Oral Administration of Salecan-Based Hydrogels for Controlled Insulin

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Oral administration of salecan-based hydrogels for controlled insulin delivery Xiaoliang Qi, Yue Yuan, Jianfa Zhang, Jeff W. M. Bulte, and Wei Dong J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b02879 • Publication Date (Web): 21 Sep 2018 Downloaded from http://pubs.acs.org on September 22, 2018

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Journal of Agricultural and Food Chemistry

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Oral administration of salecan-based hydrogels

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for controlled insulin delivery

3 4

Xiaoliang Qia, b, g, Yue Yuan a, b,, Jianfa Zhangg,

5

Jeff W.M. Bulte a, b, c, d, e, f, *, Wei Dongg, *,

6 7

a

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Research, The Johns Hopkins University School of Medicine, Baltimore, MD 21205,

9

USA;

Russell H. Morgan Dept. of Radiology and Radiological Science, Division of MR

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b

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Engineering, the Johns Hopkins University School of Medicine, Baltimore, Maryland

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21205, USA;

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c

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Baltimore, Maryland 21287, USA;

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d

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Institute, Baltimore, Maryland 21205, USA;

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e

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Medicine, Baltimore, Maryland 21205, USA;

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f

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University Whiting School of Engineering, Baltimore, Maryland 21218, USA;

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g

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Nanjing 210094, China.

Cellular Imaging Section and Vascular Biology Program, Institute for Cell

Department of Oncology, The Johns Hopkins University School of Medicine,

F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger

Department of Biomedical Engineering, The Johns Hopkins University School of

Department of Chemical & Biomolecular Engineering, The Johns Hopkins

Center for Molecular Metabolism, Nanjing University of Science & Technology,

ACS Paragon Plus Environment


23 24

*Corresponding author: email: [email protected] (J.W.M. Bulte). email: [email protected] (W. Dong).

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Abstract

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We present an improved type of food gum (salecan) based hydrogels for oral

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delivery of insulin. Structural hydrogel formation was assessed with Fourier transform

30

infrared spectroscopy, thermogravimetric analysis and X-ray diffraction. We found

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that the hydrogel modulus, morphology, and swelling properties can be controlled by

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varying the salecan dose during hydrogel formation. Insulin was introduced into the

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hydrogel using a swelling–diffusion approach and then further used a drug prototype.

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In vitro insulin release profiles demonstrated that the release of entrapped insulin was

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suppressed in acidic conditions, but markedly increased at neutral pH. Cell viability

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and toxicity tests revealed that the salecan hydrogel constructs were biocompatible.

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Oral administration of insulin-loaded salecan hydrogels in diabetic rats resulted in a

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sustained decrease of fasting plasma glucose levels over 6 h post-administration. For

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non-diabetic animals, the relative pharmacological bioavailability of insulin was

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significantly larger (6.24%, p85.5% of its absorbed

534

water after 600 min, while SH1, SH2, SH3 and SH4 lost 90.0%, 95.6%, 97.3% and

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98.2% of their water at this time point, respectively. Generally speaking , gel

536

composed of more salecan polysaccharide had a stronger affinity for water molecules,


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which can act as water-releasing channels when collapse occurred, thus benefiting for

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the removal of water.29, 45

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3.2.7.5 Erosion assay

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Table S3 (supporting information) shows the results of erosion test of

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salecan/PMA hydrogel samples at pH 7.4 buffers. As presented in Table S3, gels

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containing more salecan had high level of erosion, with values of 5.33 ± 1.55%, 6.58

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± 1.78%, 7.35 ± 2.01%, 8.17 ± 2.12% and 9.67 ± 1.88% for PMA, SH1, SH2, SH3

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and SH4 after 12h in buffers at 37 °C, respectively. This phenomenon can be

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explained by the incorporation of salecan that decreases the stiffness of hydrogel

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matrix and enhances the susceptibility of polymer chains, thereby benefiting the

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erosion.46

548 549

3.3 Cytotoxicity of salecan/PMA hydrogels

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Cytotoxicity is an indispensable consideration for a drug delivery carrier

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design.47 To serve as safe carrier for drug delivery, the carrier itself needs to possess a

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proper biocompatibility.48 In vitro cytotoxicity assay was performed using a cell

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staining assay (Figure 6). Hoechst 33342 dye labels nuclei of all cells present, while

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PI only stains nuclei of dead cells.49 As shown in Figure 6, few cells incubated with

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salecan/PMA hydrogels exhibited uptake of PI with no differences compared to the

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negative control. These findings were further corroborated by an MTT assay

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according to the ISO 10993-5 protocol as reference for biomaterial testing50 (Figure

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7A). After 72 h of cultivation with different extracts of salecan/PMA hydrogels, the



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cell viability of treated 9L, HCT116 and MC38 cells was similar to untreated controls

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(>90%). MTT and cell staining assays suggested that the designed hydrogel was cell

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compatible, implying that the salecan/PMA hydrogels were suitable candidates for in

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vivo applications.

