Functional polymer materials affecting cell attachment Bo Jiang, Jian Yang, Nahla Rahoui, Nadia Taloub, Yu Dong Huang PII: DOI: Reference:
S0001-8686(17)30140-9 doi:10.1016/j.cis.2017.09.002 CIS 1827
To appear in:
Advances in Colloid and Interface Science
Please cite this article as: Jiang Bo, Yang Jian, Rahoui Nahla, Taloub Nadia, Huang Yu Dong, Functional polymer materials affecting cell attachment, Advances in Colloid and Interface Science (2017), doi:10.1016/j.cis.2017.09.002
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ACCEPTED MANUSCRIPT Functional polymer materials affecting cell attachment
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Bo. Jiang* 1,2 , Jian. Yang.1, Nahla. Rahoui1, Nadia. Taloub1, YuDong. Huang1
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1. Polymer Materials and Engineering Department, School of Chemical Engineering
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and Technology, Harbin Institute of Technology, P.O.Box: 1254, Harbin 150001, People’s Republic of China
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2. Department of Chemistry, National University of Singapore, Singapore, 117543
* Corresponding author:
B. Jiang
Tel: 86-451-8641-4806, Fax:86-451-8641-8270;
E-mail:
[email protected]
ACCEPTED MANUSCRIPT Abstract: This review discusses the functional polymer materials effect on the cell adhesion.
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The applied polymer materials for the cell adhesion purpose was prepared based on
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organic fibers and biocompatible hydrogel. On the other hand, the active peptides are incorporated into the polymer materials substrate via the cysteine-containing peptides and N-hydroxysuccinimide- active group. Cancer cells and normal cells were presented
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for the selective adhesion via the introduced polymer materials substrate containing
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active peptides including Arginine – Glycine - Aspartic and Isoleucine - Lysine – Valine - Alanine – Valine sequence peptides. This selectivity is revealed by a significant
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cooperativity between specific and non-specific cell adhesion. This study is of a great
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impact for the design of the polymeric structures for cell attachment.
Keyword：Organic fibers; Polymer materials; Surface modification; Resins; Adhesion
ACCEPTED MANUSCRIPT 1. Introduction: When the cell structure was found via microscope, researches on cell biology
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gradually become a hot field [1-3]. Contributions from other disciplines including
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molecular biology, bioengineering, biomechanics, combinatorial chemistry, and polymer materials science continue to make great advances in this exciting field [4-6]. Cell biology have been extensively applied in drug delivery [7,8], gene express [9,10]
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and disease diagnosis [11,12].
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The functional polymers linked to peptide promote a novelty biopolymer material, where each component presents a complementary advantage to the whole system. In
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addition, the functional polymer linked to peptide systems has the excellent biological
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properties [13-17]. It is not only used to study in vivo extracellular environments, but
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also to detect any change in the biological activities at the cell level. Thus, this systems might open a new feature for early diagnosis of diseases.
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Active peptide has the potential to achieve the control of the molecular structure over multiple length scales, and exhibit enriched chemical heterogeneity. The molecular design of the peptides with an amide groups presented such as cyclic, helix and dendritic structure. For the natural peptides structure, it is spontaneously organized in supramolecular architectures through noncovalent bonds interactions. For the high biocompatibility and bioactivity of the peptide molecular design, the novel biomacromolecules structure is developed also. This overview focuses on the progress made in polymer materials linked peptide for cell-adhesion, and covers the applications that arise from merging the polymer into
ACCEPTED MANUSCRIPT the biological field [18-20]. The novel strategy for cell-adhesive peptide based functional polymer materials could lead to an attractive technology.
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Herein, this review reports the various synthetic routes available for generating
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peptide-polymer materials. The functional polymer materials are outlined to provide a map of the potential structures and their applications.
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2. The peptide incorporated the polymer materials
2.1 Strategies of polymer microarray for high-throughput cell-based screening
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High-throughput microarrays have increasingly become an alternative for an effective screening of different cells’ types based on polymer libraries (Figure.1). High-
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throughput microarrays are frequently used to explore the interactions between cells and a wide range of targeted molecules include peptide. Mei et al. [21,22] used twenty
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two acrylate monomers (The acrylate monomers are optimal stem cell substrates, especially for human embryonic stem cell cultures.) to create a library of 496 different
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polymers on a conventional glass slide when each major monomer was mixed with each of 6 other minor monomers at 6 different ratios. The developed high throughput microarrayed polymer system is used to study the islet cell culture. In addition, several researchers [23,24] employed different acrylate monomers properties including the hydrophobicity, hydrophilicity and crosslinking densities at different combinations in order to establish quantitative models between polymer-surface and clonal growth of embryonic stem cells via high-throughput microarray. This study is important for the enhancement of the stem cells screening specification for the early cancer diagnosis and quick disease prevention.
