the most important biomacromolecules, exhibit unique properties in the biomedical field.1 Inspired by nature, numerous protein analogs capable of mimicking the shapes and functions of secondary protein structures have attracted great attention and resulted in the development of folded structures with potential biomedical applications.2-5 Synthetic polypeptides are the most studied protein-mimicking materials due to the similarity of their peptide backbone to that of natural proteins. In addition to biocompatibility and biodegradability,

synthetic

polypeptides

can

adopt

secondary

structures

through

intramolecular hydrogen bonds within the peptide backbones and display interesting conformation-specific behaviors and bioactivities.6-8 In particular, the introduction of polypeptides with secondary structures into the functional and unnatural components has widened the scope of these materials 9-12 and provides a promising approach to adjust and enhance their bioactivity and intelligent responsive behavior.13-17 Diabetes is a chronic disease where the body is unable to regulate blood glucose level within the normal range.18,19 Traditional administrations of exogenous insulin via subcutaneous injection and noninvasive therapy such as oral, nasal, transdermal and ocular delivery systems cannot regulate insulin release continuously and automatically in response to the blood glucose fluctuation because the glucose-sensing and insulin-releasing modules are not directly integrated.20,21 To resolve these issues for diabetic patients and reduce the incidence of hyperglycemia and hypoglycemia, smart therapies called closed-loop insulin release, which can precisely control the insulin amount on demand, have been broadly

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developed.22-29 Among them, phenylboronic acid (PBA)-based glucose-triggered systems have attracted great interest because PBA and its derivatives can conjugate with glucose molecules to form a reversible ester bond for the achievement of the closed-loop effect.30,31 Until now, a variety of PBA-based glucose-responsive materials, especially in the form of nanoparticles

including

nanogels

(microgels),32,33

micelles,34-36

vesicles,37-40

and

nanocapsules41,42, have been broadly explored to improve their glucose concentration sensitivity and on-off regulated response in a physiological environment. Most of the PBA-based nanocarriers in the reported examples rely on the versatile architectural design of the glucose-responsive materials themselves to modulate the sensitivity of insulin release in response to blood glucose level changes.43-46 The coassembly of amphiphilic copolymers is one highly efficient and convenient method to obtain nanoparticles with the special properties of the individual copolymers.

47

Inspired by the higher ordered structures of synthetic

polypeptides, we are curious whether simple changes in the secondary conformation of the nanocarriers via the coassembly of PBA-based polymers and amphiphilic polymers with polypeptide blocks will generate a great impact on the self-regulated response of the overall materials. To this end, we focus on the impact of modulating the secondary structural composition of the polypeptides on the glucose responsive behavior of PBA-based nanocarriers in this study. Herein, amphiphilic polymers containing the same total number of repeating units in the polypeptide blocks but different ratios of γ-benzyl-L-glutamate (BLG) to L-glutamic acid (GA), poly(ethylene glycol)-b-poly(γ-benzyl-L-glutamate)60 (MPEG-b-PBLG60) and poly(ethylene glycol)-b-[poly(γ-benzyl-L-glutamate)x-co-poly(L-glutamic

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acid)y]60

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(MPEG-b-[(PBLGx-co-PGAy)]60) (subscripts 60, x and y represent the number of repeating units of the corresponding polypeptide blocks), were synthesized by the ring-opening polymerization (ROP) of γ-benzyl-L-glutamate-N-carboxy-anhydrides (BLG-NCA) and the deprotection reaction of the benzyl groups in the presence of hydrobromic acid. Due to varying PGA contents, these amphiphilic polymers with polypeptide blocks exhibit major secondary structure conformational changes from α-helix to β-sheet to random coil. Based on the

coassembly

of

these

glycol)-block-poly(2-phenylboronic

polymers

and

glucose-sensitive

ester-1,3-dioxane-5-ethyl)

poly(ethylene

methyl

acrylate

(MPEG-b-PPBDEMA) to form complex nanoparticles (CNPs), the effect of different secondary structure conformations on the salt-tolerance and glucose concentration sensitivity of the CNPs is in detail investigated by using circular dichroism (CD) spectroscopy and fluorescence probe technology. It is demonstrated that simple changes in the secondary structure of these polypeptides can be utilized to modulate the intelligent glucose-responsive behavior of the nanocarriers and their stability in the physiological environment. Furthermore, insulin release in vivo is studied.

