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Gold nanoparticles for photothermally controlled drug release
In this article, we describe how nanoparticles work in photothermally triggered drug delivery, starting with a description of the plasmon resonance and the photothermal effect, and how this is used to release a drug. Then, we describe the four major functionalization strategies and each of their different applications. Finally, we discuss the biodistribution and toxicity of these systems and the necessary requirements for the use of gold nanoparticles for spatially and temporally controlling drug release through the photothermal effect. Keywords: cancer • drug delivery • near-infrared irradiation • photothermal release • spatial and temporal release
Although metallic nanoparticles have been used as new therapeutic agents since the turn of this century, their use has increased in the last few years. After the appearance of the first reviews on this topic in major scientific journals, interest in the field has become widespread and the number of published papers has surged. These new strategies attempt to reduce or eliminate the side effects of metallic nanoparticles, mostly by improving the targeting of the drugs through the spatial and temporal control of the nanoparticles. In particular, the systems described here liberate a drug when irradiated by light, usually in the near-infrared (NIR) region. The use of metallic nanoparticles has been developed to a great extent towards drug delivery and therapy in cancer treatment. Traditional chemotherapy drugs have well-known pernicious side effects; chemotherapy attacks healthy cells as well as sick cells, causing hair loss, GI tract problems, loss of bone marrow and general distress, all due to the lack of drug specificity. New therapies attempt to relieve some of these effects by improving drug targeting through dedicated drug delivery strategies. In this article, we discuss strategies that harness the power of the photothermal effect of plasmonic gold
10.2217/NNM.14.126 © 2014 Future Medicine Ltd
nanoparticles (AuNPs) to produce controlled drug delivery. Most of the efforts described here are cancer-related strategies, but other diseases can be targeted as well. Plasmon resonance All of the systems that we will describe in this article are composed of plasmonic nanoparticles, so it is best to start our discussion with the plasmon, which is the basis of photothermal applications. Nanoparticles made of metals, such as gold or silver, have what is termed a localized surface plasmon resonance (LSPR) [1,2] , which is usually shortened to ‘plasmon’. The plasmon is the collective oscillation of the electrons on the surface of the metal, and in the case of metallic nanoparticles, this plasmon is very well localized, hence the term ‘LSPR’. The LSPR confers properties that are absent in the bulk metal and are unique to the nanostructured form, and these properties are due to the interaction of light with the electrons on the surface of the nanoparticle. Bulk gold has the characteristic yellow–orange tones we commonly associate with the metal, but gold at the nanoscale, such as typical colloidal gold, is red colored. This finding was demonstrated in the first gold colloids prepared
Nanomedicine (Lond.) (2014) 9(13), 2023–2039
Ariel R Guerrero1,2, Natalia Hassan1, Carlos A Escobar3, Fernando Albericio4,5,6,7, Marcelo J Kogan*,‡,1,2 & Eyleen Araya*,‡,3 Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago, Chile 2 Advanced Center for Chronic Diseases (ACCDiS), Santos Dumont 964, Independencia, Santiago, Chile 3 Universidad Andres Bello, Facultad de Ciencias Exactas, Departamento de Ciencias Químicas, Av. República 275, Santiago, Chile 4 Institute for Research in Biomedicine (IRB) Barcelona & CIBER-BBN, Networking Centre on Bioengineering, Biomaterials & Nanomedicine, 08028 Barcelona, Spain 5 School of Chemistry & Physics, University of Kwazulu-Natal, Durban 4001, Kwa-Zulu Natal, South Africa 6 Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain 7 School of Chemistry, Yachay Tech, Yachay Cityof Knowledge, 100119-Urcuqui, Ecuador *Authors for correspondence: mkogan@ ciq.uchile.cl; eyleen.araya@ unab.cl ‡ Authors contributed equally 1
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ISSN 1743-5889
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Review Guerrero, Hassan, Escobar, Albericio, Kogan & Araya by Michael Faraday and in the typical citrate-reduced gold nanospheres originally developed by Turkevich et al. [3] . The surface plasmon in nanosized gold makes the particle absorb and scatter light very efficiently at certain wavelengths, which gives them their color. In addition, some of the absorbed light is dissipated as local heat in what is called the photothermal effect, which we will describe later. The position of the absorption maximum in the spectrum varies with the size of the particle. AuNPs between approximately 10 and 40 nm have an absorption peak that falls in the green region of the visible spectrum, which makes them red when they are viewed with the naked eye. The plasmons of larger particles, such as gold nanoshells (AuNSs) or gold nanorods (AuNRs), are further shifted towards red, making them appear bluer and even brownish when