Rational Chemical Engineering in Natural Protein Derived Functional

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Letter

Rational Chemical Engineering in Natural Protein Derived Functional Interface Arpita Shome, Adil Majeed Rather, Aindrila Ghosal, Bibhas Bhunia, Biman B. Mandal, and Uttam Manna ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.9b00501 • Publication Date (Web): 01 Apr 2019 Downloaded from http://pubs.acs.org on April 2, 2019

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ACS Sustainable Chemistry & Engineering

Rational Chemical Engineering in Natural Protein Derived Functional Interface Arpita Shome a, Adil M. Rather a, Aindrila Ghosal a, Bibhas K. Bhunia b, Biman B. Mandal b, Uttam Manna a,c * a Department of Chemistry, Indian Institute of Technology Guwahati, Amingaon, Kamrup, Assam 781039, India b Biomaterial and Tissue Engineering Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Amingaon, Kamrup, Assam-781039, India c Centre for Nanotechnology , Indian Institute of Technology-Guwahati, Amingaon, Kamrup, Assam 781039, India

Correspondence and requests for materials should be addressed to U.M. (email: [email protected]) Supporting Information ABSTRACT: Catalyst-free and readily chemically reactive functional coatings that have immense prospects in various relevant applications, is unprecedentedly synthesized directly using naturally existing bovine serum albumin (BSA), where facile Michael addition reaction between amine and acrylate groups provided a simple basis for the covalent integration of deposited BSA and rendered residual chemical reactivity to the protein derived coating. Such chemically reactive BSA based coating was further extended for tailoring various water wettability, including biomimicked superhydrophobicity through appropriate chemical optimizations, and the chemically modulated water wettability was rationally utilized for controlling the rate of release of selected drugs (aspirin and tetracycline) from days to months. The release drug (tetracycline) from the superhydrophobic cotton remained highly bioactive and prevented the proliferation of bacteria (E.coli and S.aureus). Further, the synthesized BSA based superhydrophobic coating is capable of withstanding various physical and chemical challenges. This simple and green approach of synthesizing stable BSA based functional coating has potential in addressing various healthcare and environment related challenges. Keywords: Catalyst free, Chemically reactive, superhydrophobicity, serum protein, biomacromolecular coating, Michael addition reaction

INTRODUCTION Over the last two decades, catalyst-free chemically reactive coatings were explored for various relevant medical applications—including patterning of proteins and mammalian cells, developing antibacterial coatings, tissue engineering, drug delivery etc.1-14 In general, such chemically reactive coatings are developed through uncontrolled polymerization of chemical vapor deposited monomers and layer-by-layer repetitive deposition of non-biodegradable synthetic polymers.1-14 In this present study, naturally synthesized serum protein is unprecedentedly

and directly utilized rather than using synthetic polymer for developing chemically reactive polymeric coatings through the rational use of i) de-solvation technique and ii) catalyst-free Michael addition reaction. This approach is likely to pave way for environment friendly sustainable design of various functional materials. In the past, Michael addition reaction between amine and acrylate groups was exploited for synthesizing various important small molecules and degradable polymers.15-17 Further, this same chemistry was efficiently extended in developing chemically reactive functional polymeric coatings, mostly using non-

Scheme 1 The Michael addition reaction between primary amines and acrylate groups (A) is exploited for the synthesis of bovine albumin serum (BSA) protein based chemically reactive coating (B-D). Desolvation process allowed deposition of BSA having globular domains (C) and this deposited BSA was covalently crosslinked with readily chemically reactive small molecule (dipentaerythritol penta-acrylate, 5Acl; B). (D)The residual acrylate groups in the BSA coating makes it chemically reactive. (E) The post covalent modification of the chemically reactive BSA derived coating with primary amine containing small molecules (e.g. octadecylamine) allowed to achieve superhydrophobicity.

