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    Laponite® - A Key Nanoplatform For Biomedical Applications - Elsevier Enhanced Reader

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    Lucas Carvalho

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    © All Rights Reserved
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    ® ESEEEEIES n nomedicine = Nanomodicine: Nanotechnology, Biology, and Medicine 14 (O18) 2407-2420 ora Review Article ranomedjoural com Special Topic: Two-Dimensional Biomaterials in Regenerative Medicine Laponite®: A key nanoplatform for biomedical applications? Helena Tomis*, Carla $. Alves, Jofio Rodrigues* COM Conro de Qunica da Madina, MAMRG, Universidade da Madera, Campus da Pencada, 020105 Funchal, Pormgal Received 20 Novenber 2016; accep 3 Api 2017 Abstract Laponite® isa synthetic smectite clay that already has many important technological applications, which go beyond the conventional uses oof clays in pharmaceutics and cosmetics. In biomedical applications, particularly in nanomedicine, this material holds great potential Laponite® is a 2-dimensional (2) nanomaterial composed of disk-shaped nanoscale crystals that have a high aspect ratio. These disks can strongly interact with many types of chemical entities (from small moleeules or ions, to natural or synthetic polymers, to different inorganic nanoparticles) and are also easily functionalized and readily degraded in the physiological environment giving rise to non-toxic and even bioactive products. This review will highlight the potential of Laponite™ as a nanomaterial in the fields of drug delivery, bioimaging, tissue ‘engineering and regenerative medicine. New concepts, as well as novel innovative materials that stand out from the usual ones duc to the lunigue properties of Laponite, will also be presented and discussed, © 2017 Elsevier Ine. All rights reserved. Key words: Laposite; Nanomedicine; Drug delivery; Bioimaging; Tisue engineering and regenerative medicine ‘According to the Clay Minerals Society, clay minerals are ‘minerals which impart plasticity to clay and which harden upon applications.” Due to their favorable physicochemical properties, as well as their associated low cost and wide availability, «drying or firing”.' Most clay minerals are phyllosilicates, that is, they are made up of sheet silicate erystal structures that may vary in composition and dimensions.” The use of phyllosilicate clay minerals by humans dates back to prehistoric times, already then phyllosifiate clay minerals are now often applied in many pharmaceutical and cosmetic products. In fact, these materials ‘generally possess high sorption capability, swelling capacity and surface area, and are also reactive to acids.“ The smectite group playing a significant role in a wide range of health-related of phyllosilicate clay minerals, in particular, has been used in ‘Abbreviations: Aectal-PEG-b-PAMA, (a-acctal-ply(chyleneglyco)-black {poly2-(N.N-dimethylamino) ethyl methacrylate]: ALP, alkaline phospha- tase; APMES, 3ainopropyldimetylehoxysilane; ASGPR, assloglycoprocin eer, ATP, adenosine phosphate BMP-2, bone morphogenic protein? (CT, computed tomography; DTA, diatizoic acid; DTPA, diethyloneiaminepentaacetic acid; EDC, t- Another beautifil example that demonstrates the versatility of Laponite® after non-covalent functionalization is reported by Liu ‘et al.’ Here, an asymmetric functionalization of Laponite® was donc in which a femplate formed by polystyrene microspheres twas used, ‘The authors obtained amphiphilic Janus Laponite disks with hydrophobic polystyrene chains on one side and hydrophilic quatemized poly(2-(dimethylamino)ethyl methacry- late) (-PDMAEMA) on the other side Biomedical applications of Laponite® Drug Delivery Clays can serve as a means of protecting drugs against gradation in the physiological environment. They are also known to play a key role in the transport and release of drugs (particularly insoluble drug molecules) into the human body. ‘These observations were already established several years ago as reviewed by others fora set of natural and synthetic clays."*”* in these early studies, the interest Laponite™ as aclay was mainly focused on its sorption properties with litle emphasis being placed on the importance of its nanoscale dimensions Notwithstanding, these experiments revealed the potential of Laponite® XLG as a vehicle for drug delivery. Park et al for example interealated donepezil (a drug used as palliative treatment in Alzheimer's disease) into several different smectite clays including in Laponite® XLG.”" The drug-clay hybrids ‘were prepared by mixing the drug withthe clay of interest in solution. After centrifugation and a freezedrying step, the products were ground into fine powders using a pestle and mortar and were then further coated with Eudragit® E100. Following a similar approach, Jung et al also prepared @ ‘composite made up of Laponite® XLG and itraconazole (an antifungal agent that poorly dissolves in water)" In both studies, the release profile of the drugs was evaluated in simulated human gastric media since an oral administration route ‘was planned. Indeed, like other smecttes, Laponite™® presents a rich surface and intercalation chemistry and can establish imeractions with charged species, as well as with polar and non-polar