ACCEPTED MANUSCRIPT The performance of polymer materials directly influences the high-throughput cell screening. Anderson et al. [25,26] studied the polymer-cell interactions, and designed
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polymer libraries for specific cell’s types. 576 different combinations from 25 different
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acrylate monomers type with a radical initiator were designed. High-content image analysis is routinely applied in high-throughput cell-based screening in order to assure its adaption to the analysis of micro-arrayed cells. The developed polymeric libraries
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could provide a novel control over cell behavior. This technology might be useful for
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the screening of biomaterials interactions with other synthetic materials. On the other hand, Hook et al. [27] reported a novel polymer materials system, resistant to the
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bacterial attachment by using a high throughput methodology. The first generation
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array was composed of 116 homo polymers, 8 of them were selected as “hits” onto a
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poly- (hydroxyl ethyl methacrylate) coated glass slide. The second generation array was consisted of 324 copolymers, formed by mixing 18 “hit” monomers pairwise. This
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results reveals that the presented polymer microarray technology can provide an efficient manner to polymeric substrates screening of a variety of biological cells for multiple applications. In order to provide a guide for polymer microarrays and novel polymer formulations, Epa et al. [28] developed the model of the complex process in pathogen attachment to polymer libraries via molecular descriptors, where 496 polymers was synthesized by mixing 22 monomers at various ratios. Pathogen attachment to the polymer included in this second generation library could be predicted by using a set of models generated from the first generation library. The accuracy of these predictions could then be
ACCEPTED MANUSCRIPT assessed using pathogen attachments measurement from the second library. This technique is advantageous and presents a valuable contribution to the rational design of
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functional materials including the generation of implantable and indwelling medical
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devices.
The developed acryloyloxy polymer libraries are illustrated in the Figure. 2, these polymers are cured via ultraviolet light due to its selectivity to grow up different types
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of cells. This technology could be applied to early diagnosis of several diseases such as
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the early screening of cancerous cells. The discussed polymer libraries are applied for high-throughput screening based on acryloyloxy molecular structure, which suits the
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rapid addition polymerization under ultraviolet light.
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Polymeric microarray for high-throughput cell-based screening has several
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advantages such as: it needs little amounts of reagent and can enhance the screening effect. Contributions from the disciplines of medicine, chemistry, molecular biology,
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mathematics, and computer science continue to make a great development in this exciting field. Moreover, polymer microarray for high-throughput screening strategy is mainly applied in vitro like as extracellular environments of the living cells. In vivo experiment, however cannot fully illustrates the adhesion process between the polymer and the targeted cell. In addition, polymer library for in vivo experiments is limited and needs a continued improvement. With the technical development of high-throughput screening and the study of novel and practical polymer library, the polymer library system gives more abundant information about various diseases and provides an early diagnosis.
ACCEPTED MANUSCRIPT 2.2 Peptides synthesis strategies based on functional polymeric materials Peptides are natural biological molecules with short chains of amino acid monomers
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linked by amide bonds. The molecular structure design of the peptides mainly affects
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their biological properties. Hamley and co-workers [29] studied the self-assembly of cyclic, amyloid peptides and surfactant-like peptides into nanotubes structure. Typically, the designed peptides types includes the linear, cyclic and helix or dendritic
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structures [30]. Khew and co-workers [31] designed the triple-helical peptides for cell
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adhesion via the collagen peptides template. This structure advantage is directly connected to the N-termini of three collagen peptides by three carboxyl groups in the
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peptide template
2.2.1 Design of the peptides molecular structure
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Cardin and co-workers [32] proved that a particular pattern of amino acids could represent putative heparin-binding sequences. Two methods was provided for peptide
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design. First method is basic and hydropathic amino acid combination [33,34]; Second method is different charges amino acid combination [35]. (1) Peptides designed by basic and hydropathic amino acid combination. B-B-B-X (48 compounds modes) B:
Basic amino acid (Lys, Arg);
X: Hydropathic amino acid (Asp, Glu, Ser, Thr, Asn,Gln); This type of combination has 48 different peptides. X-B-B-X-B-X B:
(64 compounds modes) ;
Basic amino acid (Lys, Arg);
ACCEPTED MANUSCRIPT X: Hydropathic amino acid (Asp, Ser); This type of combination has 64 different peptides.
