Modification of Solid Lipid Nanoparticles for Drug Delivery
Corresponding author: Dr. Thao Truong-Dinh Tran, Pharmaceutical Engineering Laboratory, Biomedical Engineering Department, International University, Vietnam National University – Ho Chi Minh City, Vietnam
Recently, tremendous attention has been drawn on the prog- ress of nano based-systems, which would optimize drug bio- availability [1-3]. Varieties of drug carrier systems such as polymeric nanoparticles, liposomes, magnetic nanoparticles, micelles, and solid lipid nanoparticles (SLNs) have been wide- ly investigated [4-10]. Among those advanced strategies, SLNs have been reported to be a promising nanocarrier system that can enhance the bioavailability, permeability, solubility and stability of the drug loaded [11, 12].
SLNs were first studied in the 1990s as alternative colloidal systems to emulsions, liposomes, polymeric microparticles and nanoparticles . They are submicron (50–1,000 nm) colloidal particles derived from oil-in-water emulsions by re- placing liquid lipids with a lipid matrix that is solid at room temperature, in which drugs are dispersed and stabilized . Generally, SLNs contain lipophilic or hydrophilic surfactants as stabilizers [14, 15], and physiologically tolerable lipid matrices
solid at room temperature such as complex mixtures of purified triglycerides, glycerides, paraffin or even waxes [13, 16].
Due to their biocompatibility, biodegradability, physicochem- ical stability, and low cytotoxicity [12, 17, 18], SLNs are not only feasible for the incorporation of lipophilic and hydropho- bic drugs but also able to enhance drug payload and stability , thereby facilitating the sustained release and controlled release of drugs. Moreover, SLNs can overcome the membrane stability and drug leaching problems of emulsions, or the tox- icity problems of polymeric nanoparticles. SLNs also offer oth- er unique characteristics such as small size, large surface area, high drug loading capacity, active interface interaction and possibility for large-scale production, which are all attractive in pharmaceutical fields .
Extensively, SLNs are attractive for targeted drug delivery ap- plications and bioavailability enhancement via diverse routes, including oral, rectal, nasal, pulmonary, ocular, parenteral, and dermal routes, so on and so forth . For parental route, they can be injected intravenously to circulate in the microvascu- lar system and prevent macrophage uptake in the hydrophilic coating or can be used for gene delivery through electrostatic interactions and gene therapy in cancer treatment . For oral route, SLNs granulates or powders can be encapsulated into capsules or pellets for investigation of oral administra- tion . For nasal and pulmonary delivery, SLNs could also be considered as effective colloidal with reducing the dosing frequency, improving drug bioavailability and diagnostics [21, 22].
Up to now, SLNs have been successfully used to enhance the bioavailability of poorly water-soluble drugs such as pacli- taxel, cyclosporin A, etc. [13, 14, 23, 24]. Subsequently, with all the current advantages, they will continue to be widely studied as potential colloidal drug carriers compared to their polymer- ic counterparts and liposomes in targeting and delivering of drugs.
SLNs are produced and then modified by various approaches in order to improve the efficiency of drugs incorporated. This review focuses on modification methods including surface modification, surfactant modification, and lipid modification.
Surface modification Targeting modification
Among the nanoparticulate formulations, SLNs hold great po- tential advantages for site-specific drug delivery with small distribution and large surface areas. Therefore, SLNs can fa- vorably modify its surface by functionalized groups [25-27]. Many researchers reported on alterations in the surface of SLNs by conjugating nanoparticles with specific substances such as ligands, antibodies, pH sensitive, magnetic agents and cations that specifically target tumor cells/ inflamed tissues or facilitate cellular uptake [25, 28-30]. Targeting drug delivery of SLNs to a specific organ, coupling with a sustained drug release profile would make SLNs an effective drug delivery system.
Kashanian et al.  proposed that the surface – modified SLN was prepared with the pH-sensitive carrier, N-glutaryl-phos- phatidylethanolamine, as an outer shell to deliver triamcino- lone acetonide to treat cancer and inflamed tissues in lymph nodes. The research reported that drug release from nanopar- ticles was found higher in the acidic condition. In another work, the targeted peptide ligand-coated SLN loaded with atorvasta- tin calcium (ATC) was fabricated by attaching the conjugated group of CSK peptide (CSKSSDYQC) and stearic acid with the beforehand manufactured ATC-loaded SLN . The result showed that CSK peptide ligand-modified SLN had spherical shape, small particle size (150-160 nm), uniform distribution and high drug encapsulation efficiencies (around 80%) with sustained release behavior. The targeting modified SLN could improve drug absorption and facilitate the drug penetration across the intestinal mucosa.