563 564

Figure 6. Fluorescence images of 9L, HCT116 and MC38 incubated with the various hydrogel

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extracts for 72 h (scale bar=50 µm). Cells were stained with PI (red) and Hoechst 33342 (blue).

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Figure 7. Cell viability of 9L, HCT116 and MC38 cells after treatment with different hydrogel

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extracts (A). Insulin-loading efficiency of salecan/PMA and PMA hydrogels (B). In vitro insulin

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release curves for simulated gastric fluid (C, pH=1.3) and intestinal fluid (D, pH=7.4).

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3.4 In vitro and in vivo insulin delivery

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3.4.1 In vitro insulin delivery

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We employed insulin, a widely used therapeutic agent for treatment of diabetes,

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as a model drug to assess the release characteristics of the PMA and salecan/PMA

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hydrogels. Insulin was incorporated into the PMA and salecan/PMA polymeric

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network by swelling-diffusion strategy.7 The gel-loaded insulin content was acquired

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by subtracting the remaining insulin amount in the incubation solution from the initial

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added amount used for loading.47 It can be observed from Figure 7B that the insulin



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loading efficiency (ILE) of PMA was 27.5%. Moreover, an increase in salecan content

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from 0.7 mL to 2.8 mL enhanced the ILE from 30.3% to 60.8%, as a result of a larger

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WU of the semi-IPN architecture.51 On the one hand, the increase in the number of

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salecan molecules contributes to increased water uptake by the hydrogel, promoting

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the penetration of external insulin into the interior of the hydrogel. On the other hand,

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the semi-IPN architecture helps preventing the collapse of the insulin-loaded hydrogel

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during the desiccation process.51

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To determine the in vitro release curves of insulin from PMA and salecan/PMA

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hydrogel specimens, experiments were conducted in simulated intestinal fluid

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(pH=7.4) and gastric fluid (pH=1.3). The amount of released insulin was

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pH-dependent (Figure 7C, 7D). At 24 h, the cumulative insulin release at pH=1.3 was

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19.7%, 21.5%, 26.9%, 32.7%, and 36.2% for PMA, SH1, SH2, SH3, and SH4,

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respectively, while at pH=7.4 these values were 32.1%, 49.4%, 59.3%, 65.6%, and

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74.5%. The higher release at pH=7.4 can be expected, as this is above the pKa value

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of PAA (4.3)41 and the isoelectric point of insulin (5.4)52. Here, the stronger

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electrostatic repulsion between the negatively charged insulin and the negatively

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charged carboxyl groups of the PAA segment in the PMA hydrogel facilitates the

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release of insulin. At the low pH value (pH=1.3), the hydrogen bonding interactions

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between the protonated carboxylic groups of the PAA might preserve the hydrogel

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network in a compact collapsed state, preventing the release of insulin.3

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In addition to the effect of pH on drug release, we also noted that the total salecan

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content in the gel significantly (p


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SH3 > SH2 > SH1 > PMA, in agreement with the WU discussed above. A recent

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report confirmed that the drug release properties of the hydrogel are increase with the

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water uptake.53

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major hurdles preventing the success of oral delivery of insulin are overcoming the

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enzymatic degradation in the stomach.55,

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have desirable insulin release features when orally administered, as it can initiate and

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maintain a low release in the acidic stomach at pH=1.3, while an accelerated release is

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triggered in the intestinal environment (pH=7.4).