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degradable synthetic polymer i.e. branched polyethylenimine.9,13-14, 18-20 This protein derived chemically reactive coating was successfully utilized in modulating the extent of water repellency. A medically relevant porous substrate with complex geometry i.e. water absorbent fibrous cotton became extremely water repellent after successful deposition of this chemically reactive protein derived coating (scheme 1) followed by post covalent modulation with octadecylamine (ODA). Such a synthetic approach is likely to address the existing challenge of adverse environ-

challenges and other practically relevant and environmentally safe applications.21 RESULTS AND DISCUSSION In the past, de-solvation process was commonly adopted for synthesizing serum albumin protein nanoparticles that are used for therapeutic applications,23-25 where bi-functional crosslinker that is glutaraldehyde, is mostly used for stabilizing the protein nanoparticles.23-25 Recently, a chemically reactive non-degradable polymeric nano-complex, which was prepared from synthetic polymer, was associated for developing chemically reac-

Figure 1. FESEM images of BSA coated fibers of medical cotton at low (A) and high (B) magnifications. Schematic (C) illustrating post covalent modulation of chemically reactive BSA coating through Michael addition reaction between the residual acrylate groups and selected amine containing different small molecules. FTIR spectra (D) of chemically reactive BSA coated cotton before and after post covalent modification with pentylamine, hexylamine, octylamine, decylamine and octadecylamine. The peaks at 1410 cm-1 and 1735 cm-1 correspond to the symmetric deformation of the C-H bond of the β carbon of the vinyl group and carbonyl stretching respectively. E) Bar diagram representing the static water contact angles on BSA coated cotton after the post modifications with amine containing different small molecules including pentylamine, hexylamine, octylamine, decylamine and octadecylamine. F-G) Digital images of beaded water droplet on bare cotton (F) and on BSA coated cotton (G) after post modification with octadecylamine. H-I) Digital images of beaded water droplet on superhydrophobic cotton after post loading of dye molecules—including rhodamine 6G (H) and fluorescein (I).

mental impact—from materials that are mostly developed using synthetic non-degradable polymers and fluorinated molecules.21-22 The water repellency in the current synthesized material remained intact even after post-loading with hydrophilic small molecules. The chemically modulated water wettability provided a facile basis for tailoring the release rate of post encapsulated drug molecules (aspirin, tetracycline) from days to months. Such naturally existing protein derived functional coatings would be useful in addressing various relevant biomedical

tive polymeric coating.13-14 Inspired from these previous early demonstrations,13-14 here a completely different design is developed, where the bovine serum albumin (BSA) was directly deposited on a geometrically complex fibrous substrate (i.e. medical cotton) without any prior surface modifications, unlike in the past reports,13-14 following ethanol based desolvation process. The deposited BSA protein strongly adheres to the cotton fibers likely through hydrogen bonding, similar to the mussel inspired chemistry.26 The durability of the synthesized coating on cotton fiber will be later discussed in details. The successful