Recently, SLNs targeting drug delivery – the combination be- tween inorganic magnetic nanoparticles and SLNs – found its applications in creating magnetic-guided SLNs for improving cancer therapy [32, 33]. In the research of Pang et al. , Ibu- profen-loaded magnetic SLN (Ib-MSLN) was prepared by the method of emulsification dispersion-ultrasonic. A lipophilic magnetic carrier (oleic acid-loaded Fe3O4) incorporated with lipid phase containing Ibuprofen, was emulsified in an aque- ous surfactant solution. The warm microemulsion was dis- persed in cold water to form Ib-MSLN. Spherical shaped SLN with a mean diameter in the range 100-200 nm were obtained. The drug encapsulation efficiency was calculated about 86 % of drug entrapped in MSLN. The SEM and XRD pattern also in- dicated that magnetic nanoparticles were successfully embed- ded in SLN. Similarly, in the study published by Albuquerque et al , the multi-functionalized SLN was co-incorporated with Methotrexate (MTX) as therapy agent and superparamagnetic iron oxide nanoparticles (SPIONs) as contrast agent of MRI for rheumatoid arthritis (RA) diagnosis. The dual-encapsulation SLN system was then conjugated with anti-CD64 that could target the cell receptors presented in RA macrophages. The re- sults showed that the encapsulation of SPIONs could alter the surface structure of lipid in the SLN, leading to the increase in nanoparticle size; in addition, the efficiency of MTX and SPI- ONs within SLN were higher than 98%.
In another research, the SLN/siRNA complexes were success- fully developed by Kong et al.  for specific treatment of the liver, the cationic SLN were prepared by modified emulsifica- tion and solvent evaporation of lipid components reassembled natural apolipoprotein-free of low-density lipoprotein (LDL) with PEG-coated and positively charged surfactant on the monolayer. These nanoparticles could mimic natural lipopro- teins, which could interact with lipoprotein receptors such as LDL and remnant receptor that are located in the liver. Their bio-distribution evaluated by confocal microscopy, ex vivo flu- orescence bio-imaging and single-photo emission computed tomography (SPECT) revealed that the cationic SLN/siRNA complexes were successfully delivered and attached to the liver. Therefore, the coating of nanoparticle with cationic lip- id could allow the targeting of the drug to the specific parts of the body to improve drug efficacy and safety in therapeutic treatment.
Positively charged SLNs are promising genetic materials for intracellular gene delivery. The ionic interaction between nano molecules and cell membranes is important to open the cell pathway. Surfactants and cationic lipids are often used to modulate positive charge of the SLNs surface to enhance drug bioavailability and facilitate cellular uptake via electrostatic interactions [36, 37]. The cationic modified SLN was reported in 2001 by Olbrich et al. , which was prepared by hot homogenization method using Compritol ATO 888 as lipid, Tween 80/Span 85 as surfactant and EQ1 as charged carri- er. The modified SLN could form complexes with polyanionic DNA. The results also proposed that the binding effect between SLN and DNA was influenced by the compatibility of the lipid matrix and the domain hydrophobic modifier, affecting the as- sociation of the tension from the particle surface upon attach- ment to DNA. Other applications of positive modification SLNs have been developed actively; especially, cationic SLNs loaded with anticancer agents have been investigated. The positively charged SLNs coated by cationic surfactant can bind to can- cer cells through the electrostatic interactions with negatively charged phospholipids that are overexpressed on the surface of the cancer cells [39-41]. A research by Hwang et al.  in- vestigated the capability of cetyltrimethylammonium bromide as a cationic surfactant. These novel cationic modified SLNs containing cetyl palmitate, soybean phosphatidylcholine (lipid phase) and Pluronic F68 (aqueous phase) were fabricated by high-shear homogenization method. The results revealed that cationic SLNs could affect the immune system by the activation of the human polymorphonuclear neutrophil cells.
Cationic SLN loaded with Saquinavir which was developed by Kuo and Chen , investigating the influence of cationic lipid in increasing the entrapment efficiency of Saquinavir. The av- erage diameter and zeta potential of Saquinavir-loaded SLNs were about 140-190 nm and 8-14.5 mV, respectively. More- over, an increase in cationic lipids stearyl amine caused an in- crease in the diameter and a decrease in the zeta potential. The cationic SLN carrying Saquinavir also showed the sustained re- lease behavior with no burst release in the early stage.