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The terminal group of these peptides is Cys (C), it can react with double bond polymer
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library. (2) Peptides were designed by different charges
1) Cyclic peptide containing Arginine Glycine and Aspartic acid (RGD) sequence
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within different charge (positive, negative and neutral) is given. The positive amino
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acids are from K, R, H; the neutral amino acids are from S, T, N, Q, Y, G; the negative amino acids are from E, D. This kind of cyclopeptide could be used for specific cell
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adhesion due to the RGD peptide effect.
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2) Linear oligopeptide such as KKKGGGC, GGGGGGC, DDDGGGC sequences.
charges.
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peptide with positive, negative and neutral to non-specific cell adhesion via different
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Terminal group of peptides is Cys (C), it can react with double bond of the polymer library via thiol–ene addition. Uttamchandani et al. [36] have synthesized 20 peptides vinyl sulfone probes as a microarray based high-throughput strategy in order to get an active fingerprinting of cysteine proteases. This strategy relies on the miniaturization ability of microarray technology, it allows subarrays of many proteins to be assayed simultaneously in a single slide. 2.2.2 Functional polymeric materials with an active peptides This system is elaborated by using a click chemistry reaction as an excellent strategy due to its versatility in terms of reaction conditions. Click chemistry reaction can ensure
ACCEPTED MANUSCRIPT a reaction between the polymeric materials with the end activity group of the peptides. The peptide could be incorporated into the polymer materials substrate via the thiol–
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ene addition with cysteine-containing peptides as shown below in (1), and NHS--
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containing peptides as shown below in (2).
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(1) Thiol–ene addition with cysteine-containing peptides
(1)
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Some chemical activity groups such as amine, carboxylic acid and thiol are
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potentially present in peptides, they could be used for specific reaction, especially
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cysteine residues for thiol-ene chemical reaction. It could to be related to the wider scope of reaction possible with thiol groups, which is responsible for the popularity of
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cysteine-based modifications. Nalini and co-workers [37] developed a facile strategy to fabricate multifunctional high-throughput microarrays embedded at the surface of a
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hydrogel substrate using thiol-ene chemistry. The robust and orthogonal nature of thiolene chemistry allows a range of covalent attachment in a fast and reliable manner. Missirlis and co-workers [38] presented thiol group terminated functional groups attachment to PEG-based hydrogels. The peptide is incorporated on hydrogels via thiol–ene addition reaction. Authors emphasized that persistent migration of cells is sensitive to the mechanics and the biochemistry of the substrate. 2) NHS –active group
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Reference [39]
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(2)
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The coupling of polymer-linked peptide with an NHS-terminus group is general
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method. In most cases, the attachment of peptides through the NHS terminus results in the formation of an amide linkage. Tsurkan and co-workers [39] elaborated an active
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molecular linker, which is the multi-functional star PEG-peptide heparin hydrogels
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based on NHS as an ending group (Fig. 3) by following this process: At first, the peptide
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was incorporated into 4-armed-PEG hydrogel via NHS active group. Then, the heparinmaleimide was conjugated by coupling to the novel peptides via Michael addition
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reactions to the NHS active group. At least, the functional hydrogels with peptides cell adhesion was investigated. In addition, with the NHS-terminus group, the substrates can theoretically be stored in polymer active form for further functionalization. Ying and co-workers [40] synthetized functional hydrogel nanoparticles from the soap-free emulsion copolymerization using PEG with NHS and N,N’-methylene bisacrylamide crosslinker. They developed an electro-responsive hydrogel nanoparticle modified with angiopep2 as the targeting ligand for antiepileptic drug delivery and drug release. Danial and coworkers [41] coupled cyclic peptide-polymer conjugates through NHS activity group,
ACCEPTED MANUSCRIPT the designed system with a single cyclic peptide core and polymeric shell exhibits a thermo-responsiveness. The thermo-responsive channels can provide new insights for
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the creation of transport links between the cytosol and the extracellular media.
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3. Active peptides affecting cell attachment based on functional polymer materials
3.1 The active peptides effect on the cell attachment
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Cell attachment is an important aspect in cellular response to biomaterials [42- 44].
