Synthesis and characterization of carbohydrate-based biosurfactant mimetics (2024)

Abstract

Glycolipid biosurfactants are of interest for various industry sectors. We report the synthesis and characterization of enantiopure poly-amido-saccharides (PASs) containing myristoyl (C14), palmitoyl (C16), or stearoyl (C18) terminal chain lengths as mimetics of glycolipid biosurfactants. These amphiphilic polymers are water soluble, adopt a helical secondary structure, decompose at temperatures greater than 240 °C, are non-cytotoxic, and self-assemble into nanostructures. Polymers containing the shorter hydrophilic chain lengths and the hydrophobic C14 chain exhibit the lowest surface tension among all polymers.

Keywords: Fatty acid, polysaccharides, Poly-amido-saccharide, Amphiphilic polymers, Surfactants, Nanoparticles

1. INTRODUCTION

Biosurfactants are amphiphilic substances produced by micro-organisms [1] Both low molecular weight and high molecular weight surfactants including, glycolipids, amphipathic polysaccharides, lipopolysaccharides, and lipoproteins efficiently lower surface and interfacial tensions. Due to their low critical micelle concentration, superior emulsifying activity, low toxicity, and ability to lower surface/interfacial tension, this class of surfactants is garnering increased attention.

Glycolipids, composed of one or more fatty acid chains covalently linked to a sugar moiety such as mono- or polysaccharides are the most widely studied biosurfactants. Examples of glycolipids include lipopolysaccharides found in the outer membrane of Gram-negative bacteria, rhamnolipids produced by P. aeruginosa [2], trehalolipids produced by Gram-positive bacteria such as Mycobacterium, Nocardia and Corynebacterium [3] and sophorolipids produced by yeast strains Candida bombicola, C. magnoliae, C. apicola, and C. bogoriensis[4]. Representative structures of several common glycolipids are shown in Figure 1.

Synthesis and characterization of carbohydrate-based biosurfactant mimetics (1)

The natural functions of glycolipids include cell recognition, adhesion, and signaling, while antimicrobial, hydrophobic drug encapsulation, and hemolytic effects of glycolipids are also currently studied [5]. Moreover, due to the amphiphilic nature and biocompatible composition of glycolipids, they are used in the environmental, cosmetic and food industries [6–8]. For example rhamnolipids are biodemulsifiers used for destabilizing waste crude oil [9], mannosylerythritol lipids produced from yeast exhibit favorable skin [10] and hair-care [11] properties, and biosurfactants produced from Candida utilis are used within the food industry [12] as bioemulsifying agents in common products such as ice-cream. While glycolipid based biosurfactants are used in many industries, the high cost of production and recovery, as well as the highly heterogeneous structure of these bio-derived materials hinder greater use and optimization for specific applications [13]. Thus, improved isolation and purification methods and new synthetic routes to prepare glycolipids and glycolipid-mimetics are of keen interest to expand the application space of glycolipids.

Our interest is in synthetic glycolipid-mimetics, [14–17] and, herein, we report the synthesis and characterization of a new class of such mimetics based on poly-amido-saccharides (PASs) [18–26] Specifically, glucose poly-amido-saccharides (^OHglcPASs) are enantiopure, helical, polysaccharide mimicking linear polymers with amide linkages between glucose monomers instead of glycosidic linkages present in polysaccharides. GlcPASs are synthesized by the anionic ring opening polymerization of a protected glucose β-lactam monomer, followed by removal of protecting groups [18,26]. To prepare a library of amphiphilic glycolipid-mimicking PASs, we synthesized glcPASs of different chain-lengths (12 and 25) and incorporated fatty acids, of varying chain-lengths (C₁₄, C₁₆ and C₁₈), at the N-terminal of glcPASs (Figure 1d). We chose C₁₄, C₁₆, and C₁₈ fatty acids due to their prevalence within glycolipid biosurfactants [5,8]. These types of glycolipid biosurfactants have been studied for their tumor inhibition activity[27] and biodegradation of oil-contaminated water systems [28].We characterized the amphiphilic polymers by proton nuclear magnetic resonance spectroscopy (¹H NMR), Fourier-transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), and surface tension measurements. These new amphiphilic polymers self-assemble into nanometer diameter particles which were further evaluated using fluorescence-based critical aggregation concentration (CAC) measurements, dynamic light scattering (DLS), scanning electron microscopy (SEM), circular dichroism spectroscopy (CD), and a colorimetric MTS cytotoxicity assay.