Lately, cationic SLNs that provide cytoprotection against ultra- violet A (UVA) radiation damage and H2O2 have been studied . The study reported that the number of hydrophobic tails of cationic lipids influenced the crystalline structure of parti- cles, as well as affected the drug entrapment efficiency and in vitro release behavior. Cytoprotective study against UVA and H2O2 in HaCaT cells indicated that the presence of cationic lip- ids resulted in a high intracellular uptake and exhibited an ef- fective protection against UVA irradiation and H2O2 .
More recently, the novel positively charged surface-modified SLN consisted of chitosan or hydroxylpropyl trimethyl ammo- nium chloride chitosan was proved to have the ability to im- prove the absorption of Docetaxel through significant cellular uptake in Caco-2 cells .
Various studies indicated the effectiveness of surfactant mod- ification in SLNs fabrication using poloxamers, lecithins, poly- sorbates and polyethoxylated monoglycerides for further sta- bilizing SLNs . The surface area of particles is related to the stability of colloid particles, accompanying with solidification
during crystallization [46, 47]. In fact, surfactants supply bet- ter interface quality of nanoparticles to gain stable properties. Lecithin whose molecules existed as the form of bilayer mem- brane was chosen by Han et al.  for stabilizing nanostruc- tured lipid carriers system, based on its properties which can balance particle surface. In this study, ionic surfactant showed significantly low emulsification efficiency, but non-ionic emul- sifier poloxamer 188 (POX 188) with additional steric stabili- zation possessed fine particles, which helped to avoid aggre- gation in the system. The combination of POX 188 and lecithin also created a narrow size distribution that could be applied for PEG-modified SLN to improve the performance of nebiv- olol for hypertension treatment . In another investigation of surfactant modification by Na et al. , the modified SLNs were prepared with WGA-N-glut-PE (wheat germ aggluti- nin-N-glutaryl-phosphatidylethanolamine) and showed that this system significantly promoted insulin absorption.
Lipid is the main ingredient, which affects lipid nanoparticles drug loading capacity, stability, and the sustained release be- havior. Several lipid materials comprising of fatty acids, fatty alcohol, triglycerides, glycerides, and waxes have been inves- tigated. The influence of lipid matrices on drug encapsula- tion efficiency, loading capacities and the usefulness of lipid nanoparticles in drug delivery have also been studied . The study of fabricated SLNs using fatty acid (stearic acid) revealed that as the lipid content increased, the entrapment efficiency was increased. Small particle size (around 500-700 nm) was also observed. Moreover, the high amount of lipid also prevent- ed the drug diffusion from the internal phase to the external phase by increasing the viscosity of the system, leading to the faster solidification . Another factor that affects the prop- erties of lipid nanoparticle system is lipid polymorphism. The perfect crystalline form of the lattice which is thermodynami- cally stable is preferred to be produced rather than an appro- priate lipid forming prefect crystalline lattice structure. The “nanostructure lipid carrier” was developed to avoid various problems [59, 60] of fatty acids and wax based lipid nanopar- ticles by combining two different solid lipid matrices [61-63]. Jun et al.  also developed an SLN system based on crystal structure and polymorphism with lattice defects by incorpo- rating PEG 2000 into lipid matrix, which was distributed in SLN surface to increase the repulsion between nanoparticles and prevent aggregation. Surface steric hindrance of PEG2000 was highly maintained for stable nanoparticle size distribution of the system, which made it suitable for controlled release systems .
The potential applications of solid lipid nanoparticles for drug delivery with loading capacity of various active compounds have attracted a lot of attentions in recent studies. The modi- fied forms of SLNs such as lipid conjugation, targeted delivery
SLNs, positively charged SLNs are emphasized by their advan- tages of biocompatibility, biodegradability, physicochemical stability, low cytotoxicity, targeting drug delivery, improved bioavailability and hence, cultivating the increasing impor- tance of SLNs among tradition colloidal carriers.
Although some multi-nanosystems based SLN upon dosage forms of SLN-loaded gels, creams, and emulsions have under- taken and showed evidence of advantageous delivery, which could enhance therapeutic effectiveness, the numbers of such studies do not sufficiently reflect versatile applications of this system. In the near future, more dual/multi-system based- SLNs are believed to be further developed to give a new insight into their drug delivery and controlled release applications.
This research is funded by Vietnam National University – Ho Chi Minh City (VNU-HCM) under grant number C2016-28-03.
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