the plasmon absorption is well into the infrared region (as observed in larger rods). The scattering produced by the particles reaches a maximum slightly towards the red of the absorption peak. Light scattered by the nanoparticles amplifies Raman and fluorescence signals in the form of surface-enhanced Raman scattering and surface-enhanced fluorescence. Photothermal effect: how it works The goal of the photothermally controlled drug release strategy is to obtain a chemotherapy system that is spatially and temporally controlled. Ideally, the drug would not be released until the particles arrive at the site of action. This would reduce the toxic side effects of cancer chemotherapy by providing a more specific delivery that reduces the harming of healthy cells, as this comprises the major problem of classical chemotherapy methods. In plasmonic nanoparticles, the photothermal effect manifests as phonons, in which energy is transformed from light into vibration of the crystal structures. Absorbed photons are transformed into phonons in a process that involves a rapid electron–phonon relaxation, followed by a phonon–phonon relaxation, resulting in an increase of the temperature of the system and by conduction to its surroundings [4–6] , thus producing local heat (Figure 1) . Several papers and reviews have already described how this has been applied to directly kill a cancer cell by hyperthermia [6–10] . Thus, in this article, we will focus on the application of the photothermal effect in photothermally triggered drug delivery. It is also important to mention that because of the nature of this strategy, most of the nanostructures employed for this purpose need a plasmon absorption in the NIR region. This is because human tissue absorbs very little in this region of the spectrum (wave-
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lengths between 700 and 1100 nm, the so-called physiologically transparent region or the NIR window due to its position in the spectrum), and therefore this radiation can penetrate very well without causing harm [9] . Gold is the most commonly employed metal in these approaches due to its low inherent toxicity, as demonstrated in many assays (see the ‘Toxicity & biodistribution’ section at the end of this article) and because it allows for the fabrication of nanostructures that have plasmon absorptions in this region. Typical citratereduced gold nanospheres have plasmon absorption peaks at 510–540 nm, which is outside of the transparent region. Therefore, these are less suitable for photothermal therapy, although several papers have been published in which these are employed. Notably, when AuNPs are confined in space (i.e., in a cell compartment), the plasmon resonance shifts to the NIR region. The best studied nanostructures for this purpose are AuNSs [12–14] , hollow gold nanospheres (HGNs), AuNRs [15–18] and gold nanocages (AuNCs) [19,20] , which are shown in Figure 2. These will be discussed in more detail in the next section. What nanostructures are used? It is not an accident that the first to envision the potential of nanoparticles as photothermal agents for the treatment of diseases, especially cancer, were groups with previous experience in the synthesis of plasmonic nanoparticles who collaborated with biomedical groups in the search for new nanostructure applications. The first paper published on the subject was written by the groups of Naomi Halas from Rice University (TX, USA) and Jennifer West from the University of Texas (TX, USA). In 2000, Halas and colleagues first demonstrated the use of their nanosystem as a platform for a more efficient drug delivery [25] . Later, in their 2003 paper, they demonstrated the use of nanoshells as direct photothermal therapy agents [12] . Halas’s group had developed the synthesis of AuNSs [13–14,26] for applications towards surface-enhanced Raman scattering [13] and surface-enhanced fluorescence [27] . AuNSs are sphere-like nanostructures in which the metallic part is only their outer shell, hence their name. The resulting nanostructures have a single plasmon absorption band in the red or NIR window, right in the region required for photothermal activity (Figure 2) . Similar to AuNSs are the so-called HGNs, which are also a shell-like spherical nanoparticle, but are actually hollow on the inside [28,29] . The plasmon of these particles is very similar to that of AuNSs. For both AuNSs and HGNs, the peak position of the surface plasmon depends on the ratio between the shell diameter and the thickness of the HGNs. These particles are very attractive for treatment through NIR light due to their
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Gold nanoparticles for photothermally controlled drug release
Review
Figure 1. The photothermal effect in gold nanoparticles. Upon irradiation (visible or near-infrared radiation according to the plasmonic band of the gold nanoparticle), the gold nanoparticle absorbs light (hν, left). The absorption of energy leads to an electronic transition of the surface electrons from a ground state (S0 ) to an excited state (S1). The energy is dissipated to the surroundings of the nanostructure as local heat (right) in all directions. hv: Photon of light. Adapted from [11] © Royal Society of Chemistry.