2. Experimental section 2.1. Materials and methods. The synthesis of MPEG-b-PPBDEMA and MPEG-b-PBLG is in detail described in the supporting information section. Insulin (27 UI/mg) purchased from Genview (Beijing, China) labeled by fluorescein isothiocyanate (FITC) according to a previous report

48

was used to

study the glucose-responsive behavior of the CNPs in vitro. Human recombinant insulin (Zn

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salt, 27.5 IU/mg) purchased from Sigma-Aldrich was used in the animal experiments. Streptozocin (STZ) from Sigma-Aldrich was used to induce diabetes in the rats. Glucagon chemiluminescent ELISA Kit was purchased from Millipore Corporation. Male age-matched (8–12 weeks) rats ordered from Beijing Bioscience Company (China) were used throughout all animal experiments. All animal studies were performed in accordance with the policies on animal research in the context of Clinic Research Institute of China-Japan Friendship Hospital. Trifluoroacetic acid (TFA) and 33 wt% hydrobromic acid in acetic acid solution (HBr/AcOH) from J&K Chemical were used without further purification.

2.2. Characterization A 400 MHz NMR instrument (Bruker Corporation, Germany) was used at room temperature with CDCl3 or DMSO-d6 as solvent. The molecular weight and polydispersity index of the block polymers were analyzed on a Waters 515-2410 instrument equipped with a differential refractive-index detector using THF as the eluent (flow rate of 1.0 mL/min at 30 ºC), and polystyrene standards were employed for calibration. The size and morphology of the CNPs were characterized by using a laser light scattering (DLS) spectrometer (ZEN3600, Malvern) with Zetasizer software and a Hitachi H800 transmission electron microscopy (TEM) operated with 100 KV, respectively. Circular dichroism (CD) measurements collected on a Jasco J-810 CD spectropolarimeter at 25 °C with a cell length of 0.1 cm were accumulated 3 times at the scanning speed of 100 nm/min and in the wavelength range of 260 to 190 nm. The secondary structure population was calculated using CD Pro software. A Hitachi F-4600 Fluorescence instrument (Hitachi High-Technologies Corporation, Tokyo Japan) was used to measure the steady-state fluorescence emission. Blood glucose levels were monitored by Glucometer (OneTouch UltraEasy).

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2.3. Synthesis of MPEG-b-(PBLG-co-PGA) The mixture of 260 mg MPEG-b-PBLG60 and 3.0 mL TFA was kept stirring for 30 min, followed by the dropwise adding of 33% HBr/AcOH (3 equiv. to PEG-b-PBLG). After 1 h, the reaction solution was poured into excess anhydrous ether to form precipitates. The supernatant was removed by centrifuging, and the obtained solid was again washed by ether. The dried solid in vacuum was dissolved in N,N’-dimethylformamide (DMF) and further purified by dialyzing against ultrapure water in a dialysis bag with a molecular weight cutoff of 3500 for 3 days, during which the dialysis water was refreshed every 6 h. Finally, the white spongy solid was obtained via lyophilization. The PGA content in the resulting polymer was controlled by adjusting the dose amount of HBr/AcOH and reaction time. 1H NMR (400 MHz, CDCl3, δ) (ppm) was performed: 7.34-7.33 (5H, C6H5-), 5.07 (2H, CH2C6H5), 3.60-3.31 (s, 4H, CH2CH2O), 2.25-2.23 (2H, BnOCO-CH2-), 2.25-2.23 (2H,CH2-CHβ-sheet>random coil. Among the studied CNPs, CNP-3 with a high α-helix conformation content in the core showed the best salt-tolerance in 0.15 M PBS and could controllably release insulin in response to normoglycemia and hyperglycemia in vitro. In vivo, the good hemocompatibility and benign controllability to steadily maintain BG levels indicated that CNP-3 has great potential to improve the treatment efficacy for diabetes. A further study on the long-lasting impact of therapy is underway in our laboratory.

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Associated content. Supporting information The Supporting Information is available free of charge on the ACS Publications website. Materials and methods, synthesis, FITC-insulin loading procedure, 1H NMR spectra of P-1~ P-4, GPC curves of P-1 and P-4, critical micellar concentrations of P-1~P-4, one standard curve of fluorescence intensity dependence of FITC-insulin concentration.

Acknowledgements. This work was supported by the Fundamental Research Funds for the Central Universities (PYBZ1702),National Natural Science Foundation of China (NSFC, Grant No. 21374005, U1663227) and Beijing National Laboratory for Molecular Sciences (BNLMS20150127).