compounds. Several execllent review articles. have ‘been published that describe in detail the different strategies that may be used to intercalate small organic molecules and polymers within smectite crystal stacks.” When in the form of diserete cexystals dispersed in solution, Laponite® can also adsorb many types of ions or molecules at its surface (Figure 3). The mechanisms underlying these interactions may involve elasscal ion-exchange, van de Waals forces, hydrogen bonding and 2410 1H Tomis etal / Nanomedicine: Nanorechsolog, Biolegy, and Medicine 14 (2018) 2407-2420 A B c Figure 3. Drugs can be transported by Laponite™-based material in diferent ways: by adsorption at the Laponit® surfaces when the clay isin the exfoliated state (Achy covalent attachment to the lay edges (B); by intercalation within the lay crystal stacks (C); by interaction or enespsulation with the polymer in ation to interations with the clay (Dy, and by encapsulation inside the inter-crytal spaces defined by the selFassembled crystals (E), cation/water bridging, and also protonation and ligand exchange at the erystal edges.” Since Laponite® crystals can aggregate when dispersed in solution due to electrostatic interactions between the negative surfaces and the positive ‘edges, drug encapsulation inside the inter-crystal spaces defined by the “House of Cards” structure is also a possibility (Figure 3), As a vehicle for drug delivery in nanomedicine, Laponite!® has ‘been studied either as a single component or in combination with ‘other materials (mainly polymers) In fact, a series of drug delivery systemshave been proposed in which this clay minera has been used. both atthe nanoscale (exfoliated clay) and at the micro/macto scale (here Laponite® nanocrystals are integrated into larger hydrogel’ scaflold structures). In each case, the mechanism of drug release was shown to be dependent on the overall design of the drug delivery system combined with the interactions established between the drug, ‘and the material's components. Laponite®-based drug delivery systems at the nanoscale In a very elegant work, Wang et al incorporated positively, charged doxorubicin molecules into Laponite® crystals. with very high efficiency.” It was shown that this well-known anticancer drug, which has a broad application in a range of ‘cancer types, primarily intercalated within the clay crystal stacks at the interlayer spaces through an ion-exchange process. Small stack aggregates were formed in water with hydrodynamic diameters of =41 nm and ~238 nm for the non-loaded and the loaded specimens, respectively, that increased in size in phosphate buffered saline (PBS) solution (pH = 7.4, =970 nm) and in acetic acid Sodium acetate buffer (pH = 5.4, ~385 nm). In vitro studies showed a pH-dependent drug release, which was higher at acidic pH values (pH = 5.4) than at physiological pH (7.4). Using the KB cell line (ruman epithelial carcinoma cells) as @ model of cancer cells, the authors also showed that higher cytotoxicity effect was obtained when using. the Laponite™ crystals as a vehicle for drug delivery relative to ‘when using the drug alone. Following a similar procedure to ‘obtain Laponite® crystals loaded with doxorubicin, Xiao et al further coated the rysials with polyelevtolyte multilayers using the layer-by-layer technique.” For this, two water-soluble polyelectrolyte polymers were employed, namely positively ‘charged poly(allylamine) hydrochloride (PAH) and negatively ‘charged poly(sodium styrene) sulfonate (PSS). This approach resulted in a finesuning of the extension of drug release at neutral and acidic pH values sine eombined the polyelectrolytes served asa barter for drug diffusion, The cytotoxicity presented by these nanohybrid controlled release systems toward MCF-7 breast cancer cells was in accordance with their drug delivery profiles. A different approach in which dhe Laponite® disks were H Tomas etal / Nanomedicine: Nanotechnology, Biology, and Medicine 14 (2018) 2407-2420 aait Laponite RDS (LP) Pt, a: &- z sp eee See LD= Laponite with DOX LDP= Laponite hybrids with DOX Figure 4 Role of PEGS/ation inthe colloidal stability of Laponite™ loaded with doxorubicin Hybrid nanomaterials formed by se asembly of Laponite® with poly(ethylene plycol) polylitic acid) result in the formation of an cuter shell of poly(ethylene glyco! that di hes nanopatcle aggregation. The improved colloidal stability behavior of Laponit® hybrids in PBS and in fetal bovine serum (FBS) along time is ilustated in he image below. There eolor is ‘duc tothe presence of doxombcin. Adapted with pennission fram reference 36, Copyright © 2014 American Chemical Society. coated with alginate, a naturally occurring polysaccharide, was also used with the aim of delaying doxorubicin release.” The nanohybrids prepared here were also found to be more sensitive to acidic environmental pH values, In vitro studies with the CAL-72 osteosarcoma cel line showed that, for the same drug ‘concentration, these nanohybrids presented a remarkably higher cytotoxicity toward the cancer cells relative to the free drug, Beyond the possibility of controlling the rate of drug delivery, ‘another important feature to consider when designing drug delivery vehicles for nanomedicine applications is their colloidal stability over time, In fact, the high sensitivity of Laponite® to high polyelectrolyte concentrations may lead to aggregation, ‘This is a problem that needs to be addressed, particularly since biological fluids (e.g, blood, extracellular fuid, ef.) are rich in relanivity isthe parameter affected and thus darker T,-weighted MR images may be obtained.