Perspective Article
Nanoparticles of self-organizing ionic complexes based on a copolymer of N,N′-diallyl-N,N′-dimethylammonium chloride with N-vinylpyrrolidone modified by betulonic acid

https://doi.org/10.1016/j.reactfunctpolym.2021.104968Get rights and content

Highlights

  • The lyophilizing ability of cationic copolymers was evaluated.

  • The ionic complexes self-assemble into nano- and microparticles in aqueous solutions.

  • The ionic complexes based on a DADMAC-VP modified by triterpenoid were prepared.

  • The particles of ionic complexes can solubilize water-insoluble substances.

Abstract

The lyophilizing ability of a series of water-soluble cationic copolymers based on N,N′-diallyl-N,N′-dimethylammonium chloride (DADMAC) was estimated by turbidimetric titration. The copolymer of DADMAC with N-vinylpyrrolidone (DADMAC-VP) that has the best lyophilizing ability was chosen for further modification with betulonic acid (BA) triterpenoid to give ionic complexes with various compositions. The DADMAC-VP/BA complexes were characterized by spectroscopy, thermal analysis, and laser light scattering. The DADMAC-VP/BA complexes self-assemble into nano- and microparticles in aqueous solutions. It has been shown that these particles can solubilize molecules of compounds that are poorly soluble in water.

Introduction

Pentacyclic triterpenoids are among the most abundant natural compounds in the plant kingdom. They received particular attention in the past decade due to their important medicinal properties [1]. Betulonic acid (BA, 3-oxolup-20(29)-en-28-oic acid), a triterpenoid with a lupane skeleton, has poor water solubility [1,2]. BA and its derivatives proved to have biological activity, including hepatoprotective, hypoglycemic, immunomodulatory, anti-inflammatory, antioxidant and antitumor properties [3]. However, the low solubility in water limits their use considerably [4]. The preparation of particles that comprise ionic complexes of triterpenoids with polyelectrolytes (PEs) may help overcome this drawback [5].

PEs are defined as hydrophilic polymers containing ionizable groups that can dissociate to form charged polymer chains (macro-ions) and small counter-ions upon dissolution in a polar solvent [6]. The interaction of a water-soluble PE with organic counter-ions such as an ionizable drug (D) or surfactant (SAS) at certain component ratios results in stable colloidal dispersions in aqueous media. In such dispersions, a considerable fraction of the organic counter-ion is electrostatically attached to the PE to give complexes that behave as drug carrier systems [[7], [8], [9]]. If an ionizable drug is used as the organic counter-ion, the complexes are generally referred to as polyelectrolyte-drug ionic complexes (PED) [7]. If surfactant ions are used as the counter-ions, the complexes are called polyelectrolyte-surfactant complexes [10]. Apart from electrostatic interactions, complexes can be stabilized by hydrophobic interactions [[10], [11], [12]]. The interaction of a PE with organic counter-ions can result in insoluble products [7,13]. The stability of dispersions formed by complexes in an aqueous medium depends not only on the component ratio but also on the lyophilizing ability of the PE [14].

Polyelectrolyte particles are mainly obtained from various synthetic polyelectrolytes. Strong polyelectrolytes, such as sodium polystyrene sulfonate [15], poly(vinyl sulfonic) acid and weak polyelectrolytes, for example, polyacrylic acid [16], can serve as the polyanions. N-Containing polymers with a various number of substituents at the nitrogen atom, such as polyallylamine hydrochloride, polyethyleneimine, poly-N,N′-diallyl-N,N′-dimethylammonium chloride [[15], [16], [17]], etc., are mainly used as the polycationic components. In addition to synthetic polyelectrolytes, natural polyelectrolytes are also used, for example, polyacids such as DNA [18], RNA [19], poly(glutamic acid) [20,21], poly(aspartic acid) [22], various polysaccharides such as carboxymethylcellulose [23], alginates [24,25], chitosan [26,27], dextran sulfate [28], hyaluronic acid, and heparin [26,27].

Water-soluble copolymers of N,N′-diallyl-N,N′-dimethylammonium chloride (DADMAC) are attractive as a PED basis. DADMAC polymers are non-toxic and possess physiological activity by themselves [29,30]. Polyelectrolyte microparticles of a DADMAC homopolymer were studied [[31], [32], [33]]. Considerable attention is paid to the biocompatibility of DADMAC polymer microparticles and their application in bioseparation, cell encapsulation, and drug delivery [34,35].

Currently, very little information is available on the modification of PEs by hydrophobic drug compounds, including triterpenoids, whose moieties can be involved in the formation and stabilization of PED particles serving as drug carriers. Studies on these issues are relevant and important for the development of methods for synthesizing and controlling the characteristics and properties of PED particles, both from scientific and practical points of view. This work deals with the preparation and study of particles of ionic complexes based on water-soluble DADMAC polymers and a triterpenoid, viz., betulonic acid (BA).

Section snippets

Materials

1-Vinyl-2-pyrrolidinone (≥99.0%), DADMAC (≥97.0%), Acrylamide (≥98.0%), sodium dodecyl sulfate (≥98.5%), and vinyl acetate (≥99.0%) were purchased from Sigma-Aldrich.

Synthesis and characterization of BA and its potassium salt

BA was obtained as described previously [36]. To obtain potassium betulonate (BAK), 150 ml of 15% KOH solution was added to a solution of BA (11.94 g, 26.26 mmol) in 300 ml of benzene. The reaction mixture was refluxed for 30 min and then cooled to room temperature. The precipitate that formed was filtered off, washed with water

Structure and lyophilization capability of DADMAC polymers

PDADMAC, DADMAC-VP, DADMAC-AA, DADMAC-VA and DADMAC-DS water-soluble polymers were synthesized from the corresponding monomers by radical polymerization in solutions. The structures of the polymers synthesized were determined by 13C NMR spectroscopy (Table 2). The polymers are cationic type PEs capable of ion exchange reactions with organic counter-ions. To obtain particles of PED complexes that are stable in aqueous medium based on such a large and water-insoluble molecule as BA, the polymer

Conclusions

Thus, particles based on a copolymer of N,N′-diallyl- N,N′-dimethylammonium chloride with N-vinylpyrrolidone modified with various amounts of a triterpenoid, i.e., betulonic acid, were obtained. These compounds represent a variety of polyelectrolyte-surfactant self-organizing systems in which the hydrophobic regions of the molecules form intramolecular micelles capable of solubilizing water-insoluble organic molecules. The size range of such particles and their resistance to aggregation depend

Author statement

Marat Babaev: Conceptualization, Administration, Funding acquisition, Methodology, Investigation, Writing – Original Draft and Final version preparation. Alexander Lobov: Writing - Original draft preparation, Formal analysis, Visualization; Investigation. Nikolai Shishlov: Writing, Formal analysis, Visualization; Investigation. Elena Zakharova, Andrei Orlov, Andrei Baymiev, Sergey Kolesov: Resources.

Declaration of Competing Interest

There are no conflicts to declare.

Acknowledgement

The reported study was funded by RFBR, project number 19-33-60083. The NMR, IR and UV spectra were recorded on equipment at the Center for the Сollective Use “Chemistry” of the Ufa Institute of Chemistry of the UFRC RAS and RCCU “Agidel” of the UFRC RAS. Registration and analysis of NMR, IR and UV spectra was carried out in accordance with state assignments of UIC UFRC RAS No AAAA-A20-120012090029-0. Thermal analysis was performed in the framework of state assignment FZWU-2020-0027.

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