Formation of hydrotropic drug/gemini surfactant based catanionic vesicles as efficient nano drug delivery vehicles
Graphical abstract
Introduction
Amphiphilic molecules self-assembles in aqueous medium to form a wide variety of aggregates with different morphological structures such as spheres, rods, disk, lamellar, reverse vesicles and liquid crystals among others [1]. These self-assemble aggregates are driven by various non-covalent interactions such as hydrophobic-hydrophobic, electrostatic, steric and van der Waals interactions and exhibit numerous rheological, biological and chemical properties than that of their monomeric units [[1], [2], [3], [4]]. Self-assemble structures and their properties depends on the structural variety of the constituting surfactant molecules, i.e. surfactant heads, alkyl chain and counter ions [5]. Rational designing of the head groups influences the self-assembly behavior and ultimately the properties and applications. In this regard gemini surfactants (GS) with an additional head group than the conventional single chain surfactant and a spacer group through which the two head groups are attached covalently are studied extensively by several groups including our own group [[6], [7], [8], [9], [10], [11], [12], [13]]. Additional head group in GS provides the additional site for the electrostatic interaction with the external additives and influence the hydrophile–lipophile balance whereas the spacer unit influences the surface curvature, which offers aggregates with different shapes and sizes in aqueous medium [14]. With increasing the alkyl chain length, the spontaneous curvature of the aggregates decreases, the cap-energy increases and the size of the aggregates increases as well [[15], [16], [17]]. Although GS exhibit various structural aggregates in the aqueous solution, the tailor-made structures could be envisaged by controlling the molecular interactions between the GS and the external additives [[18], [19], [20], [21], [22]].
The hydrophobicity of the surfactant in the catanionic systems comprising of oppositely charged surfactants governs the aggregate structures. Further, in such systems, in addition to critical micelle concentration (cmc), when the aggregation is significant, a critical aggregation concentration (cac) occurs. If the attractive hydrotropic interactions are sufficiently strong, it causes the micellar growth leading to the formation of bilayer structures as observed in several lipid systems [[23], [24], [25], [26], [27], [28], [29], [30], [31]]. These mixtures at the charge neutralization composition, i.e. at equimolar composition, forms precipitates, which prevent these mixtures to be used in various fields, including drug delivery and cosmetics. Attempts are made to control the interaction between the components of the catanionic mixtures through deliberately changing the structure of the surfactants and/or replacing one of the surfactants with hydrotropes [[32], [33], [34]]. Hydrotropic drug such as diclofenac sodium (DS) is studied recently due to its hydrotropic character to transform the spherically shaped micellar aggregates of the traditional cationic surfactant cetyltrimethylammonium bromide (CTAB) into vesicles through intermediate worm like micelles [27,[35], [36], [37], [38], [39]]. DS is an analgesic and non-steroidal anti-inflammatory drug with high biological activity and high potential against pain and rheumatic inflammations [[40], [41], [42]]. By using hydrotropic drug to form the vesicles, we are purposefully avoiding the third component other than the amphiphile and drug, and prevent the system to become more complex which improves the pharmacokinetics and physico-chemical properties of the drugs. Moreover, catanionic vesicles with drug as one of the components can encapsulate other hydrophilic/hydrophobic drugs inside the aqueous and hydrophobic compartment of the vesicles to have multifunctional drug delivery system [35,36,43]. Further, interaction with the amphiphile enhances the solubility of the hydrophobic drugs and increases the encapsulation efficiency of the amphiphile in its changed morphological state from spherical to vesicles. Recently doxorubicin hydrochloride was used to form the catanionic vesicles with the amino acid based GS through synergistic interactions, the system was then used to study the controlled release of the drug for the chemotherapy [44].
Herein, we aim to study the synergistic interaction between the cationic GSs with the DS. The parameters adjusted to get the morphology with variable shape and size includes (i) concentration of DS and (ii) alkyl chain length of the GS. We believe that rationally designing the interaction through judiciously adjusting the above mentioned parameters could result in aggregates useful for the drug delivery application. The electrostatic interaction between the polar head groups of the GS and DS along with the hydrophobic interaction between the alkyl chains of the GS and aromatic part of the DS causes the probable micellar transition. The size of the aggregates are measured using dynamic light scattering (DLS) and small angle neutron scattering (SANS) measurement, whereas the shapes of the aggregates were determined though TEM and SANS data. These systems were tested for their potential drug delivery applications at human body temperature.