®' Another application for SPIONs involves the treatment of cancer via magnetic hyperthermia, in which the nanoparticles used generate heat when exposed to a magnetic field." Ding etal reported the synthesis of new contrast agents for MRI that were obtained by controlled coprecipitation of iron ‘oxide in a Laponite® solution (Figure 5).° These hybrid nanomaterials presented a high colloidal stability and an ‘approximate 2-fold increase in Tp relaxivity when compared with iron oxide nanoparticles alone. The authors also performed in vivo studies in which mice bearing HeLa xenograft tumors ‘were used. Four hours post-injection, an approximate 50% loss n the intensity of the MRI signal in the tumors was detected that ‘began to recover 6 h post-injection due to body clearance. It was concluded that 24 h after intravenous injection, the Laponite™ nanohybrids were completely cleared from the body since the ron content in several major organs (e.g., heart, liver, spleen, Tung, kidney and tumor) was comparable with the iron content prior to injection. To confirm the absence of long-term organ toxicity, the authors observed the cell morphology of the major ‘organs half a month post-injection. Overall, no. significant changes were detected in the imaged organs when compared ‘with the organs of mice that underwent no treatment, Computed tomography (CT) imaging is also a technique that ‘often requires the use of eontrast agents." The iodinated contrast agents that are generally used to attenuate X-rays are very small, compounds and are quickly removed from the body (eg, diatrizoic acid (DTA) or iohexol)."* As such, itis necessary to immediately record the images after injection, Although the ‘concentration of the contrast agents may also be increased in ‘order to acquire CT images, this ean cause severe side effects in patients (e.g, renal toxicity). Altemative CT contrast agents are presently being investigated to obtain efficient X-ray attenuators, ‘with longer residence times in the body. Mustafa et al combined DTA with Laponite® for CT imaging of organs and tumors." ‘The Laponite® disks were first silanized to obtain amino groups atthe clay edges and then modified with DTA via EDC coupling chemistry. This was followed by acetylation of the remaining surface amines. The prepared nanohybrids had better in vitro X-ray attenuation properties than DTA alone, Jn vivo CT maging performance was tested after intravenously injecting healthy mice and mice bearing HeLa xenograft tumors with the DTA-modified Laponite® nanodisks. The results showed that the nanohybrids had an excellent performance in the CT imaging of the tumors, as well as of the hear, liver, and bladder. Since Laponite® can interact with drug molecules, the authors anticipate that the developed nanohybrids may constitute a versatile platform for theranosties (simultaneous diagnosis and therapy) of different diseases, Regenerative medicine and tissue engineering Laponite™ can play a relevant role in the fields of regenerative ‘medicine and tissue engineering at three different levels: first, Laponite® by itself can elicit specific biological responses; second, it can serve as a cartier for biochemical factors (e.g., mitogens and differentiation factors) as dispersed nanoscale particles or immobilized within a gel/scaffold and, finally, it can 1H Toms eat Oh 2h 4h 6h s Signal-to-noise Ratio enw)” gos ane Nts Figure 5. Laponite” hybrids containing iron once nanoparticles for resonance imaging. fn vivo T=weighted images of tumor (rd irl (red arow) and hidney (rod sa) after intravenous injetion of LAP-Fe,O, nanoparticles in mice at different time intervals (A). J» view MR signal intensity of liver, kidney and wumor ale intravenous injection of LAP-FeQs nanoparticles also at different ime intervals (B). A schematic representation ‘ofthe preparation of the nanohybrids (C). Adapted fom reference 63 with pemmission fom the Royal Society of Chemisty ‘be used to improve the mechanical properties of gelvscaffolds that are used for tissue growth, Laponites® asa bioactive nanomaterial “The degradation of Laponite® in the physiological environ- ment leads othe release of products that have known biological roles. Orthosilcie acid (Si(OH)), which can normally be found inthe plasma at concentrations ranging from 5 10 20 yM, was shown by Refit etal to inerease collagen type I synthesis in hhuman osteosarcoma cells (MG-63), primary osteoblast-like cells derived fiom human bone marrow stromal cells and immortalized human early osteoblastic cells (HCC) at SiOH), concentrations of 10 and 20 j1M." This effect was abolished in the presence of proly hydroxylase inhibitors, which points to the possibilty ofthis enzyme being directly or indiretly regulated by Si(OH),. Gene expression of alkaline phosphatase (ALP) and / Nanomedicine: Nanotechnology, Biology, and Medicine 1 (2018) 2407-2420 ais osteocalcin also increased significantly in MG-63 cells following Si(OID, exposure, revealing an enhancement in osteoblastic

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