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References. (1) Nelson, D. L.; Lehninger, A. L.; Cox, M. M. Lehninger Principles of Biochemistry, Freeman, W. H., New York 2008. (2) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Foldamers as Versatile Frameworks for the Design and Evolution of Function. Nat. Chem. Biol. 2007, 3(5), 252-262. (3) Guichard, G.; Huc, I. Synthetic Foldamers. Chem. Commun. 2011, 47(21), 5933-5941. (4) Azzarito, V.; Long, K.; Murphy, N. S.; Wilson, A. J. Inhibition of α-Helix-Mediated Protein-Protein Interactions Using Designed Molecules. Nat. Chem. 2013, 5(3), 161-173. (5) Crisma, M.; Zotti, De M.; Formaggio, F.; Peggion, C.; Moretto, A.; Toniolo, C. Handedness Preference and Switching of Peptide Helices. Part II: Helices Based on Noncoded α-Amino Acids. J. Pept. Sci. 2015, 21(3), 148-177. (6) Lu, H.; Wang, J.; Song, Z.; Yin, L.; Zhang, Y.; Tang, H.; Tu, C.; Lin, Y.; Cheng, J. Recent Advances in Amino Acid N-Carboxyanhydrides and Synthetic Polypeptides. Chemistry, Self-Assembly and Biological Applications. Chem. Commun. 2014, 50(2), 139-155. (7) Rad-Malekshahi, M.; Lempsink, L.; Amidi, M.; Hennink, W. E.; Mastrobattista, E. Biomedical Applications of Self-Assembling Peptides. Bioconjugate Chem. 2016, 27(1), 3-18. (8) Carlsen, A.; Lecommandoux, S. Self-Assembly of Polypeptide-Based Block Copolymer Amphiphies. Curr. Opin. Colloid Interface Sci. 2009, 14(5), 329-339. (9) Hauser, C. A. E.; Zhang, S. Designer Self-Assembling Peptide Nanofiber Biological Materials. Chem. Soc. Rev. 2010, 39(8), 2780-2790. (10) Gazit, E. Self-Assembled Peptide Nanostructures: the Design of Molecular Building Blocks and Their Technological Utilization. Chem. Soc. Rev. 2007, 36(8), 1263-1269.

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Page 28 of 35

Page 29 of 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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(11) Huang, J.; Heise, A. Stimuli Responsive Synthetic Polypeptides Derived from N-Carboxyanhydride (NCA) Polymerisation. Chem. Soc. Rev. 2013, 42(17), 7373-7390. (12) Deming, T. J. Synthesis of Side-Chain Modified Polypeptides. Chem. Rev. 2016, 116(3), 786-808. (13) Yin, L.; Tang, H.; Kim, K. H.; Zheng, N.; Song, Z.; Gabrielson, N. P.; Lu, H.; Cheng, J. Light-Responsive Helical Polypeptides Capable of Reducing Toxicity and Unpacking DNA: Toward Nonviral Gene Delivery. Angew. Chem. Int. Ed. 2013, 52(35), 9182-9186. (14) Kramer, J. R.; Deming, T. J. Multimodal Switching of Conformation and Solubility in Homocysteine Derived Polypeptides. J. Am. Chem. Soc. 2014, 136(15), 5547-5550. (15) Wang, H.; Feng, Z.; Wang, Y.; Zhou, R.; Yang, Z.; Xu, B. Integrating Enzymatic Self-Assembly and Mitochondria Targeting for Selectively Killing Cancer Cells Without Acquired Drug Resistance. J. Am. Chem. Soc. 2016, 138(49), 16046-16055. (16) Zhou, J.; Du, X.; Yamagata, N.; Xu, B. Enzyme-Instructed Self-Assembly of Small D-Peptides as a Multiple-Step Process for Selectively Killing Cancer Cells. J. Am. Chem. Soc. 2016, 138(11), 3813-3823. (17) Xiong, M.; Han, Z.; Song, Z.; Yu, J.; Ying, H.; Yin, L.; Cheng, J. Bacteria-Assisted Activation of Antimicrobial Polypeptides by a Random-Coil to Helix Transition. Angew. Chem. Int. Ed. 2017, 56(36), 10826-10829. (18) Atkinson, M. A.; Eisenbarth, G. S. Type 1 Diabetes: New Perspectives on Disease Pathogenesis and Treatment. Lancet 2001, 358(9277), 221-229. (19) Stumvoll, M.; Goldstein, B. J.; Haeften, van T. W. Type 2 Diabetes: Principles of Pathogenesis and Therapy. Lancet 2005, 365(9467), 1333-1346.