DS was purchased from Sigma-Aldrich (purity 99.0%), pyrene from Merck (purity ≥96.0%) and methyl orange (MO) from Acros (purity 95.0%). GS was synthesized and characterized as given elsewhere [9,38]. Briefly, we reacted N,N-dimethyldodecylamine with 1,3-dibromopropane (molar ratio 1:2.1, respectively) in dry acetonitrile under reflux for 4 h, followed by solvent removal, washing the surfactant with cold ethyl acetate and dried. The absence of surface-active impurities in GS was confirmed from the absence of surface tension minimum before the cmc (Krüss K9 tensiometer; 25 °C; curve not shown). 1H NMR spectrum of the surfactant in CDCl3 (Bruker Avance III-300; 300 MHz) was used to check the purity of the surfactants. Data are given in supplementary information. Structures of the different GS, DS, MO and pyrene are presented in Scheme SI-1 of the supplementary information.
For the solution preparation, double distilled deionized water having conductivity of 6.1–6.4 μScm−1 was used. Experimentally, in aqueous micellar solution of GS, DS is added in incremental amount.
Section snippets
Turbidity measurements
Turbidity measurements were carried out using Varian Carry 50 spectrophotometer (Varian, Switzerland). The quartz cuvette having a path length of 1 cm was used. Optical density for the solutions were determined at 500 nm as individual components show no absorption at this wavelength. For dilution study, concentration of MO was kept constant 20 μM.
Size distribution measurements
Dynamic light scattering measurements were performed using Zeta sizer Nano ZS90 (Malvern) with a HeNe laser (633 nm, 4 mW). The samples were equipoise
Effects of DS on gemini surfactant solutions
Incorporating the hydrotrope into the ionic micelles resulted in the electrostatic and hydrophobic interaction between the components of the mixture. The electrostatic interactions screens the repulsion between the head groups, induce the tight packing and resulted in the increased size and change shape of the aggregates. Herein, we explored the formation of various aggregate structures in the aqueous GS solutions through addition of charged drug, DS having pKa of 4.5 ± 0.5. The aqueous GS
Conclusions
The aggregation behavior of three cationic gemini surfactants (GS), i.e. propanediyl-1,6-bis(dimethyldodecylammonium bromide) (12–3-12), propanediyl-1,6-bis(dimethyltetradecylammonium bromide) (14–3-14) and propanediyl-1,6-bis(dimethylhexadecylammonium bromide) (16–3-16) in the presence of hydrotropic drug diclofenac sodium (DS) has been investigated. Various non-covalent interactions (electrostatic, hydrophobic) between positively charged GS and the negatively charged DS resulted in the
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.
Acknowledgements
We thank Department of Science and Technology, India (SR/FT/CS-014/2010), and Council of Scientific and Industrial Research (CSIR), New Delhi, India (Grant No. 01 (2545)/11/EMR-II) for the financial assistance. M.K. acknowledges UGC-DAE for the Collaborative Research Scheme (UDCSR/MUM/AO/CRS-M-276/2017).
References (70)
- et al.
Phase behavior of mixed polyoxyethylene-type nonionic surfactants in water
J. Mol. Liq.
(2001) - et al.
Synergism between anionic double tail and zwitterionic single tail surfactants in the formation of mixed micelles and vesicles, and use of the micelle templates for the synthesis of nano-structured gold particles
Colloids Surf. A
(2015) Controlling surfactant self-assembly
J Colloid Interf Sci.
(2004)- et al.
Aggregation behavior in aqueous solutions of a new class of asymmetric bipolar amphiphiles investigated by surface tension measurements
J. Colloid Interf Sci.
(2001) - et al.
The effect of temperature on the interfacial tension between crude oil and gemini surfactant solution
Colloids Surf. A Physicochem. Eng. Asp.
(2008) - et al.
Synthesis, micellization behaviour and cytotoxic properties of imidazolium-based gemini surfactants
Colloid Interface Sci. Commun.
(2020) - et al.
