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Cyclodextrin Nanosponges Inclusion Compounds Associated with Gold Nanoparticles for Potential Application in the Photothermal Release of Melphalan and Cytoxan

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Cyclodextrin Nanosponges Inclusion Compounds Associated with Gold Nanoparticles for Potential Application in the Photothermal Release of Melphalan and Cytoxan International Journal of Molecular Sciences Article Cyclodextrin Nanosponges Inclusion Compounds Associated with Gold Nanoparticles for Potential Application in the Photothermal Release of Melphalan and Cytoxan Sebastián Salazar 1,2,3,* , Nicolás Yutronic 1, Marcelo J. Kogan 2,3,* and Paul Jara 1,* 1 Departmento de Química, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile; [email protected] 2 Departamento de Química, Farmacológica y Toxicológica, Universidad de Chile, Sergio Livingstone 1007, Santiago 8380492, Chile 3 Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santos Dumont 964, Independencia, Santiago 8380494, Chile * Correspondence: [email protected] (S.S.); [email protected] (M.J.K.); [email protected] (P.J.); Tel.: +56-229-787-396 (P.J.) Abstract: This article describes the synthesis and characterization of β-cyclodextrin-based nano- sponges (NS) inclusion compounds (IC) with the anti-tumor drugs melphalan (MPH) and cytoxan (CYT), and the addition of gold nanoparticles (AuNPs) onto both systems, for the potential release of the drugs by means of laser irradiation. The NS-MPH and NS-CYT inclusion compounds were characterized using scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), energy Citation: Salazar, S.; Yutronic, N.; dispersive spectroscopy (EDS), thermogravimetric analysis (TGA), UV–Vis, and proton nuclear Kogan, M.J.; Jara, P. Cyclodextrin magnetic resonance (1H-NMR). Thus, the inclusion of MPH and CYT inside the cavities of NSs Nanosponges Inclusion Compounds was confirmed. The association of AuNPs with the ICs was confirmed by SEM, EDS, TEM, and Associated with Gold Nanoparticles β for Potential Application in the UV–Vis. Drug release studies using NSs synthesized with different molar ratios of -cyclodextrin Photothermal Release of Melphalan and diphenylcarbonate (1:4 and 1:8) demonstrated that the ability of NSs to entrap and release the and Cytoxan. Int. J. Mol. Sci. 2021, 22, drug molecules depends on the crosslinking between the cyclodextrin monomers. Finally, irradiation 6446. https://doi.org/10.3390/ assays using a continuous laser of 532 nm showed that photothermal drug release of both MPH and ijms22126446 CYT from the cavities of NSs via plasmonic heating of AuNPs is possible. Academic Editors: Keywords: β-cyclodextrin; cyclodextrin polymers; anti-tumor; drug delivery; photothermal therapy; Antonino Mazzaglia, Lajos Szente plasmon surface resonance and Francesco Trotta Received: 29 May 2021 Accepted: 14 June 2021 1. Introduction Published: 16 June 2021 In recent years, nanotechnology has received increasing attention and consideration Publisher’s Note: MDPI stays neutral due to its potential to improve the effectiveness of various drugs that are currently being with regard to jurisdictional claims in used in cancer treatment. An inappropriate drug concentration at the tumor site and published maps and institutional affil- toxicity complications are the main causes of inadequate chemotherapeutic efficiency [1,2]. iations. Localized delivery is imperative in order to develop efficient treatments for aggressive types of cancer, such as melanoma, ovarian cancer, neuroblastoma, and multiple myeloma, among others [3–5]. Melphalan (MPH) and cytoxan (CYT) (Figure1) are anti-cancer chemotherapy drugs classified as alkylating agents [5,6]. Alkylating agents work by damaging the DNA of Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. cancer cells. Unfortunately, alkylating agents do not differentiate between cancerous cells This article is an open access article and normal cells. Common side effects for patients taking MPH and CYT include low distributed under the terms and blood counts, nausea, vomiting, and hair loss, to name a few [7–9]. conditions of the Creative Commons To overcome the limitations associated with anti-cancer agents and to minimize the Attribution (CC BY) license (https:// adverse side effects, nano-materials and nano-porous systems (such as cyclodextrin-based creativecommons.org/licenses/by/ nano-sponges (NS) have been synthesized and characterized, as they have great potential 4.0/). for applications in nano-therapies and drug delivery systems [10–15]. Cyclodextrins (CD) Int. J. Mol. Sci. 2021, 22, 6446. https://doi.org/10.3390/ijms22126446 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 6446 2 of 19 are water soluble oligosaccharides, most commonly consisting of six, seven, or eight glucopyranose units which are linked by α-1,4 glycosidic bonds. Among CDs, β-CD is interesting due to its cavity dimensions and its stability