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Application of Solid Lipid Nanoparticles to Improve the Efficiency of Anticancer Drugs

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Application of Solid Lipid Nanoparticles to Improve the Efficiency of Anticancer Drugs nanomaterials Review Application of Solid Lipid Nanoparticles to Improve the Efficiency of Anticancer Drugs Laura Bayón-Cordero 1, Itziar Alkorta 1,2 and Lide Arana 1,* 1 Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Barrio Sarriena S/N, 48940 Leioa, Spain; [email protected] (L.B.-C.); [email protected] (I.A.) 2 Instituto Biofisika (CSIC, UPV/EHU), Barrio Sarriena S/N, 48940 Leioa, Spain * Correspondence: [email protected]; Tel.: +34-94-601-2568 Received: 12 February 2019; Accepted: 20 March 2019; Published: 22 March 2019 Abstract: Drug delivery systems have opened new avenues to improve the therapeutic effects of already-efficient molecules. Particularly, Solid Lipid Nanoparticles (SLNs) have emerged as promising nanocarriers in cancer therapy. SLNs offer remarkable advantages such as low toxicity, high bioavailability of drugs, versatility of incorporation of hydrophilic and lipophilic drugs, and feasibility of large-scale production. Their molecular structure is crucial to obtain high quality SLN preparations and it is determined by the relationship between the composition and preparation method. Additionally, SLNs allow overcoming several physiological barriers that hinder drug delivery to tumors and are also able to escape multidrug resistance mechanisms, characteristic of cancer cells. Focusing on cell delivery, SLNs can improve drug delivery to target cells by different mechanisms, such as passive mechanisms that take advantage of the tumor microenvironment, active mechanisms by surface modification of SLNs, and codelivery mechanisms. SLNs can incorporate many different drugs and have proven to be effective in different types of tumors (i.e., breast, lung, colon, liver, and brain), corroborating their potential. Finally, it has to be taken into account that there are still some challenges to face in the application of SLNs in anticancer treatments but their possibilities seem to be high. Keywords: solid lipid nanoparticles; drug delivery; cancer; tumor; chemotherapy 1. Introduction 1.1. Drug Delivery Systems The development in the last fifty years of biochemistry, molecular biology, biophysics, and cell biology, among other scientific disciplines, has led to significant advances in biomedicine based on the molecular knowledge of many diseases. This has made possible the development of therapeutic molecules effectively directed to the origin of the problem: the molecular and cellular processes that lead to the development of diseases. This is particularly important in cancer research where continuous progresses are made. Unfortunately, the development of new drugs is not enough to improve their effects on therapy. Some drugs are poorly soluble in water and cannot be administered unless they are encapsulated into drug carriers. In other occasions, drugs cannot permeate cell membranes and as a consequence the concentration at the target site is insufficient. To overcome this, high doses of drugs are required, causing high toxicity and many undesired side effects. Consequently, a targeted drug delivery system could selectively carry sufficient drug concentrations into the targeted tissue (or cell), improving its bioavailability and reducing the associated side effects due to high doses. In this regard, nanotechnology has expanded the therapeutic options of a priori efficient molecules by developing efficient Drug Delivery Systems (DDS). In fact, the application of nanotechnology in the Nanomaterials 2019, 9, 474; doi:10.3390/nano9030474 www.mdpi.com/journal/nanomaterials NanomaterialsNanomaterials 2018, 82019, x FOR, 9, 474PEER REVIEW 2 of 222 of 20 (DDS). In fact, the application of nanotechnology in the administration and delivery of drugs has broughtadministration significant advances and delivery in medicine, of drugs promot has broughting the significant emergence advances of a new in field: medicine, nanomedicine promoting the [1]. Diverseemergence DDS of have a new been field: developed nanomedicine by combining [1]. Diverse their DDS composition have been developed (organic, byinorganic, combining or their hybrid),composition size (small (organic, or large), inorganic, shapes (sphere, or hybrid), rod, size or cube), (small and or large), surface shapes properties (sphere, (surface rod, or charge, cube), and functionalsurface groups, properties PEGylation (surface or charge, other functionalcoating, and groups, attachment PEGylation of targeting or other moieties) coating, [2]. and By attachment doing of so, differenttargeting properties moieties) of [ 2therapeutic]. By doing molecules, so, different su propertiesch as solubility, of therapeutic pharmaco molecules,kinetic