Micellization, anti-proliferative activity and binding study of cationic gemini surfactants with calf thymus DNA
Colloid Interface Sci. Commun.
(2020) - et al.
Impact of organic solvents on the micellization and interfacial behavior of ionic liquid based surfactants
Colloids Surf. A Physicochem. Eng. Asp.
(2016) Effects of substituent, n-butanol, and sodium chloride on the solubilization of 4-alkylphenols in TTAB solutions
Colloid Interface Sci. Commun.
(2018)Effects of various alcohols and salts on the mixed micellization of cationic surfactant (CPC) with nonionic surfactant (TX-100)
Colloid Interface Sci. Commun.
(2017)
Thermodynamic, spectroscopic and biological investigation of interaction of anionic surfactants with [Cu(im)6]F2· 4H2O complex in aqueous solution colloid
Interface Sci. Commun.
Aggregation behavior of short-chained archaeal phospholipid analogs: contribution of methyl branches to lipid hydrophobicity and membrane formability
Colloid Interface Sci. Commun.
Environmental stimuli induced phase transition in the aqueous mixture solution of Gemini surfactants and sodium deoxycholate
Colloids Surfaces A
Surfactant enhanced spreading: catanionic mixture
Colloid Interface Sci. Commun.
Effect of surfactant head group on micellization and morphological transitions in drug-surfactant catanionic mixture: a multi-technique approach
Colloids Surf. A Physicochem. Eng. Asp.
Formation of drug/surfactant catanionic vesicles and their application in sustained drug release
Int. J. Pharm.
Recent developments in ophthalmic drug delivery systems for therapy of both anterior and posterior segment diseases
Colloid Interface Sci. Commun.
Synthesis of colloidal delivery vehicles based on modified polysaccharides for biomedical applications
Colloid Interface Sci. Commun.
Enhanced intercellular release of anticancer drug by using nano-sized catanionic vesicles of doxorubicin hydrochloride and gemini surfactants
J. Mol. Liq.
Characterization and encapsulation efficiency of rhamnolipid vesicles with cholesterol addition
J. Biosci. Bioeng.
Thermodynamic insights and molecular environments into catanionic surfactant systems: influence of chain length and molar ratio
J Colloid Interf Sci.
Spectroscopic studies of the interaction of methyl orange with cationic alkyltrimethylammonium bromide surfactants
J. Colloid Interface Sci.
Studies on the encapsulation of diclofenac in small unilamellar liposomes of soya phosphatidylcholine
Colloids Surf. B
Insights into the binding of the drugs diclofenac sodium and cefotaxime sodium to serum albumin: Calorimetry and spectroscopy
Eur. J. Pharm. Sci.
Non toxic biodegradable cationic gemini surfactants as novel corrosion inhibitor for mild steel in hydrochloric acid medium and synergistic effect of sodium salicylate: experimental and theoretical approach
Mater. Chem. Phys.
Thermo-switchable de novo ionogel as metal absorbing and curcumin loaded smart bandage material
J. Mol. Liq.
Surfactant Science and Technology
Solubilization of oil in a mixed cationic liquid crystal
Colloid Polym. Sci.
Gemini surfactants
Angew Chem Int Edit.
Gemini-induced columnar jointing in vitreous ice. Cryo-HRSEM as a tool for discovering new colloidal morphologies
J. Am. Chem. Soc.
Interaction between ionic liquids and gemini surfactant: A detailed investigation into the role of ionic liquids in modifying properties of aqueous gemini surfactant
J Surfactants Deterg.
Effects of 1-alkyl-3-methylimidazolium bromide ionic liquids on the micellar properties of [butanediyl-1, 4-bis (dimethyldodecylammonium bromide)] gemini surfactant in aqueous solution
Colloid Polym Sci.
Self-assembly of cationic gemini surfactants, alkanediyl-bis-(dimethyldodecyl-ammonium bromide), in cyclohexane: effects of spacer length on their association into reverse lyotropic liquid crystalline or reverse vesicles
Soft Matter
Microemulsions and the flexibility of oil/water interfaces
J. Phys. Chem.
Micelles, vesicles and microemulsions
J. Chem. Soc. Farad. Trans.
Cited by (0)
- 1
SR and KM share the equal contribution.