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ACS Sustainable Chemistry & Engineering coating were strategically exploited for post covalent modulation with selected primary amine containing small molecules (i.e. pentylamine, hexylamine, octylamine, decylamine (DA) and octadecylamine (ODA) as shown in Figure 1C-D. During the Michael addition reaction between acrylate and amine groups, the hybridization of carbon atoms for the vinyl moiety changed from sp2 to sp3, and subsequently, C=C is converted to C-C, however, the carbonyl moiety remained unaffected and provided an internal reference to monitor the progress of the reaction.8 Thus, reduction in the IR peak intensity at 1410cm-1 for C-H stretching of β carbon of the vinyl groups, with respect to the normalized IR peak intensity for carbonyl groups at 1735cm-1 confirmed the successful post chemical modification of the chemically reactive protein derived coating as shown in Figure 1D. The medical cotton (Figure 1F) remained hydrophilic even after deposition of BSA nanoparticles as shown in Figure S1A-B. A small change in water contact angle (10°) was noticed after treatment with 5Acl molecules, but, overall the material remained highly hydrophilic as shown in Figure S1C-D. Nevertheless, the post covalent modulation of the chemically reactive coating with selected small molecules provided a facile basis to tailor the hydrophobicity in the medically relevant substrate. The chemically reactive BSA derived hydrophilic (water contact angle (WCA) of 10°; Figure S1C-D) coating was found to be highly hydrophobic with WCA of 144° after post chemical modification with octylamine (Figure S2A-B) due to covalent modulation of the chemically reactive coating through Michael addition reaction. In a control study, the same chemically reactive BSA coating was treated with octanol (having the same hydrocarbon tail but with a hydroxyl head group), instead of octylamine. After the treatment with octanol, the BSA derived coating remained hydrophilic (Figure S2C-D) as the hydroxyl groups of octanol are inappropriate for reaction with residual acrylates through Michael addition reaction at ambient condition. Thus, the significant change in water wettability on treating the chemically reactive BSA coating with selected small amine suggested the covalent optimization of essential chemistry through Michael addition reaction. Furthermore, the chemically reactive BSA coated medical cotton became more hydrophobic on increasing the hydrocarbon tail in the amine containing small molecules. After, the DA and ODA treatments, the water absorbing fibrous substrate became extremely water repellent, with static water contact angle above 155° as shown in Figure 1E. Such controlled optimizaFigure 2. (A-I) Digital images (A, B, D, E, G, H) and water contact angle tion of water wettability (Figure 1E) is not posimages (C, F, I) of beaded water droplet on the protein derived superhydrosible without strategic and covalent modificaphobic cotton after performing finger wiping test (A-C), tissue paper wiping tion of the precursor e.g. albumin as evident (D-F) and arbitrary cutting with scissor (G-I) to demonstrate the physical dufrom the demonstration in Figure S1G-H. This rability. J) Plot accounting for the advancing contact angle (black) and contact superhydrophobic property remained intact angle hysteresis (red) of the beaded water droplet on BSA derived superhyeven after post loading with different hydrodrophobic cotton after exposure to harsh aqueous chemical conditions includ-

deposition of BSA protein nanoparticles (~7.2 wt %) having granular domains on the randomly entangled microfibers of cotton were characterized through FESEM imaging as shown in Figure 1A-B. The deposited protein nano-aggregates were covalently cross-linked with a multifunctional small molecule (MW ~ 524.51gmol-1, 5Acl) having penta-acrylate groups, where the acrylate groups of the 5Acl molecules provided a facile basis for a) covalent crosslinking through Michael addition reaction and b) the residual acrylate moieties made this protein derived coating chemically reactive. The FTIR analysis revealed the presence of residual acrylate groups in the synthesized coating, where the IR peaks at 1410 cm-1 and 1735 cm-1 correspond to the asymmetric stretching vibration of C-H bond of β carbon of the vinyl groups and stretching vibration of carbonyl groups respectively. These residual acrylate groups in the

ing extremes of pH (1,12), surfactant contaminated water (SDS,DTAB), river water (Brahmaputra river, Assam, India) and artificial sea water for 7 days.



Figure 3. (A-B) Digital images (A) and contact angle images (B) of beaded water droplet on biomacromolecule based superhydrophobic cotton after post loading tetracycline. C-D) Bright field (C) and fluorescence (D) microscopic images of tetracycline loaded superhydrophobic cotton. E-F) Digital and contact angle images accounting for the beading of water droplet on aspirin loaded superhydrophobic cotton. G-J) Plots illustrating the release of tetracycline (G, I) and aspirin (H, J) from the BSA derived superhydrophobic cotton for 2 days (G, H) and 110 days (I, J) in phosphate buffer at pH 7.4 and 37ᵒC.