2. RESULTS AND DISCUSSION

We prepared a library of C_N-^PMBglc-PASs with varying hydrophilicity (degree of polymerization of glucose PAS, DP= 12 and 25) as well as hydrophobicity (C₁₄, C₁₆ and C₁₈) by lithium bis(trimethylsilyl)amide (LiHMDS) catalyzed anionic ring opening polymerization (AROP) of the ^PMBglc lactam using myristoyl (C14), palmitoyl (C16), and stearoyl (C18) acid chlorides as co-initiators. The polymerization is initiated by LiHMDS deprotonation of the lactams, followed by the reaction between the lactamate anion and the acid chloride to generate a highly reactive imide lactam intermediate. The imide intermediate then reacts with a lactamate anion to result in polymers with controlled molecular weights [18]. (Scheme 1). Polymer chain-lengths were controlled by varying monomer to initiator ratio, [M_o]/[I_o], where [M_o] is the initial concentration of monomer and [I_o] is the initial concentration of initiator. A control ^OHglcPAS (DP=25) was prepared using the 4-^tertbutyl benzoyl chloride initiator following reported procedures [18,26] We characterized the PMB-protected polymers by ¹H NMR, gel permeation chromatography (GPC), and FT-IR. The ¹H NMR spectra of C_N-^PMBglcPAS polymers (Figures S1–S6) revealed broad, overlapping peaks with chemical shifts consistent with the aromatic, anomeric, and saturated alkane protons, confirming successful polymerizations. GPC analyses with tetrahydrofuran (THF) as the eluent (Figure 2) showed polymers with slightly lower molecular weights than expected, with narrow polydispersity (Table 1). The FT-IR spectra contained peaks corresponding to amide NH stretch, aliphatic and aromatic CH stretches and carbonyl amide C=O stretches (3328, 2930, and 1678 cm⁻¹, respectively; see Figure S13), in line with previous reports.

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Synthesis and characterization of carbohydrate-based biosurfactant mimetics (3)

Table 1.

Molecular weight and polydispersity analyses of CN-^PMBglcPASs by THF GPC.

Polymer	[M_o]/[I_o]	M_{n, theory} (kDa)	M_{n, GPC} (kDa)	N_GPC	Đ_GPC	Yield %
C₁₄- ^PMBglcPAS-12	12	6.81	4.74	8	1.13	75
C₁₄- ^PMBglcPAS-25	25	13.9	9.66	18	1.08	71
C₁₆- ^PMBglcPAS-12	12	6.83	4.90	9	1.14	72
C₁₆- ^PMBglcPAS-25	25	14.0	8.97	16	1.08	68
C₁₈- ^PMBglcPAS-12	12	6.86	5.17	9	1.15	56
C₁₈- ^PMBglcPAS-25	25	14.0	11.47	21	1.08	82
C_-tertbutyl-^PMBglcPAS-25	25	11.5	9.0	20	1.09	80

Table 2.

Molecular weight, surface tension, critical aggregation concentration, and thermal stability characterization of CN-^OHglcPASs.

Polymer	[M_o]/[I]	M_{n, theory} (kDa)	M_n,NMR (kDa)	N_NMR	Yield %	Surface tension (mN/m)	CAC (μM)	T_{deccomposition} (°C)
C₁₄-^OHglcPAS-12	12	2.48	1.91	9	76	41.3	3.3	243.3
C₁₄-^OHglcPAS-25	25	4.94	3.17	15	34	49.5	10.1	258.3
C₁₆-^OHglcPAS-12	12	2.50	1.56	7	44	45.3	8.0	250.3
C₁₆-^OHglcPAS-25	25	4.96	3.42	11	17	45.4	1.8	252.9
C₁₈-^OHglcPAS-12	12	2.53	1.40	6	77	52.1	8.9	245.6
C₁₈-^OHglcPAS-25	25	4.99	3.48	17	57	51.2	1.8	252.6
^OHglcPAS-25	25	4.7	6.04	32	70	69.6	>1000	230.0

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M_n= number average molecular weight, N= number of monomer repeat units, Đ = dispersity.

Biosurfactants, due to their amphiphilic nature, self-assemble in water to form nanostructures like micelles, vesicles and tubules.[29,30] To evaluate the formation of nanostructures from C_N-^OHglcPASs, we dissolved C₁₄-^OHglcPAS-12, C₁₆-^OHglcPAS-12 and C₁₈-^OHglcPAS-12 in DI water (0.25 mg/mL) and evaluated the particle diameter by dynamic light scattering. The particle diameter increased with decreasing hydrophobicity of fatty acid end group (589, 421 and 293 nm for C₁₄, C₁₆ and C₁₈-^OHglcPASs, respectively). These diameters were greater than the expected diameter of a micelle (twice the length of the polymer) [25] i.e. ~6 nm for 12mer and ~12 nm for 25mer). Evaluation of the secondary structure of C_N-^OHglcPASs at the same concentration using circular dichroism spectroscopy revealed that the polymers adopted a helical secondary conformation at 0.25 mg/mL concentration with a maximum at 189 nm and minimum at 220 nm, consistent with the reported helical secondary structure of other PASs [18] (Figure 3).