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Page 30 of 35

(20) Sonia, T. A.; Sharma, C. P. An Overview of Natural Polymers for Oral Insulin Delivery. Drug Discovery Today 2012, 17(13-14), 784-792. (21) Sung, H.-W.; Sonaje, K.; Liao, Z.-X.; Hsu, L.-W.; Chuang, E.-Y. pH-Responsive Nanoparticles Shelled with Chitosan for Oral Delivery of Insulin: from Mechanism to Therapeutic Applications. Acc. Chem. Res. 2012, 45(4), 619-629. (22) Gordijo, C. R.; Shuhendler, A. J.; Wu, X. Y. Glucose-Responsive Bioinorganic Nanohybrid Membrane for Self-Regulated Insulin Release. Adv. Funct. Mater. 2010, 20(9), 1404-1412. (23) Hovorka, R. Closed-Loop Insulin Delivery: From Bench to Clinical Practice. Nat. Rev. Endocrinol. 2011, 7(7), 385-395. (24) Yu, J.; Zhang, Y.; Bomba, H.; Gu, Z. Stimuli-Responsive Delivery of Therapeutics for Diabetes Treatment. Bioengineering & Translational Medicine 2016, 1(3), 323-337. (25) Wang, C.; Ye, Y.; Sun, W.; Yu, J.; Wang, J.; Lawrence, D. S.; Buse, J. B.; Gu, Z. Red Blood Cells for Glucose-Responsive Insulin Delivery. Adv. Mater. 2017, 29(18), n/a. (26) Yu, W.; Jiang, G.; Zhang, Y.; Liu, D.; Xu, B.; Zhou, J. Near-Infrared Light Triggered and Separable Microneedles for Transdermal Delivery of Metformin in Diabetic Rats. J. Mater. Chem. B, 2017, 5, 9507-9513. (27) Xu, B.; Jiang, G.; Yu, W.; Liu, D.; Zhang, Y.; Zhou, J.; Sun, S.; Liu, Y. H2O2-Responsive Mesoporous

Silica

Nanoparticles

Integrated

with

Microneedle

Patches

for

the

Glucose-Monitored Transdermal Delivery of Insulin. J. Mater. Chem. B, 2017, 5, 8200-8208. (28) Li, L.; Jiang, G.; Yu, W.; Liu, D.; Chen, H.; Liu, Y.; Huang, Q.; Tong, Z.; Yao, J.; Kong, X. A Composite Hydrogel System Containing Glucose-Responsive Nanocarriers for Oral

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Delivery of Insulin. Mater. Sci. Eng. C 2016, 69, 37-45. (29) Liu, D.; Zhang, Y.; Jiang, G.; Yu, W.; Xu, B.; Zhu, J. Fabrication of Dissolving Microneedles with Thermal-Responsive Coating for NIR-Triggered Transdermal Delivery of Metformin on Diabetic Rats. ACS Biomater. Sci. Eng. 2018, 4, 1687−1695. (30) Matsumoto, A.; Ikeda, S.; Harada, A.; Kataoka, K. Glucose-Responsive Polymer Bearing a Novel Phenylborate Derivative as a Glucose-Sensing Moiety Operating at Physiological pH Conditions. Biomacromolecules 2003, 4(5), 1410-1416.

(31) A. Matsumoto, T. Ishii, J. Nishida, H. Matsumoto, K. Kataoka, Y. Miyahara, Angew. Chem. Int. Ed. 2012,51(9), 2124-2128. (32) Mandal, D.; Mandal, S. K.; Ghosh, M.; Das, P. K.; Phenylboronic Acid Appended Pyrene-Based Low-Molecular-Weight Injectable Hydrogel: Glucose-Stimulated Insulin Release. Chem. Eur. J. 2015, 21(34), 12042-12052. (33) Zou, X.; Zhao, X.; Ye, L. Synthesis of Cationic Chitosan Hydrogel with Long Chain Alkyl and Its Controlled Glucose-Responsive Drug Delivery Behavior. RSC Adv. 2015, 5(116), 96230-96241. (34) Guo, Q.; Wu, Z.; Zhang, X.; Sun, L.; Li, C. Phenylboronate-Diol Crosslinked Glycopolymeric Nanocarriers for Insulin Delivery at Physiological pH. Soft Matter 2014, 10(6), 911-920. (35) Guo, H.; Li, H.; Gao, J.; Zhao, G.; Ling, L.; Wang, B.; Guo, Q.; Gu, Y.; Li, C. Phenylboronic Acid-Based Amphiphilic Glycopolymeric Nanocarriers for in Vivo Insulin Delivery. Polym. Chem. 2016, 7(18), 3189-3199.