philic small molecules (e.g. rhodamine, fluorescein and methylene blue) as shown in Figure S3-S5. The synthesized material was separately exposed to solutions of rhodamine and fluorescein in ethanol, and after removal of ethanol, selective dye molecules were deposited on the BSA protein coated fibrous substrate as confirmed from visual change in color of the medical cotton (Figure 1H-I). The ethanol solvent having low surface tension can readily wet the superhydrophobic interfaces, and the material restored its water repellency after removal of this volatile organic solvent, and eventually allowed the post loading of external small molecules. Further, the fluorescence images of these materials confirmed the uniform deposition of the selected hydrophilic small molecules on each fibers of the used cotton substrate (Figure S6). Thus, the super water repellency remained unaffected, even after deposition of external hydrophilic small molecules on the biomacromolecules based superhydrophobic material as shown in. Next, the protein derived superhydrophobic cotton was exposed to various physical and chemical challenges for examining the

durability of the embedded anti-wetting property. Firstly, the cotton was rubbed with the finger in to and fro motion for 15 times (Figure 2A). The anti-wetting property of the as synthesized cotton remained intact as shown in Figure 2B-C and the beaded water droplet completely rolled from the physically abraded surface (see movie 1). Next, the superhydrophobic cotton was rubbed with a rough substrate (i.e. tissue paper) for multiple times (Figure 2D). However, the physical integrity and the water repellent property remained unperturbed with advancing contact angle 155º as shown in Figure 2E-F and movie 2. Furthermore, the BSA derived superhydrophobic cotton was cut along one edge with a sharp edged scissor (Figure 2G). During this scissor cutting process the material is exposed to two extreme physical challenges; a) large compression and b) forceful disconnections of randomly entangled coated cotton fibers, which resulted in exposure of the interior of the synthesized material. However, the anti-wetting property remained unaffected and beaded water droplets completely rolled off from the newly exposed interface as shown in Figure 2H-I and movie 3. Hence,


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ACS Sustainable Chemistry & Engineering

Figure 4. (A-D) The plots illustrate the controlled release of tetracycline (A, C) and aspirin (B, D) from the chemically reactive BSA coated cotton after the post modification with strategically selected primary amine group containing different small molecules, including pentylamine (blue), hexylamine (grey), octylamine (yellow) and decylamine (red) respectively for 2 days (A, B) and 50 days (C, D).

these results implies that the BSA derived superhydrophobic property of the cotton is highly durable towards harsh physical conditions. Moreover, the chemical durability of the as synthe-

sized superhydrophobic cotton was explored in which the superhydrophobic cotton was exposed to various harsh aqueous chemical conditions including extremes of pH (1, 12), surfactant (SDS, DTAB) stabilized water, river (Brahmaputra Assam,

Figure 5. (A-F) Digital images of Disc-diffusion assay of released tetracycline (180 µg/ml) from BSA derived superhydrophobic cotton at different time intervals including one day (A, D), three days (B, E) and seven days (C, F) against E.coli (AC) and S.aureus (D-F). +ve and -ve control represent as freshly added tetracycline (180 µg/ml) and sterile PBS impregnated discs, respectively. In digital images, “S” represents “released tetracycline” from BSA derived superhydrophobic cotton.



Table 1. Measurement of antibacterial activity (zone of inhibition) of releasate tetracycline against the test bacteria (Staphylococcus aureus and Escherichia coli) following disc-diffusing method. +ve control = tetracycline (180 µg/ml), -ve control = sterile PBS (pH 7.4) and N.D. = not detected.