Synthesis and characterization of carbohydrate-based biosurfactant mimetics (4)

Next, we used an emulsion method to prepare nanoparticles from C_N-^OHglcPASs, wherein the polymer was suspended in a mixture of DI water and ethyl acetate, and then ultrasonicated for 10 minutes. DLS evaluation revealed that the particle size decreases using an ultrasonication method (diameters 236, 189 and 256 nm for C₁₄, C₁₆ and C₁₈-^OHglcPAS-12, respectively). We also prepared nanoparticles from C₁₄-^OHglcPAS-25, C₁₆-^OHglcPAS-25 and C₁₈-^OHglcPAS-25 using the same emulsion method, as discussed previously. However, these polymers formed NPs larger in diameter between 261 and 279 nm with PDI <0.3 (Figure 4a). All the nanoparticles displayed diameters less than 500 nm, even after 7 days of incubation at 4°C, indicating the stability of the nanoparticles within this time frame (Figure S19). Scanning electron microscopy analysis revealed spherical and cylindrical particles with diameters ranging from 10 nm to 450 nm for all samples (Figure 4b–g), consistent with DLS analysis. The differing morphologies were independent of the fatty acid identity and polymer chain length. Further studies are ongoing to probe the polymer packing in these nanoparticles.

Synthesis and characterization of carbohydrate-based biosurfactant mimetics (5)

The helical secondary structure of the polymers observed in CD spectra indicated that the hydrophilic glcPAS polymers likely form a corona around the hydrophobic core of the nanoparticles. However, due to the higher-than-expected diameter of the particles observed in the DLS studies and SEM images, it is clear that the self-assembled structures are not micelles. Future small angle x-ray scattering and TEM studies will help ascertain the morphology of the particles.

Next, we used a pyrene-based fluorescence assay to determine the critical aggregation concentration (CAC, the concentration above which the polymer self-assembles) of the fatty acid PASs. All the polymers exhibited critical aggregation concentrations between 1–10 μM (6–12 mg/L), consistent with the literature reports of glycolipids such as rhamnolipids (between 1–200 mg/L) and lower than sophorolipids (138 mg/l and 95 mg/l) and other synthetic surfactants [31].

Low molecular weight surfactants like glycolipids reduce the surface tension of water at the air-liquid interface [31] Surfactants that reduce the surface tension of water from ~72 mN/m to 30 mN/m are considered efficient surfactants [8]. For example, rhamnolipids produced by Pseudomonas aeruginosa and sophorolipids extracted from asexual ascomycetes yeast reduce the surface tension of water from 72 to 35.26 mN/m [32] and 35 mN/m, respectively [33]. Dissolving the C_N-^OHglcPASs in water (20 wt%) decreased the surface tension of water from 70.7 mN/m at 24°C to 40–55 mN/m, while ^OHglcPAS-25 with no fatty acid end-group did not decrease the surface tension considerably (Table 2, entry 7). Decreasing the chain-length of fatty acid end-groups resulted in a greater reduction of surface tension, with C₁₄-^OHglcPAS-12 displaying the greatest reduction in surface tension (41.3 mN/m). On the other hand, varying the chain-length of the hydrophilic PASs afforded minimal variation on surface tension (see entries 1 vs 2, 3 vs 4 and 5 vs 6 in Table 2).

A major advantage of biosurfactants over synthetic surfactants is their reduced toxicity compared to synthetic surfactants [34]. Therefore, we next evaluated the cell viability of NIH-3T3 fibroblasts 72 hours after C_N-^OHglcPASs treatment using an MTS assay. All the polymers displayed minimal toxicity up to a concentration of 0.125 mg/mL. At higher concentrations, cell viability increased with increasing glcPAS chain-length (C₁₈-^OHglcPAS-25 vs C₁₈-^OHglcPAS-12) and decreasing fatty acid chain-length (C₁₈-^OHglcPAS-25 vs C₁₆-^OHglcPAS-25 vs C₁₄-^OHglcPAS-25).

