ALTMET Polymerization of Amino Acid-Based Monomers Targeting

Article pubs.acs.org/Macromolecules

ALTMET Polymerization of Amino Acid-Based Monomers Targeting Controlled Drug Release Luana Becker Peres,†,‡ Laura C. Preiss,‡ Manfred Wagner,‡ Frederik R. Wurm,‡ Pedro H. H. de Araújo,† Katharina Landfester,‡ Rafael Muñoz-Espí,*,‡,§ and Claudia Sayer*,† †

Department of Chemical Engineering, Federal University of Santa Catarina - UFSC, 88040-900, CP 476, Florianópolis, SC, Brazil Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany § Institute of Materials Science (ICMUV), University of Valencia, C/Catedràtic José Beltrán 2, 46980 Paterna, València, Spain ‡

ABSTRACT: Giving the imminent necessity of a new generation of biodegradable and biocompatible polymers prepared from feedstock, the synthesis of a potentially biodegradable amino acid-based copolymer by the alternating diene metathesis (ALTMET) strategy is herein presented. The reaction was tailored to minimize isomerization and deactivation of ruthenium catalysts by intramolecular coordination with the amide carbonyl group of the aminoacid-based monomer. Alternated L-lysine−phosphoester copolymers with molar masses higher than 18 000 g/mol were obtained using Hoveyda−Grubbs second-generation and Umicore M2 catalysts. The copolymer was further used to prepare nanoparticles loaded with rifampicin (up to 50 wt %) by the miniemulsion/solvent evaporation technique. The L-lysine-based copolymer is shown to be a promising material for biomedical applications, such as controlled drug delivery system. ring-opening metathesis polymerization (ROMP)11−14 and ADMET3,8,15−17 polymerization reactions have been used to synthesize amino acid-based polymers. However, in spite of ROMP living/controlled chain-growth polymerization features,18 ROMP reactions usually result in amino acid-grafted polyolefins. Besides, the source of cyclic monomers necessary for ROMP is limited.19 On the other hand, incorporation of amino acid units in the polymer main chain by ADMET might be more easily attained. Despite metathesis catalyst tolerance toward polar or protic functional groups, inactivation of metathesis catalysts due to intramolecular coordination of the amide carbonyl group of amino acid-based monomers to the catalyst metal center has been observed in ADMET reactions,3,8,9,16 yielding low monomer conversion and low molecular weight polymers. It has been reported, however, that catalyst deactivation can be avoided or less favored by extending the methylene units between the olefin and amino acid functionality in the monomer.3,8 Hopkins and co-workers3 obtained amino acidbearing polymers with molecular weight varying from Mn = 900 g/mol to Mn higher than 27 000 g/mol simply by extending the monomer from two to eight methylene units. Isomerization has also been observed as a side reaction under metathesis conditions, especially at high temperature. Recently, Führer and co-workers8 were able to suppress isomerization by copolymerizing amino acid-based monomers with ethylene

1. INTRODUCTION Synthetic polymers have long ago become an indispensable part of human life. Because of their unique mechanical and thermal properties and their long-term stability and durability, they have replaced many natural materials products. However, the depletion of fossil resources and the raise of public awareness of the waste problem and its impact on the environment have caused the necessity of a new generation of biodegradable and renewable polymers.1 Moreover, biodegradable polymeric materials are of high interest for biologically useful materials in applications such as tissue engineering, drug delivery systems, and temporary prostheses.2 Acyclic diene metathesis (ADMET) polymerization has been attracting considerable attention in this context as a promising strategy to obtain new polymers from renewable materials. With the development of well-defined, highly active metathesis catalysts, almost any functional group can be inserted into a polymer main chain by ADMET reactions.3−5 In this sense, materials from renewable feedstock such as fatty acids, carbohydrates, and amino acids have gathered much interest as alternative resources for production of biodegradable polymers.3,6−8 Amino acid-constructed polymers are a subject of great interest due to their inherent biological compatibility and degradability, with potential applicability in biomedicine and in chiral recognition.3,9,10 Amino acid moieties have been incorporated either within the polymer main chain or pendant to it. Polymers that exhibit amino acid units in the main chain will likely be biodegradable, while those with amino acid units as pendant groups will be hydrolytically more stable.3 Both © XXXX American Chemical Society

Received: July 15, 2016 Revised: August 24, 2016

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DOI: 10.1021/acs.macromol.6b01530 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

