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Functional polymer-based nanomaterials

Low-dimensional polymer-based nanomaterials exhibiting unique physicochemical properties have recently emerged as promising tools for different biomedical applications ranging from tissue engineering to cancer diagnosis and treatment. Among this class of materials, two-dimensional nanomaterials have attracted much attention owing to their large surface area and prominent optical, electrical, photothermal, and photodynamic properties along with outstanding drug loading capacity and fast cellular uptake. Two-dimensional polymers (2D polymers), on the other hand, are single-monomer-thick two-dimensional nanomaterials (2D nanomaterials) with defined and covalently linked repeating units. The physicochemical properties of both 2D nanomaterials and 2D polymers depend strongly on their surface chemistry, which is defined by a combination of parameters including functionality, charge, heteroatom doping, defects, edges and number of layers. All of these factors must be standardized or clearly defined to shed more light on the correlation between the molecular structure and physicochemical properties of 2D polymers and guide further development for biomedical applications.

My research interests are primarily focused on two-dimensional polymers and polymer-coated two-dimensional nanomaterials and deepening our understanding of the mechanism of their synthesis as well as the investigation of the relationship between their physicochemical properties and interactions at biointerfaces (Figure 1). I am seeking straightforward polymerizations for the preparation of a broad family of 2D polymers at high scale for wide range of biomedical applications.

To achieve these goals, we have focused on three strategies:

i)       Synthesis of polymer-coated two-dimensional nanomaterials with defined functionality: investigation of their interactions at nano-biointerfaces and their applications for cancer therapy and pathogen interactions

ii)      Synthesis of two-dimensional polyols using colloidal platforms: New systems for drug delivery, molecular recognition at biointerfaces, atherosclerosis treatment and diabetic wound healing

iii)     Metal-assisted synthesis of two-dimensional polymers: biosensing applications

Figure 1. Our group aims to push forward novel multifunctional nanomaterials for the purpose of minimally invasive therapeutics. We have accumulated experience and expertise in ring opening polymerization, nanomaterial production and functionalization, cancer therapy, wound healing, atherosclerosis and pathogen interactions to perform interdisciplinary projects and create a platform for the future applications.

i) Synthesis of polymer-coated two-dimensional nanomaterials with defined functionality: investigation of their interactions at nano-biointerfaces and their applications for cancer therapy and pathogen interactions

Over the past several years my group has developed a variety of functional nanomaterials based on the ring-opening polymerization of cyclic monomers including, glycidol, ε-caprolactone, lactide and oxazoline (Figure 2 a, e). Polymer-based nanomaterials have been used for the loading of different therapeutic agents for tumor therapy. Moreover, we have synthesized polyoxazoline nanoparticles on a 200 g scale and have used them for diabetic wound healing. Results of the clinical phase I study are very promising and we are pushing this project for the next stages. In addition, we have developed a new nondestructive covalent functionalization method for the low-dimensional nanomaterials through which we have been able to prepare new polymer-coated platforms with defined functionalities. Polymer coated two-dimensional nanomaterials have shown great potential in nematode- and pathogen incapacitation as well as healing of infected diabetic wounds (Figure 2 c, d, f-k). The selective and stepwise post-functionalization of nanomaterials together with the nondestructive features of our functionalization opens up new avenues for the construction of photoswitchable nanodevices and functional nanomaterials as candidates for the efficient treatment of multidrug-resistant bacteria and cancer cells as well as the incapacitation of viruses including SARS-CoV-2, HSV, VSV and influenza (Figure 3 a-d).

The non-biodegradability of platforms that are coated by polymers and related health risks, however, is a major concern for in vivo applications. We have used two strategies to overcome this problem:

In the first strategy we have conjugated a combination of glucose peroxidase and myeloperoxidase on the surface of two-dimensional platforms to create macrophage-mimicking nanomaterials with self-degradation property under physiological conditions.

The second strategy, which is the elimination of the platform from the sheets, forwarded us to the next motif:

One of our current and future plans is to construct highly functional biocompatible two-dimensional polyols using colloidal platforms for biomedical applications. We use covalent and noncovalent methods to construct the polymers. In the covalent method, polyglycerol branches are conjugated to the surface of the platform by pH-cleavable linkers. These branches are then crosslinked side by side to obtain a two-dimensional polyglycerol network on the surface of the platform. Finally, two-dimensional polyglycerol is separated from the platform by acidification and breaking the pH-cleavable linkers (Figure 4a). The obtained two-dimensional polyglycerols with a thickness of 3 nm and lateral size of 200 nm are water-soluble polyfunctional nanomaterials and have shown great potential in nanomedicine (Figure 4 b, c). We have used two-dimensional polyglycerols to strongly inhibit herpes simplex virus type 1 (HSV-1) and SARS-CoV-2. The IC50 of the sulfated version of two-dimensional polyglycerol for the inhibition of infection was 3 nM (Figure 4 d-f).


ii) Synthesis of two-dimensional polyols using colloidal platforms: New systems for drug delivery, molecular recognition at biointerfaces, atherosclerosis treatment and diabetic wound healing