3. CONCLUSION

In conclusion, we synthesized a library of amphiphilic poly-amido-saccharides containing fatty acid initiators via an AROP of a β-lactam monomer. Selective PMB group deprotection resulted in amphiphilic polymers which self-assembled upon dispersion into an aqueous solution. Protected polymers gave slightly smaller molecular weights than expected. The molecular weight analyses of the deprotected polymers by NMR were consistent with the THF GPC analyses. All polymers adopted helical secondary structures and had similar thermal stabilities despite the varied polymer chain lengths and hydrophobic fatty acids. Additionally, all polymers reduced the surface tension of water and displayed low cytotoxicity up to a concentration of 0.125 mg/mL, demonstrating their potential use as biosurfactants. By incorporating the PAS backbone into a biosurfactant composition, we accessed a new class of biocompatible glycolipid mimetics which are of interest for further study.

4. EXPERIMENTAL SECTION

4.1. Materials

D-glucal was purchased from Carbosynth, LLC (San Diego, California). All other reagents were purchased from Millipore Sigma (Burlington, MA), TCI (Portland, OR), or Chem-Impex (Wood Dale, Illinois) and used without further purification. Solvents were purchased from Thermo Fisher Scientific (Waltham, MA). Reactions were monitored by thin-layer chromatography (TLC) analysis and stained with potassium permanganate. All NMR spectra were obtained with compounds dissolved in CDCl₃ (D, 99.8%), or D₂O (D, 99%), and recorded on a Varian INOVA 500 MHz spectrometer. Chemical shifts (δ) were recorded in ppm and coupling constants (J) were reported in Hz. Unless otherwise noted, all reactions were performed under a nitrogen atmosphere using anhydrous solvents and oven-dried glassware and stir bars. Lyophilization was performed using a Virtis Benchtop 4K freeze dryer Model 4BT4K2L-105 at −40 °C. Infrared spectroscopy (IR) was performed on a Nicolet FT-IR with a horizontal attenuated total reflectance (ATR) adapter plate.

Protected polymer molecular weights were determined by size exclusion chromatography (SEC) with polystyrene standards (with Mp = 2,327,000 g/mol, 321,300 g/mol, 75,050 g/mol, 9,310 g/mol and 580 g/mol) using THF as the mobile phase at a 1.0 mL min⁻¹ flow rate through Styragel HR 5E 7.8 × 300 mm and Styragel HR 4 7.8 × 300 mm SEC column with THF as the eluent (purchased from Waters Corporation; Milford, MA) at 25 °C in series with a refractive index detector. Polymeric analysis was completed with Breeze GPC software (purchased from Waters Corporation; Milford, MA). Thermogravimetric analysis (TGA) studies of deprotected polymers were performed on a Mettler Toledo Polymer DSC R. Circular dichroism (CD) of the polymer solutions (0.25 mg/mL in DI water) was completed on an Applied Photophysics CS/2 Chirascan (NSF MRI grant CHE-112654). MALDI-TOF analyses were carried out by AxisPharm (San Diego, California). The critical aggregation concentration (CAC) of the polymers was determined by Fluorescence measurements on a Horiba Jobin Yvon FluoroMax 3 Fluorimeter. Nanoparticles were prepared by ultrasonication via an emulsion method using a Sonics Vibra-Cell VCX-600 Ultrasonic Processor (Sonics & Materials; Newtown, CT). Dynamic light scattering (DLS) studies were carried out on a Brookhaven NanoBrook Particle Size Analyzer. Scanning electron micrographs were performed with a Zeiss Supra 55 at 3 kV. Surface tension of polymer solutions (0.2 mg/ml in DI water) were measured using Kruss K11 Force Tensiometer.

4.2. Polymer Synthesis

The tri-O-PMB-glucose β-lactam (^PMBglc lactam) monomer was prepared from D-glucal using a previously reported procedure [26].

Polymers were prepared following a previously reported procedure.[18] Briefly, to prepare the C₁₆-^PMBglc-12, ^PMBglc lactam (150 mg, 0.273 mmol, 1 eq.) was added as a solid over activated 3Å molecular sieves and dissolved in anhydrous THF (2.7 mL, 0.1 M) to an evacuated round-bottom flask under nitrogen. In a separate evacuated reaction vessel, a 0.01mg/mL solution of the initiator (palmitoyl chloride) in anhydrous THF was prepared. The initiator (6 mg, 0.023 mmol, 0.083 eq.) was added to the reaction vessel and cooled to 0 °C. LiHMDS (10 mg, 0.057 mmol, 0.208 eq.) was added from a 0.01 mg/mL THF solution, after which, the reaction was warmed to room temperature and stirred overnight. The polymerization was quenched with 0.5 mL of saturated ammonium chloride and concentrated. The crude residue was re-dissolved in dichloromethane and the organic phase was extracted with 1 M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The combined organic phases were dried over sodium sulfate and concentrated to give the polymer as a white solid (109 mg, 72%). To prepare polymers with chain lengths of 25, lower quantities of initiator (0.04 eq.) and LiHMDS (0.1 eq.) were used.

