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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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ACS Applied Bio Materials

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


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



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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