Insulin is susceptible to biodegradation and denaturation.1, 54 The

56

Our salecan/PMA semi-IPN hydrogels

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3.4.2 In vivo insulin delivery

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Finally, we assessed the pharmacokinetics and therapeutic effects of orally

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administered insulin-loaded salecan/PMA semi-IPN hydrogels in STZ-induced

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diabetic rats. SH4 hydrogel was selected for its optimal pH-dependent release

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behavior, where the hydrogel protects the insulin from the harsh stomach conditions

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and only effectively releases insulin in the small intestine environment. Figure 8A

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shows the time course of blood glucose level following oral administration of

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insulin-free and insulin-loaded hydrogels, as compared to s.c. injection of saline or

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pure insulin. No therapeutic effect (absence of hypoglycemia) could be noticed after

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oral administration of free insulin and s.c. injection of saline. For the animals given a

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s.c. injection of free insulin, blood glucose levels quickly dropped achieving a

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minimum of 36.0% at 2 h after injection after which the blood glucose returned to

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previous levels. This outcome is in agreement with the short half-life of insulin in



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blood.7 Animals treated with different dosages of insulin-loaded hydrogel exhibited

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dosage-dependent blood glucose changes. Two hours after administration, blood

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glucose gradually declined to 82.1% and 78.7% after administration of 25 and 50

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IU/kg insulin-loaded SH4 gel, respectively. Unlike the rats injected with insulin s.c.,

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hypoglycemia persisted for longer time periods, in agreement with the slower insulin

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release observed in vitro, with a maximum effect at 4-6 h after administration. The

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rPA (%) of insulin for orally administering insulin-loaded hydrogel was calculated to

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be 5.02%, much larger than that of orally administering free insulin (0.48%). It is

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noteworthy that the rPA (%) of the salecan/PMA semi-IPN hydrogels (5.02%) is

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comparable to that of recently reported hydrogel-based vehicles regarding the in-vivo

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sustained release of insulin, such as carboxymethyl cellulose/poly(acrylic acid)

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(6.35%)7 and poly(N-isopropylacrylamide-co-β-methyl acrylic acid) hydrogels

636

(4.77%)3.

637

In order to further measure the bioavailability parameters of orally administered

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insulin-loaded hydrogels, the intestinal uptake of insulin was assessed by measuring

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plasma insulin levels in non-diabetic rats (Figure 8B). S.c. injection of insulin

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triggered a rapid increase in plasma insulin peaking at 63.4 mIU per ml, followed by a

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gradual reduction after 1 h. In contrast, animals receiving insulin-loaded hydrogels

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showed a more gradual increase in plasma insulin, reaching a maximum of 11.7 mIU

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per ml 4 h post-administration. A similar time course of insulin delivery from other

644

types of hydrogels has been observed by others.3,

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bioavailability of s.c. injection of free insulin set as 100%, the pharmacological

54


With the pharmacological

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bioavailability of orally treated sal/PMA semi-IPN hydrogel-loaded insulin was

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calculated to be 6.24%.

648

649

Figure 8. Blood glucose levels of STZ-induced diabetic rats after orally administering

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insulin-loaded hydrogel (25 or 50 IU/kg), free insulin (25 IU/kg), insulin-free hydrogel, s.c.

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injection of free insulin (2.5 IU/kg), or saline via gavage (A, n=6). Blood insulin levels of

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STZ-induced diabetic rats after oral administration of insulin-loaded hydrogel (25 IU/kg), free

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insulin (25 IU/kg), or s.c. insulin injection (2.5 IU/kg) (B, n=6).

654 655

4 Conclusions

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A series of smart salecan-incorporated semi-IPN hydrogels comprised of a soft

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segment of salecan and a high strength network of poly(acrylamide-co-acrylic acid)

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were created using a free radical polymerization approach. These hydrogels displayed

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excellent stability, rapid response rate, high elasticity, and good biocompatibility. In

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vitro insulin release assay demonstrated that the entrapped insulin is protected within

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the hydrogel matrix under acidic conditions, with a selective release at neutral pH

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values. The release of insulin can be properly controlled by simply varying the



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salecan content in the hydrogel composition. Cell viability assays showed that

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salecan/PMA hydrogels were non-toxic. Orally administered insulin-loaded

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salecan/PMA hydrogels to diabetic rats resulted in a successive decrease of blood

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glucose levels, and exhibited a greater than 10-fold rise in pharmacological

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availability compared to free insulin solution given orally. The present findings

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demonstrate that salecan-based hydrogels loaded with insulin have potential for

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controlled delivery of insulin following oral administration.

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Acknowledgements

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This work was supported by the National Natural Science Foundation of China

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(51573078), the China Scholarship Council (Scholarship 201606840064), and the

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National Institutes of Health (R01 DK106972).

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Oral Administration of Salecan-Based Hydrogels for Controlled Insulin

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