4.3. Polymer Deprotection

The PMB deprotection for all polymers was carried out following a previously reported procedure using anhydrous triflic acid and 1,3-dimethoxybenzene in anhydrous dichloromethane [35]. Briefly, to remove the PMB groups for C16-^PMBglc-12, the polymer and 1,3-dimethoxybenzene (0.107 mL, 0.819 mmol, 3.0 eq.) were dissolved in anhydrous dichloromethane (0.2 M), followed by dropwise addition of triflic acid (0.012 mL, 0.136 mmol, 0.5 eq.). The reaction was stirred at room temperature for 15 minutes, quenched by anhydrous methanol and the solvent was evaporated under reduced pressure to give a pink solid. The crude residue was washed with toluene and dichloromethane to remove residual dimethoxybenzene and triflic acid, respectively, dialyzed and lyophilized to produce a white, amorphous solid (35 mg, 44% yield). Successful deprotection was confirmed by ¹H NMR and FTIR spectroscopy.

4.4. Nanoparticle synthesis and characterization

Nanoparticles were prepared via the emulsion method. Polymers were suspended in ethyl acetate at a 5 mg/mL concentration and DI water was added (1mL of water for 1 mg of polymer) for phase separation. The emulsion was sonicated in a water bath for 10 minutes at 25°C, followed by ultrasonication for 30 minutes with a 9 second pulse, 1 second delay at 20% amplitude. The solutions were stirred overnight at room temperature to allow for ethyl acetate evaporation.

4.5. DLS studies

The mean diameter and polydispersity index of all nanoparticles was determined using a Brookhaven NanoBrook Particle Size Analyzer from five measurements at room temperature. The stability of the particles was monitored by DLS at days 0, 2, 5, and 7.

4.6. Critical aggregation concentration (CAC)

Polymers dissolved in water were serially diluted (1:1) beginning with 0.4 mg/mL seven times. Dilutions were lyophilized and re-dissolved in 200 μL of water saturated with pyrene. The solutions were sonicated in a sonication bath for 30 minutes at room temperature. The intensity of pyrene at 373 nm (I₁) and 384 nm (I₃) in the resulting fluorescence emission spectra after excitation at 332 nm of each dilution was measured and the ratio I₁/I₃ was plotted against the polymer concentration. The concentration at which the ratio of I₁/I₃ steeply declined was determined to be the CAC.

4.7. Scanning electron microscopy (SEM)

Nanoparticle solutions (1 mg/mL) were diluted 50- and 500-fold. 2 μL droplets were drop-casted onto silicon wafers to dry overnight and then sputter coated with a Au/Pd target for 12 seconds prior to imaging. Scanning electron micrographs were taken on a Zeiss Supra 55 at 3 kV, 6.8 mm working distance, and 30 μm aperture.

4.8. Cytotoxicity

Toxicity of the nanoparticles was evaluated against mouse fibroblasts (NIH-3T3) via tetrazolium-based assay (MTS; CellTiter 96^® AQueous One Solution Cell Proliferation Assay). Polymer solutions of C₁₄-^OHglc-25, C₁₆-^OHglc-25, C₁₈-^OHglc-25, C₁₈-^OHglc-12, and dextran at 10 mg/mL were prepared in DI water. Prior to treatment, all polymers were sterile filtered through 0.22 μm PES. NIH 3T3 cells were seeded in 96-well plates 24 hr prior to treatments in complete DMEM media (+10% bovine calf serum +1% penicillin streptomycin). Polymer solutions were diluted 2-fold into complete media for dose curve concentrations. Polymer dose curves were further diluted 10-fold onto the cell plate, adding 10 μL polymer solution to 90 μL media for treatment. 72 hours after treatment, cell viability was assessed using Promega CellTiter 96^® AQueous One Solution Cell Proliferation Assay (MTS).

Supplementary Material

Supporting Information

NIHMS1899287-supplement-Supporting_Information.pdf^{(3MB, pdf)}

Synthesis and characterization of carbohydrate-based biosurfactant mimetics (6)

Acknowledgements

This work was supported in part by Boston University and the National Institutes of Health (R01HL164650). The authors would like to thank BU Chemical Instrumentation Center for and BU BioInterface Technologies (BIT) Facility for providing access to instruments used in this study.

Footnotes

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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