Figure 2. a) Amphiphilic poly(caprolactone-glycerol) synthesized by ring opening polymerization with the ability of creating functional nanoparticles in aqueous solutions. b) SEM images of poly(caprolactone-glycerol) nanoparticles. c) Zwitterionic two-dimensional nanomaterials synthesized by stepwise and controlled functionalization with polyglycerol for bacteria trapping. d) SEM image of E.coli trapped by zwitterionic two-dimensional nanomaterials. e) Green synthesis of hyperbranched polyglycerol using citric acid at room temperature. f) The schematic representation of interaction between polydopamine-coated two-dimensional nanomaterial (G-BA) and bacteria. g) Optical and h) SEM images of G-BA treated nematodes. G-BA sheets attached and diffused in the nematode and killed these parasites in a short time. i) Optical images of E. coliand B. cereus colonies formed on LB agar plates after incubation to MIC of polydopamine-coated two-dimensional nanomaterial (G-BA) for 12 h. The control was E. coli colonies formed on LB agar plates in the absence of G-BA. j) SEM image of B. cereus incubated with G-BA. B. cereus bacteria were starched from both sides by several G-BA sheets. k) Animal study of wound healing by polydopamine-coated two-dimensional nanomaterials at different time frames forinfected diabetics. Polydopamine-coated two-dimensional nanomaterial showed efficient healing of diabetic wounds in a short time in comparison with the control and phenytoin (a commercially available drug).


Figure 3. a) Cryo-TEM image of polyglycerol coated graphene with wrapped influenza A virus, the virions are colored red for better recognition. b) The subvolume of the 3D structure reconstructed from cryo-ET data, shown as “voltex”-presentation (virion orange, polyglycerol coated graphene white) corresponds to the marked area in the upper cryo-electron micrograph, rotated by 45°. It is obvious that the virion is wrapped by polymer-coated sheets. c) Schematic representation of virus wrapping by polymer-coated graphene sheets. d) Surface charge conversion of a polyglycerol-functionalized nanographene sheets after permeation into the tumor tissue. Negatively charged graphene sheets change to positive sheets in tumor, sites and positively charged graphene sheets are quickly taken up by cells (top). Hyperthermia surmounting of multiple drug resistance by functionalized graphene sheets. After, charge-mediated cellular internalization, graphene sheets accumulate into the mitochondria by targeting ligands. Mitochondrial dysfunction and accelerated drug release through hyperthermia results in MDR suppression and efficient chemotherapy.

In noncovalent method, supramolecular interactions between platform and monomers are driving forces for the production of 2D polyols. For example, functionalized cyclodextrins are loaded on the surface of boron nitride by supramolecular interactions and then they are linked side by side to produce a two-dimensional polycylodextrin with a lateral size of several micrometers and thickness of one nanometer (Figure 4 j-i). Our future plan is to use two-dimensional polycylodextrins for tumor therapy and virus incapacitation. We are studying the efficiency of two-dimensional polycylodextrins for atherosclerosis treatment.

Figure 4. a) Schematic illustration and synthetic route for two-dimensional hyperbranched polyglycerol (2D-hPG). 2D-hPG can be formed on both sides of graphene; however, for simplification, it is shown only on one side. Vial in the bottom-left shows the aqueous dispersion of graphene sheets with a polyglycerol coverage. Vial in the top-middle displays the aqueous solution after click reaction and acidification. While the graphene template is precipitated in the bottom of vial upon centrifugation, two-dimensional polyglycerol remains in the supernatant. b, c) SFM and TEM images of a 2D-hPG showing monolayers of polyglycerol with 3 nm thickness and around 200 nm lateral size respectively. d) 2D-hPG is sulfated by one pot reaction to obtain extracellular matrix mimic for pathogen interactions.  e, f) Schematic representation and IC50 of sulfated version of 2D-hPG for blocking viruses and inhibiting them from infection. g, h, i) Optical microscopy, SFM and SEM images of two-dimensional polycylodextrin.

Most of the current strategies for the synthesis of 2D polymers are interface assisted techniques and influenced by chemical, physical and mechanical properties of the interfaces.

Five years ago, we started our investigations to find straightforward polymerizations to bypass limitations of the interface assisted strategy. We found that coordination chemistry can be used as a universal method for the production of 2D polymers. Accordingly, we used metal-ligand interactions to force polymerization of monomers in two directions (Figure 5). Our first article in 2D polymers field entitled: “Gram-Scale, Metal-assisted and Solvent-mediated Synthesis of Two- Dimensional Triazine Heterostructures” was published in this year. Such polymerization can be performed in solution, circumventing the limitations of other strategies. The obtained 2D polymers can be further investigated for the biosensing applications.

Figure 5. a) Schematic representation of the synthesis of two-dimensional triazine polymers by metal assisted two-dimensional directed polymerization. Monomers are mixed with appropriate metal ions at low temperature to form an organometallic 2D structure. Metal exclusion, after nucleophilic reaction between monomers, results in a two-dimensional polymer. SEM images of metal assisted pre-organized monomers (b, c) and the final products (d, e). While palladium induces a coplanar assembly of monomers and results in a 2D polymer, zinc ions create tetrahedral complexes and produced calix-shape nanomaterials.