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(36) Shi, D.; Ran, M.; Zhang, L.; Huang, H.; Li, X.; Chen, M.; Akashi, M. Fabrication of Biobased Polyelectrolyte Capsules and Their Application for Glucose-Triggered Insulin Delivery ACS Appl. Mater. Interface 2016, 8(22), 13688-13697. (37) Kim, H.; Kang, Y. J.; Jeong, E. S.; Kang, S.; Kim, K. T. Glucose-Responsive Disassembly of Polymersomes of Sequence-Specific Boroxole-Containing block Copolymers under Physiologically Relevant Conditions. ACS Macro Lett. 2012, 1(10), 1194-1198. (38) Zhang, M.-J.; Wang, W.; Xie, R.; Ju, X.-J.; Liu, L.; Gu, Y.-Y.; Chu, L.-Y. Microfluidic Fabrication of Monodisperse Microcapsules for Glucose-Response at Physiological Temperature. Soft Matter 2013, 9(16), 4150-4159. (39) Yang, H.; Zhang, C.; Li, C.; Liu, Y.; An, Y.; Ma, R.; Shi, L. Glucose-Responsive Polymer Vesicles Templated by α-Cd/PEG Inclusion Complex. Biomacromolecules 2015, 16(4), 1372-1381. (40) Guo, Q.; Zhang, T.; An, J.; Wu, Z.; Zhao, Y.; Dai, X.; Zhang, X. Block Versus Random Amphiphilic Glycopolymer Nanopaticles as Glucose-Responsive Vehicles. Biomacromolecules 2015, 16(10), 3345-3356. (41) Liang, J.; Ma, Y.; Sims, S.; Wu, L. A Patterned Porous Polymer Film for Localized Capture of Insulin and Glucose-Responsive Release. J. Mater. Chem. B. 2015, 3(7), 1281-1288. (42) Zou, Z.; He, D.; Cai, L.; He, X.; Wang, K.; Yang, X.; Li, L.; Li, S.; Su, X. Alizarin Complexone Functionalized Mesoporous Silica Nanoparticles: A Smart System

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Integrating Glucose-Responsive Double-Drugs Release and Real-Time Monitoring Capabilities. ACS Appl. Mater. Interface 2016, 8(13), 8358-8366. (43) Zhao, L.; Xiao, C.; Ding, J.; Zhuang, X.; Gai, G.; Wang, L.; Chen, X. Competitive Binding-Accelerated Insulin Release from a Polypeptide Nanogel for Potential Therapy of Diabetes. Polym. Chem. 2015, 6(20), 3807-3815. (44) Zhao, L.; Ding, J.; Xiao, C.; He, P.; Tang Z.; Pang, X.; Zhuang, X.; Chen, X. Glucose-Sensitive

Polypeptide

Micelles

for

Self-Regulated

Insulin

Release

at

Physiological pH. J. Mater. Chem. 2012, 22(24), 12319-12328. (45) Liu, G.; Ma, R.; Ren, J.; Li, Z.; Zhang, H.; Zhang, Z.; An, Y.; Shi, L.; A Glucose-Responsive Complex Polymeric Micelle Enabling Repeated On-Off Release and Insulin Protection. Soft Matter 2013, 9(5), 1636-1644. (46) Yang, H.; Ma, R.; Yue, J.; Li, C.; Liu, Y.; An, Y.; Shi, L.; A Facile Strategy to Fabricate Glucose-Responsive Vesicles via a Template of Thermo-Sensitive Micelles. Polym. Chem. 2015, 6(20), 3837-3846. (47) Li, Y.; Zhang, Y.; Yang, J.; Yang, J. Polypeptide-Participating Complex Nanoparticles with Improved Salt-Tolerance as Excellent Candidates for Intelligent Insulin Delivery. RSC Adv. 2017, 7(23), 14088-14098. (48) Li, M.-G.; Lu, W.-L.; Wang, J.-C.; Wang, L. J.; Zhang, C. X.; Wang, X. Q.; Zheng, A. P.; Zhang, Q.; Distribution, Transition, Adhesion and Release of Insulin Loaded Nanoparticles in the Gut of Rats. Int. J. Pharm. 2007, 329(1-2), 182-191. (49) Yao, Y.; Wang, X.; Tan, T.; Yang, J. A Facile Strategy for Polymers to Achieve Glucose-Responsive Behavior at Neutral pH. Soft Matter 2011, 7(18), 7948-7951.

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(50) Lin, L.-Y.; Huang, P.-C.; Yang, D.-J.; Gao, J.-Y.; Hong, J.-L. Influence of the Secondary Structure on the AIE-Related Emission Behavior of an Amphiphilic Polypeptide Containing a Hydrophobic Fluorescent Terminal and Hydrophilic Pendant Groups. Polym. Chem. 2016, 7(1), 153-163.

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Graphic for manuscript Impact of the secondary structure of polypeptides on the glucose concentration sensitivity of nanocarriers for insulin delivery

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