with crosslinking agents. As such, β-CD has been used to form nano-porous polymers [15]. The rising popularity of NSs as the material of choice over native CD is mainly due to their higher entrapment capacities, control over particle size and their ability to be regenerated and reutilized [16–19]. NSs can Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 19 also improve the physicochemical properties of the guest molecules, such as solubility and stability, and absorb liquids into their nano-porous structure to convert liquid materials into a solid form [20]. Figure 1. Chemical structure of MPH (left) and CYT (right). Figure 1. Chemical structure of MPH (left) and CYT (right). NSs main advantages also include that they can be chemically modified and decorated withTo nanoparticles, overcome the thus limitations improving associated the usefulness with anti-cancer and properties agents of and the polymerto minimize [21]. the NSs adversehave been side proven effects, to be nano-materials safe, non-toxic, biodegradable,and nano-porous and ofsystems low cost (such [22–24 ].as As cyclodex- such, NSs trin-basedhave gained nano-sponges attention in (NS) targeted have drug been delivery synthesized research and aimed characterized, at improving as they the efficacy have greatof chemotherapies potential for applications and reducing in the nano-t adverseherapies effects and related drug to delivery the drugs systems [16–18,20 [10–15].,25–29]. CyclodextrinsGold nanoparticles (CD) are water (AuNP) soluble also oligosacch show promisingarides, most characteristics commonly consisting in drug delivery of six, seven,systems, or eight as they glucopyranose present high units solubility, which highare linked stability by inα-1,4 living glycosidic systems bonds. and improved Among CDs,kinetics β-CD for is drug interesting distribution due [to30 its–33 cavity]. AuNPs dimensions can be conjugated and its stability to inclusion with complexes crosslinking (IC) agents.of CDs As if the such, guests β-CD have has functional been used groups, to form such nano-porous as thiols or amines polymers [34,35 [15].]. NSs The associated rising popularitywith AuNPs of NSs might as promotethe material the release of choice of theover included native CD drugs is mainly by means due of to irradiation, their higher due entrapmentto the plasmon capacities, effect ofcontrol AuNPs. over A controlledparticle size drug and delivery their ability system to usingbe regenerated AuNPs and and CD reutilizedhas been [16–19]. reported NSs previously can also [36 improve,37]; however, the physicochemical there are no such properties studies usingof the systems guest molecules,with NSs assuch the as matrix. solubility and stability, and absorb liquids into their nano-porous structureThe to objectives convert liquid of this materials study were intoto a solid synthesize form [20]. and characterize NS inclusion com- poundsNSs (IC)main with advantages the anti-tumor also include drugs MPHthat th andey can CYT be and chemically to conjugate modified the ICs and to AuNPsdeco- ratedto study with thenanoparticles, migration ofthus the improving guest molecules the usefulness by laser and irradiation. properties This of articlethe polymer reports [21].drug NSs release have studiesbeen proven using NSsto be inclusion safe, non-to compoundsxic, biodegradable, associated and to AuNPs of low viacost plasmonic [22–24]. Asphotothermia such, NSs have for the gained first time. attention These resultsin targeted could drug be of delivery great interest research as they aimed contribute at im- to provingthe understanding the efficacy ofof thechemotherapies potential utility and of reducing NSs associated the adverse to AuNPs effects for related the controlled to the drugsrelease [16–18,20,25–29]. of drug molecules via local photothermic effects. Gold nanoparticles (AuNP) also show promising characteristics in drug delivery systems,2. Results as andtheyDiscussion present high solubility, high stability in living systems and improved kinetics2.1. Characterization for drug distribution of the ICs [30–33]. AuNPs can be conjugated to inclusion complexes (IC)2.1.1. of 1CDsH-NMR if the Spectra guests of have the ICsfunctional groups, such as thiols or amines [34,35]. NSs associatedTo confirm with AuNPs the formation might promote of the NS-MPHthe release and of the NS-CYT included complexes, drugs by1 H-NMRmeans of spec- ir- radiation,troscopy due was to used. the plasmon The changes effect in of the AuNP chemicals. A controlled shifts of the drug drugs delivery provide system evidence using for AuNPsthe formation and CD ofhas the been ICs. reported Figure2 previouslyshows the acquired[36,37]; however, spectra ofthere the NSs,are no the such anti-tumor studies usingdrugs systems and the with ICs. NSs as the matrix. TheThe objectives proton signals of this of study both guestwere moleculesto synthesize show and high-field
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