profile, such cellular as solubility, uptake,pharmacokinetic biodistribution profile,pattern, cellular circulation uptake, time, biodistribution and clearance mechanisms, pattern, circulation can be improved time, and [1,2]. clearance Thanksmechanisms, to the fast development can be improved of nanotechnology, [1,2]. Thanks th toere the is a fast vast development variety of nanocarriers of nanotechnology, that offer a there wide isspectrum a vast varietyof options of nanocarriersto treat each therapeu that offertic a problem wide spectrum by a tailored of options approach. to treatAmong each the therapeutic most studiedproblem organic by DDS a tailored it is worth approach. mentioning Among lipo thesomes, most studieddendrimers, organic polymeric DDS it nanoparticles is worth mentioning or micelles,liposomes, polymer–drug/protein dendrimers, polymeric conjugates, nanoparticles and lipid nanoparticles. or micelles, polymer–drug/proteinAdditionally, some inorganic conjugates, nanocarriersand lipid such nanoparticles. as carbon nano Additionally,tubes and somemesoporous inorganic silica nanocarriers nanoparticles such have as carbon been developed nanotubes and [1–3].mesoporous silica nanoparticles have been developed [1–3]. 1.2. Solid1.2. Lipid Solid LipidNanoparticles Nanoparticles It is wellIt is wellknown known that lipid-based that lipid-based nanoparticles nanoparticles are less are toxic less toxicand biocompatible and biocompatible compared compared to to inorganicinorganic or polymeric or polymeric nanoparticles nanoparticles [4,5]. [4,5 ].In In particular, particular, solidsolid lipidlipid nanoparticles nanoparticles (SLNs) (SLNs) have have emerged emergedas an as effective an effective and and promising promising alternative. alternative. They They are are colloidal colloidal particles particles of of submicron submicron size, size, with a with diametera diameter between between 50 and50 and 1000 1000 nm. nm. They They are made are made of a lipid of a matrixlipid matrix solid at solid physiological at physiological temperature, temperature,surfactants surfactants and, in some and, occasions,in some occa bysions, cosurfactants by cosurfactants (Figure1 )[(Figure6]. 1) [6]. Surfactant Lipid matrix Co-surfactant FigureFigure 1. Proposed 1. Proposed model model of solid of solid lipid lipid nanoparticles nanoparticles structure. structure. Schematic Schematic representation representation of of solid solid lipid lipid nanoparticlenanoparticle (SLN) (SLN) structure, structure, showing the su surfactant,rfactant, cosurfactant, and the solid lipid matrix. SLNsSLNs can be can produced be produced by different by different methods methods descri describedbed exhaustively exhaustively in the in bibliography, the bibliography, such suchas as high highshear shear homogenization homogenization and ultrasound, and ultrasound, high-pressure high-pressure homogenization, homogenization, hot homogenization, hot homogenization, cold homogenization,cold homogenization, solvent solvent emulsification/eva emulsification/evaporation,poration, and microemuls and microemulsionion [6–9]. [Among6–9]. Among them, them, the microemulsionthe microemulsion method method stands stands out out for for beingbeing an an easy easy method method that doesthat notdoes need not very need sophisticated very sophisticatedequipment equipment or high-energy or high-energy input and input avoids and theavoids use ofthe organic use of solvents.organic solvents. All these All advantages these advantagesmake themake production the production of SLNs of at SLNs large at scale large technically scale technically and economically and economically feasible [feasible10]. Nonetheless, [10]. Nonetheless,the correct the composition correct composition is essential for is the essential formation for of microemulsionsthe formation (thermodynamicallyof microemulsions stable (thermodynamicallyand transparent stable mixtures), and transparent and therefore mixtures the optimization), and therefore of the the mixture optimization is required. of the mixture is required. 1.3. Composition and Structure of Solid Lipid Nanoparticles 1.3. CompositionSLNs and are Structure versatile of nanocarriers Solid Lipid Nanoparticles that have been applied to improve the therapeutic effect of SLNsdifferent are molecules.versatile nanocarriers However, the that crystal have structurebeen applied of their to lipidimprove matrix the is therapeutic a crucial characteristic effect of to differentobtain molecules. high quality However, SLN formulations.the crystal structure This feature, of theirthe lipid formation matrix is of a thecrucial crystal characteristic solid state to of the obtainlipids high of quality the matrix, SLN dependsformulations. on the This selection feature, and the relative formation proportion of the of crystal the components, solid state as of well the
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