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Cell adhesive molecules have the ability to bind into a substrate and meanwhile significantly enhance the cell attachment to the biomaterials. It serves as a ligand for
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the supporting cell attachment from extracellular matrix adhesion molecules. Certain
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peptides belong to a group of the fundamental surface modifiers to enhance the cell
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interactions with biomaterials and improve their ability to promote beneficial interactions with cell surface [45-47]. These peptides are desirable due to their
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chemotactic characteristics. They can be used as mediators of cell adhesion. At the same time, it can promote cell attachment ensured by their characteristic sequences, which are found in a number of different extracellular matrix molecules. Arginine Glycine Aspartic acid (RGD) amino acid sequence is the most studied and reported peptide sequence. RGD peptide sequence in the tenth type III repeat of fibronectin serves as a primary cell attachment cue [48]. Furthermore, the synthetic peptides that contain the amino acids RGD can essentially mimic cell attachment activity of the parental molecule [49-56]. However, other amino acid sequences such as isoleucine - Lysine – Valine-Alanine – Valine (IKVAV) and their derivatives also induce cell–material
ACCEPTED MANUSCRIPT interactions [57-62]. In addition, IKVAV sequences attached to polymeric surfaces mainly induce the adhesion of neuronal cells. A number of extracellular molecules
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contain one or more amino acid sequences that may function as cell attachment signals
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are Cysteine- Glycine- Arginine- Glycine- Aspartic- Serine- Proline (CGRGDSP) and Cysteine - Isoleucine - Lysine – Valine-Alanine - Valine (CIKVAV), these peptides sequences present the excellent attachment activity for this different types cell.
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3.2 Polymer materials substrate- PBO fiber
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Polymers materials that have mechanical strength, degradable and responsive performance, have been used in both simple and complex biopolymer. The chemical
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and physical properties of this polymeric materials, which include organic fiber and
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functional resins can be rather tuned to adapt to a specific application [63-65]. These
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organic fiber and functional resins can be readily processed for functional modification, which is advantageous in biologic and medicine [65-70]. Moreover, the source for these
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polymers materials is form crude carbon materials and has special advantages on the sustainable development. Fibers materials that have been used in bio- polymer [71], are the future directions for chemical biology because of its microstructure and surface property. Jain and coworkers [72] exploited engineering aligned polycaprolactone nanofibers to invade a primary intracortical tumour to an extracortical location. The implantation of the nanofiber films resulted in a significant reduction in total tumour volume. Liu et al. [73] used the two enantiomers of a 1,4-benzenedicarboxamide phenylalanine derivatives as supramolecular gelators. The specific chirality of
ACCEPTED MANUSCRIPT nanofibrous hydrogels can greatly enhances the cell adhesion and proliferation densities in a 3D environment. The left-handed helical nanofibers can increase cell adhesion and
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proliferation, whereas right-handed nanofibers have the opposite effect.
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Poly(p-phenylene benzobisoxazole) (PBO) fibers, representative of high-performance fibers, are characterized by high tensile strength, high stiffness, and high thermal stability. They are prepared using trichlorobenzene via nitration and hydrogenation, an
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intermediate of 4,6-diamionophenol dihydrochloride (DADHB 2HCl) is obtained, PBO
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is prepared using polycondensation of DADHB 2HCl and terephthalic acid in poly phosphoric acid (PPA) [74-76]. Prepared product was dry-jet wet spun using a piston-
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driven system specially designed for this purpose. Figure 4 shows the synthetic process
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of PBO.
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At first, the surface of PBO fibers was activated by epoxy chloropropane and then linked to silane coupling agent [77-79]. The active PBO fiber with homogeneously
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epoxy groups was available for the subsequent interaction with ethanediamine to obtain functional PBO fibers. Finally, CIKVAV peptide is incorporated into of the functional PBO fibers surface via thiol–ene addition with cysteine-containing peptides. This process is illustrated in Figure 5. In our study, the thiol-ene chemistry is used to fabricate covalently attached points at the surface of organic fiber substrates based on functional PBO fibers and it is therefore introduced the CIKVAV peptide spot at this position. PBO fiber is chosen as the main component of the polymer material matrix, as it presents a resistant to cell attachment, and therefore localizes cell interactions at the printed functional peptide
ACCEPTED MANUSCRIPT spots that mediate the cell adhesion. The free amine group of the Cys residue has been used as anchoring position through which the peptide can be coupled to PBO fiber
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surface. The viscosity of the pre-polymer mixture, combined with the very rapid cross-
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linking reaction, does not dissolve or perturb the peptide, it maintains the integrity of the array. Herein, we report the chemical synthesis of the designed CIKVAV peptide, which is banded on of PBO fiber surface. Hela cell is cervical cancer cells [80], it’s
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adhered selectively on functional the surface of the PBO fiber with activated peptide
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spot. This process is presented in Figure 6(i). Hela cell is attached to the positive controls CIKVAV peptide spots based on the functional PBO fiber (Figure. 6ⅱ).