India) water, artificial sea water respectively for 7 days. Nevertheless, the anti-wetting property of the cotton remained unperturbed with advancing contact above 150º and contact angle hysteresis below 10º after exposure to these harsh chemical environments as shown in Figure 2J. Such high durability can be attributed to the presence of covalently crosslinked network of BSA nanoparticles and covalent post chemical optimization through 1,4-conjugate addition reaction. In the past, the metastable trapped air that conferred extreme heterogeneous water wettability was strategically exploited for the long term release of small molecules,15,27-30 where the external trapped air phase controlled the rate of infiltration of aqueous phase in the small molecules loaded water repellent materials.30 All those demonstrations of prolonged release of encapsulated small molecules were performed with superhydrophobic material that are prepared using synthetic polymeric coatings.15,27-30 Furthermore, thin superhydrophobic coatings on flat objects are less appropriate for sustained release of small molecules, due to the presence of limited trapped air as evident from previous report.29 So, the protein derived extremely water repellent material is examined for the post-loading and release of bioactive drug molecules (i.e. tetracycline and aspirin). First, tetracycline, which is a widely used antibiotic, was post-loaded following ethanol assisted temporary and reversible switching of extreme water repellency. The super water repellency remained intact even after post loading (0.6 mg) of tetracycline in the biomacromolecules derived material, and the aqueous (blue color aids visual inspection) droplet beaded on the material with advancing water contact angle of 158°as shown in Figure 3AB. After the post loading of tetracycline, white superhydrophobic cotton turned to pale yellow, and further optical microscopic (bright field and fluorescence) images revealed the successful and uniform deposition of tetracycline as shown in Figure 3CD. Similarly, another bioactive small molecule i.e. aspirin, which is mostly used as an anti-inflammation agent was post loaded onto the medical cotton, without affecting the embedded superhydrophobicity, and the beaded water droplet was repelled with advancing water contact angle of 159° as shown in Figure 3E-F. Then, this tetracycline and aspirin loaded superhydrophobic medical cotton was separately exposed to PBS buffer at pH 7.4 and 37°C for examining the release rate of encapsulated small molecules from the biomacromolecules derived superhydrophobic material. Both tetracycline and aspirin, which are widely different with respect to their structures and functionalities, continued to release over 100 days. Initially, around 30 % of the loaded drug was released over 2 days for tetracycline

(Figure 3G) and aspirin ( Figure 3H) and then, this release sustained for a long duration, and it look 110 days for releasing 90% of the total loaded drug molecules from the as-synthesized material as shown in the Figure 3I-J. An early burst release is not observed in compact and thin polymeric superhydrophobic meshes27-28, the initial burst release from the less compact superhydrophobic medical cotton is likely due to the existence of more exposed surface area, which allowed to release surface deposited small molecules rapidly. This chemically reactive biomacromolecular coating that is capable of tailoring the water wettability through appropriate chemical modulation, was rationally exploited further in optimizing the release rate of encapsulated small molecules (aspirin and tetracycline). The pentylamine treated biomacromolecular coating with moderate hydrophobicity (static water contact angle of 125°) was noticed to release 64 % of the total encapsulated tetracycline over 2 days as shown in Figure 4A, and this extent of release was observed to have gradually decreased on increasing the hydrophobicity of the selected fibrous substrate through strategic post modification of biomacromolecular reactive coating with hexylamine and octylamine molecules. However, the extent of release over the same duration (2 days) was significantly reduced to ~36% and only ~62% of the total drug is released over 50 days as shown in Figure 4A, C after modifying the chemically reactive biomolecular coating with decylamine molecules. The material became super-water repellent after decylamine treatment and the metastable trapped air contribute to this significant change in the release rate. Very similar trend was also observed for the release of aspirin as shown in Figure 4B, D. The released drug molecules remained bioactive in the earlier demonstrations.27-28 Here in the current study, we have further performed the antibacterial study of the released tetracycline from the BSA derived superhydrophobic cotton against two different types of bacteria i.e., Staphylococcus aureus (S. aureus), a gram +ve bacteria and Escherichia coli (E. coli), a gram -ve bacteria. To determine the activity of released tetracycline from superhydrophobic cotton, an inhibition zone of bacterial growth surrounding the discs on nutrient-agar plate was estimated and this activity was compared with freshly added tetracycline drug molecules. In both the cases, the concentration of the tetracycline was 180µg/ml. In case of E. coli, around 14 mm of inhibition zone was measured, whereas a similar antibacterial activity (~ 17 mm of inhibition zone) in S. aureus was recorded for both the released tetracycline and freshly added tetracycline (Figure