2.4. Synthesis of Poly(bis(acryloyl)-L-lysine-co-phosphoester) by ALTMET Solution Polymerization. In a typical experiment (Scheme 1), N,N′-bis(acryloyl)ethyl ester L-lysine (40 mg), di(undec-

glycol diacrylate by alternating diene metathesis polymerization (ALTMET). Herein, we report an ALTMET copolymerization of a Llysine-based bis-acrylamide, an essential amino acid, with a yet rather unexplored monomer class, i.e., a phosphoester diene, for the ALTMET polymerization to introduce additional degradation points. We also demonstrate that by the ALTMET strategy the amino acid-based monomer can be successfully copolymerized without extending the methylene units between the olefin and amino acid functionality. We believe that this novel copolymer, with expected biological degradability and compatibility, may find many applications in the biomedical field. We further used this copolymer for the preparation of nanoparticles by the miniemulsion/solvent evaporation technique to be used as controlled drug delivery vehicles. Rifampicin, an antituberculosis drug, was chosen as hydrophobic model drug.

Scheme 1. ALTMET Copolymerization of N,N′Bis(acryloyl)ethyl Ester L-Lysine (L-Lysine Bis-Acrylamide) and Di(undec-10-en-1-yl)phenylphosphate in the Presence of Ruthenium-Based Catalyst

2. EXPERIMENTAL SECTION 2.1. Materials. The synthesis of di(undec-10-en-1-yl)phenylphosphate was previously described.20 L-Lysine ethyl ester dihydrochloride (Alfa Aesar, 99%), triethylamine (Sigma-Aldrich, ≥99.5%), acryloyl chloride (Sigma-Aldrich, 97%, 20 000 g/mol), demonstrating its feasibility toward ADMET polymerization reactions. Motivated by the high tolerance of Grubbs-type and Umicore catalysts toward polar functional groups,7,13,16 we investigated the influence of different catalysts on molecular weight of ALTMET copolymerization of N,N′-bis(acryloyl)ethyl ester Llysine with di(undec-10-en-1-yl)phenylphosphate. Hoveyda− Grubbs second-generation (HG-2), Grubbs second-generation (G-2), and Umicore M2 catalysts were used under different concentration, solvent, and temperature conditions (Table 1). D


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All ALTMET polymerizations resulted in sticky polymers at room temperature, which are readily soluble in common organic solvents such as chloroform, dichloromethane, and THF. Amino acid-based polymers and poly(phosphoester)s may show some degree of crystallinity,3,15,17,20 with PPEs commonly showing low glass transitions temperatures due to the flexible P−O−C groups in the chain backbone.35 The thermal properties of polymer C4 (Table 1) was examined by TGA and DSC. The onset temperature of weight loss of the polymer was between 270 and 280 °C under nitrogen, with most of the decomposition occurring until 450 °C (77% weight loss). Low temperature glass transition (Tg) at −12 °C was observed upon heating and cooling the sample (thermal history erased) (Figure 4), and no melting peak was registered, a characteristic of amorphous polymers. 3.1. Inverse Miniemulsion Polymerization. Inverse miniemulsion polymerization is a convenient one-step nanoencapsulation technique for the preparation of polymer nanocapsules with a hydrophilic core targeting controlled drug delivery because this polymerization process allows the generation of nanocapsules and in situ loading of a variety of hydrophilic drugs and biomolecules.36−39 Moreover, the possibility to synthesize nanocapsules by performing ALTMET reactions in the miniemulsion droplet interface gives rise to a new class of nanocapsules for biomedical purposes as the catalyst remains in the organic continuous phase and can be easily removed after the polymerization is complete.29 In this regard, ALTMET reactions were carried out by using the inverse miniemulsion interfacial polymerization technique. In order to obtain a completely water-soluble monomer, we attempted a deprotection reaction40 to remove the ethyl ester group from N,N′-bis(acryloyl)ethyl ester L-lysine. However, the water-soluble N,N′-bis(acryloyl)-L-lysine was found to be unstable even when stored at 4 °C. Therefore, N,N′bis(acryloyl)ethyl ester L-lysine was rather used and a mixture of methanol or DMSO and NaCl aqueous solution (volumetric ratio of 1:1 or 1:2) was used to dissolve the monomer, which was employed as the dispersed aqueous phase. Mediated by the catalyst, the ALTMET reaction takes place at the interface only, polymerizing N,N′-bis(acryloyl)ethyl ester L-lysine with di(undec-10-en-1-yl)phenylphosphate, forming a shell surrounding the water droplet. The obtained results are listed in Table 2. All ALTMET reactions performed in inverse miniemulsion resulted in low molecular weight polymers (yield not determined), even though the temperature condition and catalyst molar concentration used were similar to those applied to ALTMET solution polymerizations of C3 (Mw = 11 300 g/ mol), C4 (Mw = 18 500 g/mol), and C11 (Mw = 18 100 g/mol) (Table 1). The low reactivity could be attributed to catalyst coordination to DMSO or methanol, which are nucleophilic solvents, since both HG-2 and M2 catalysts are known to be water resistant in miniemulsion conditions.7,29 Catalyst poisoning could also be observed with the naked eye, as the reaction mixture turned brown in less than 10 min after catalyst addition. We further investigated different polymerization conditions such as lower surfactant concentration (data not shown), but no difference was observed. 3.2. Miniemulsion/Solvent Evaporation. Besides in situ polymerization processes, nanoparticles can also be prepared from a preformed polymer in direct miniemulsion. The technique of miniemulsion/solvent evaporation has shown to be a robust technique for the preparation of biodegradable nanoparticles and encapsulation of hydrophobic drugs.23,41,42