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3.3 Polymer materials substrate- PEG hydrogel resin
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Hydrogels have received much more attention for biological and bio-
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pharmaceuticals applications [81,82]. They are prepared based on poly(ethylene glycol) (PEG) molecular due to the abundant hydroxyl groups in the PEG molecular structure,
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also the high water content in the PEG, its hydrophilicity with high permeability, and biocompatibility [83,84]. Cushing and co-workers [85] synthesized PEG hydrogel via click chemistry. A chemical cross-linking between PEG and peptides has been used to encapsulate human mesenchymal stem cells. This process promotes the specific cellular interactions with the covalently bound peptides. Moriyama and co-workers [86] used horseradish peroxidase as a hydrogelation catalyzer of the polymeric thiol substrates. The prepared hydrogel can effectively encapsulate and release living mammalian cells. Moreover, Liu and co-work [87] synthesized the alkyne-functionalized hydrogel by atom transfer radical polymerization as a delivery platform. The amino acid sequence
ACCEPTED MANUSCRIPT 8Q epitope is incorporated into the functionalized hydrogel via copper-catalyzed alkyne−azide 1,3-dipolar cycloaddition click reaction. The synthetic polymer-peptide
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conjugates were able to reduce tumor growth as macromolecular vaccine candidates
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against HPV-related cancers.
In order to enhance the ability to incorporate orthogonal reactive groups of peptide, thiol-ene chemistry to fabricate high-throughput microarrays covalently attached at the
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surface of hydrogel substrates based on PEG is used [88]. The free amino group of the
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Cys residue has been used as anchoring position through which the peptide can be coupled to the surfaces of PEG-hydrogel. Therefore, the caging group (prostate-specific
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antigen-PSA protease protease substrate) is incorporated at this position [89-91]. On
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the other hand, it is also known that the amino acid in the fifth position (Asp) does not
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have significant influence on the activity of the CGRGDSP (-RGD-) peptide [92]. Functional hydrogel with Cage-RGD peptide is used for prostate cancer (PC) cell
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screening (see Figure.7). Because only PC-3 cancer cell can secrete PSA protease and release the activity of the –RGD- peptide from Cage-RGD-peptide. CHO [93], NIH3T3 [94] and Hela cells did not secrete PSA protease, so that Cage-RGD-peptide could not been activated. The developed strategy has a remarkable significance for early diagnosis and screening PC-3 cell based on high-throughput microarrays. As a perspectives for this studies, an increased consideration will be given to the hydrogel functionalization with Cage-–RGD-peptide adhesion to different cancer cells and the development of novel cell library. The developed approaches will provide expanded tools for future investigations and applications of peptide functionalization.
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Conclusion
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In this review, we have introduced several polymeric materials substrate, activated
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peptides and their application for cell adhesion. The activated peptides are incorporated into the organic PBO fiber, and PEG hydrogel resins via the thiol–ene addition with cysteine-containing peptides and NHS–active group. Based on the performance and
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structure RGD and IKVAV sequence peptides, the adhesion of the different type cells
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is investigated for different sequence activated peptides. The role of the cell adhesive molecules could provide a guide for the design of the amino acid sequence. Based on
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these findings, it can be concluded that the design peptides could be applied for an
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effective cell adhesion as one kind of a promising technology. It may significantly
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contribute in the understanding of this challenging areas including the structural design and molecular synthesis. In future, the development of novel polymer materials could
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be of great impact as cell’s targeted molecule and could expand further innovations on the cell biology.
Acknowledgements: This work was financilly supported by Grant No. 51673054 from the National Natural Science Foundation of China.
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Figure 6 CIKVAV Peptide adhesive cells on functional PBO fiber (i) Sketch of A151 coupling agent modified PBO fiber linked CIKVAV Peptides (ii) CIKVAV Peptide sports adhesive cells (Nuclei staining) on functional PBO fiber (a) Functional PBO fiber (b) Functional PBO fiber with CIKVAV peptides to adhesive cells (c) Peptide sports adhesive Hela cells (two peptide sports) (d) Peptide sports adhesive Hela cells (three peptide sports) Scale bar represents 1000µm Composites Part B: Engineering
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Figure. 7 Peptide adhesives Cell based on PEG hydrogel (7-1) Cage-peptide incorporates to Hydrogel to adhesive Cell; (7-2) Peptides adhesive Cell on hydrogel via Microarry method. First and thirdly row shows a positive control CGRGDSP-peptide adhesive cell for each image; Second and fourth row is Cage-RGD peptide adhesive cell ; Right is corresponding fluorescence, amplification cell, nuclei staining and amplification cell image. (a) PC-3cancer Cell ; (b) CHO normal cell; (C) NIH3T3 normal cell ; (d) Hela cancer cell ; Scale bar represents 500 µm.
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