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ACS Sustainable Chemistry & Engineering 5A-D). The sterile PBS (+ve control) did not show any antibacterial activity against the both bacteria. Moreover, release tetracycline over 3 day and 7 days remained very efficient in inhibiting the bacterial growth as shown in Figure 5B-F. The overall results indicated that there was no significant difference in inhibition zones by both the released tetracycline and the freshly added tetracycline against both bacteria. The details of inhibition zone by both released tetracycline and freshly added tetracycline against both bacteria are presented in Table 1. CONCLUSION In conclusion, Michael addition reaction is rationally and successfully exploited in developing serum protein based chemically reactive coating for controlled tailoring of water wettability—following strategic post covalent modulations without the aid of any catalyst. This 1,4-conjugate addition reaction guided hydrophobicity was successfully extended for the controlled release of bioactive small molecules. This early demonstration provided a facile basis to develop therapeutically potent implant—by selecting appropriate medically relevant substrates.

ASSOCIATED CONTENT Supporting Information

The Supporting Information is available free of charge on the ACS Publications website, the attached supplementary information accounting for materials and method and Figure S1-S6 illustrating the water wettability of biomacromolecular coating after post loading with different hydrophilic small molecules, successful deposition of small molecules on the biomacromolecular coating.

AUTHOR INFORMATION Corresponding Author a,c*[email protected].

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We acknowledge the financial support from Department of Biotechnology (BT/PR21251/NNT/28/1067/2016), (grant no. 5(9)/2012-NANO) and Board of Research in Nuclear Sciences (BRNS) (34/20/31/2016-BRNS, DAE-YSRA). BBM acknowledges Department of Biotechnology (DBT) and Department of Science and Technology (DST) for generous financial support. We would like to thank the Chemistry Department and Indian Institute of Technology-Guwahati for their generous support. Ms. Arpita Shome, Mr. A. M. Rather, Ms. Aindrila Ghosal and Mr. Bibhas Bunia thanks the institute for their PhD fellowship.

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(20) Ford, J.; Marder, S. R.; Yang, S. Growing “Nanofruit” Textures on Photo-Crosslinked SU-8 Surfaces through layer-bylayer Grafting of Hyperbranched Poly(ethyleneimine). Chem. Mater. 2009, 21, 476-483. (21) Su, B.; Tian, Y.; Jiang, L. Bioinspired Interfaces with Superwettability: From Materials to Chemistry. J. Am. Chem. Soc. 2016, 138, 1727-1748. (22) Conder, J. M.; Hoke, R., Wolf, W. D.; Russell, M. H.; Buck, R. C. Are PFCAs Bioaccumulative? A Critical Review and Comparison with Regulatory Criteria and Persistent Lipophilic Compounds. Environ. Sci. Technol. 2008, 42, 995-1003. (23) Xie, L.; Tong, W.; Dahai, Y.; Xu, J.; Li, J.; Gao, C. Bovine serum albumin nanoparticles modified with multilayers and aptamers for pH-responsive and targeted anti-cancer drug delivery. J. Mater. Chem. 2012, 22, 6053-6060. (24) Lee, H. J.; Park, H. H.; Kim, J. A.; Park, J. H.; Ryu, J.; Choi, J.; Lee, J.; Rhee, W. J.; Park, T. H. Enzyme delivery using the 30Kc19 protein and human serum albumin nanoparticles. Biomaterials 2014, 35, 1696-1704. (25) Lam, P.-L.; Kok, S. H.-L.; Gambari, R.; Kok, T.-W.; Leung, H.-Y.; Choi, K.-L.; Wong, C.-S.; Hau, D. K.-P.; Wong, W.-Y.; Lam, K. H.; Bian, Z.-X.; Lee, K. K.-H.; Chui, C.-H.

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TOC: The current approach introduced a green and sustainable method for tailoring various water wettability through strategic use of naturally abundant ingredients (protein and cotton fiber) and facile Michael addition reaction at ambient condition.


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Rational Chemical Engineering in Natural Protein Derived Functional

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