generation catalyst. Since G-2 deactivation by dichloromethane is essentially minimized,33 inhibition of ALTMET copolymerization toward high molecular weight polymers might be more likely attributed to a shorter lifetime of G-232 in comparison to HG-2 due to poisoning of catalyst induced by the bisacrylamide monomer. The chemical structure of the ALTMET product was confirmed by 1H NMR spectroscopy (Figure 2). By comparing the 1H NMR spectra of both monomers and the respective copolymer, the disappearance of terminal double bonds of N,N′-bis(acryloyl)ethyl ester L-lysine (6.09−6.27 and 5.46− 5.51 ppm) and di(undec-10-en-1-yl)phenylphosphate (5.79− 5.83 and 4.92−5.00 ppm) is evident as well as the formation of internal double bonds (6.75, 5.82−5.95 ppm) arising from monomers copolymerization. Moreover, NMR spectra suggest that dimerization of di(undec-10-en-1-yl)phenylphosphate has also occurred, as the appearance of an internal double bond (5.4 ppm) of the unsaturated PPE,20 typical of olefin crossmetathesis, can also be observed. Therefore, the polymerization product was characterized by 1H DOSY-NMR spectroscopy, providing information about whether the obtained product is an AB-alternating copolymer with some degree of phenyl phosphate dimers or a blend of AB-copolymer and phenyl phosphate homopolymer. DOSY-NMR spectroscopy (Figure 3) could provide evidence of an alternating copolymer

Figure 3. 1H-DOSY NMR spectrum (850 MHz) of L-lysine− phosphate copolymer THF-d8 at 298 K (entry C3, Table 1).

formation with some degree of phosphate dimers, as the obtained product is characterized by a single diffusion coefficient. The extent of AB-alternation of L-lysine-phosphate copolymer, calculated by 1H NMR spectroscopy analysis,19,34 was determined to be higher than 80% for polymer C3 (HG-2 catalyst, Table 1), 90% for polymer C4 (HG-2 catalyst, Table 1), and 92% for polymer C11 (M2 catalyst, Table 1), confirming the efficacy of the ALTMET copolymerization. In this regard, it appears that the copolymer architecture, i.e., the extent of AB alternation, is closely related to the degree of polymerization and monomer conversion. E


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Figure 4. TGA and DSC thermograms (entry C4, Table 1).

Table 2. Formulation and Results of ALTMET Inverse Miniemulsion Copolymerization of L-Lysine Bis-Acrylamide and Phenyl Phosphate Diene Monomers entry

catalyst (5 mol %)

monomer molar ratio

Mini1 Mini2 Mini3

HG-2 HG-2 M2

1:2 1:2 1:2

L-lysine

(mol/L)

phosphate (mol/L)

dispersed solvent−vol ratio

T (°C)

Mw (kg/mol)

Đ

0.090 0.090 0.090

1:1 (MeOH:NaCl 0.15 M) 1:1 (DMSO:NaCl 0.15 M) 1:1 (DMSO:NaCl 0.15 M)

55 65 65

1.6 2.4 3.0

1.1 1.6 1.7

0.6 0.6 0.6

higher RIF loading efficiency obtained for L-lysine-phosphate copolymer nanoparticles might be attributed to some hydrogen bonding interaction between the hydroxyl and amine groups of rifampicin and the amide and carbonyl groups of the copolymer.

Herein, SDS-stabilized L-lysine-phosphate copolymer (C4, Table 1) nanoparticles were prepared using this approach. Rifampicin (RIF), a frontline antibiotic mainly used in the treatment of pulmonary tuberculosis, was chosen as the model drug with low water solubility. Three RIF-loaded nanoparticle formulations, with 5, 25, and 50 wt % RIF, along with blank nanoparticles (without RIF), were produced. Nanoparticles with mean diameters between 50 and 80 nm with low dispersities indicating monomodal distributions were successfully obtained (Table 3). An important factor for drug delivery

4. CONCLUSIONS A L-lysine-based monomer was synthesized and copolymerized with a phosphate diene monomer via ALTMET strategy in inverse miniemulsion using Hoveyda−Grubbs second-generation and Umicore M2 catalysts. While the attempt to homopolymerize the L-lysine-based monomer via ADMET failed due to ruthenium catalyst deactivation, ALTMET reactions yielded copolymers with molar masses higher than 18 000 g/mol, and isomerization and catalyst deactivation could be minimized. The extent of AB alternation of L-lysinephosphate copolymer was determined to be higher than 90% for those copolymers with high molar masses (>18 000 g/mol). In addition, poly(L-lysine-co-phosphate) nanoparticles with controlled particle size in the range of 50−80 nm were prepared by the miniemulsion/solvent evaporation technique. The nanoparticles were efficiently loaded with a hydrophobic drug (up to 50 wt %), with encapsulation efficiency higher than 94%. Further studies are in progress to understand drug delivery mechanism as well as in vivo compatibility. Polymer degradability shall be also investigated.

Table 3. Summary of the Properties of the RifampicinLoaded Nanoparticlesa entry

rifampicin loading ratio (wt %)

S1 S2 S3 S4

0 5 25 50

Dpb ± SD (nm) 53 76 53 76

± ± ± ±

10 22 5 25

PDIc ± SD (nm)

encapsulation efficiency (%)

± ± ± ±

96.3 ± 1.0 94.3 ± 0.5 95.8 ± 2.6

0.180 0.217 0.203 0.103

0.008 0.087 0.044 0.032

Data represents mean ± standard deviation (n = 2). bDp: intensity average particle size. cPDI: dispersion dispersity.

a

systems is the drug entrapment efficiency. For all formulations screened, encapsulation efficiency was determined to be higher than 94%, proving L-lysine−phosphate copolymer nanoparticles to be potential candidates for use in future drug delivery applications. The drug loading of L-lysine−phosphate copolymer nanoparticles is comparable with other nanoparticle systems. Singh and co-workers,43 for example, reported the preparation of RIF loaded solid lipid nanoparticles by a modified microemulsion method, obtaining 65% of drug entrapment efficiency. Pandey and Khuller44 have reached 51% of RIF encapsulation efficiency in stearic acid solid lipid microparticles prepared by a modified emulsion/solvent diffusion method. Sharma and co-workers45 prepared RIF loaded lectin-functionalized PLGA nanoparticles by a modified miniemulsion/solvent evaporation, and the RIF encapsulation efficiency value was determined as 54%. The

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AUTHOR INFORMATION

Corresponding Authors

*Phone +34 96-35-44210; e-mail [email protected] (R.M.E.). *Phone +55 48 3721 2516; Fax +55 48 3721 9554; e-mail [email protected] (C.S.). Notes

The authors declare no competing financial interest. F


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ACKNOWLEDGMENTS The authors thank Mark Steinmann and Alper Cankaya for the synthesis of phenyl phosphate diene and Raul Silva dos Anjos for lab assistance. We thank the financial support from CAPES−Coordenaçaõ de Aperfeiçoamento de Pessoal de ́ Nivel Superior e Tecnológico (bolsista CAPES−Proc. no. 99999.014218/2013-05). R.M.E. also acknowledges the financial support from the Spanish Ministry of Economy and Competitiveness through a Ramón y Cajal grant (grant no. RYC-2013-13451).

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ALTMET Polymerization of Amino Acid-Based Monomers Targeting

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