unique combination of small size, spherical shape and strong, narrow and tunable NIR plasmons. There has long been interest in the synthesis of nanostructures with nonspherical geometry. The first researchers to successfully achieve this goal were the group of Murphy for silver nanorods [30] and later AuNRs. Nikoobakht and El-Sayed later modified Murphy’s method for the synthesis of AuNRs of varying aspect ratios, which have become a standard in the literature due to their high yield and ease of use [16] . El-Sayed’s group published a thermal therapy application of their AuNRs in 2006 [15] . This application has subsequently been used by many groups to develop photothermally triggered therapy systems. AuNRs show structure-dependent optical properties due to their two absorption bands that represent the transverse and longitudinal modes of their LSPR. These are typically observed with a peak of approximately 520 nm and another in the red or NIR region (Figure 2E) [31–35] . The other type of nanostructure that has been well studied for photothermal applications is the AuNCs developed by Xia’s group [36,37] . AuNCs are synthesized by first obtaining silver nanocubes by chemical reduction in a relatively lengthy procedure developed by the same group. These cubes then act as templates, and gold is grown on top of the silver nanocubes while
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the silver is extracted from the system. The result is a set of particles that are similar to hollow cubes made of gold, which possess the advantage that their plasmon absorption can also be tuned to match the required frequencies in the NIR window by regulating the size of the silver nanocubes. Similar to AuNSs and AuNRs, AuNCs have also been employed for direct photothermal cell ablation and for drug delivery [38–40] . Photothermally triggered drug delivery strategies As schematized in Figure 3, we can envision four major pharmaceutical scenarios in which the photothermal process is employed to trigger drug delivery with nanoparticles: • The drug (green capsules in Figure 3A) is embedded in a polymeric matrix surrounding the nanoparticle. The local heat changes the structure of the polymer, allowing for drug release; • The drug and the nanoparticle are embedded in liposomes, and the local heat breaks the liposomes to allow for drug release; • The drug is covalently bonded to a spacer molecule (yellow diamonds in Figure 3C) bound to the
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Review Guerrero, Hassan, Escobar, Albericio, Kogan & Araya
A
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Wavelength (nm) Figure 2. Nanoparticles typically employed for photothermally-controlled drug delivery. (A–D) Transmission electron microscopy images of the four gold nanostructures most typically employed for photothermal applications, taken from the cited references: (A) gold nanospheres (∼15 nm); (B) gold nanorods (∼20 × 45 nm); (C) gold nanoshells (∼100 nm); (D) gold nanocages (∼60 nm). (E) Extinction spectra and transmission electron microscopy images of gold nanorods of increasingly high aspect ratios from below to above (from aspect ratio width:length from 1:1 to 1:4, respectively), showing the redshift of the longitudinal absorption peak. This absorption can be tuned to reach the near-infrared window (700–1100 nm) and can therefore be employed for photothermal applications. This is also valid for gold nanoshells and nanocages. Copyrights of the images: (A & B) Reproduced with permission from [21] © 2010 Wiley–VCH Verlag GmbH & Co. KGaA, Weinheim; (C) [22] © 2007 American Chemical Society; (D) [23] © 2014 Ivyspring International Publisher; (E) [24] © 2013 American Chemical Society.
nanoparticle. The local heat causes the rupture of the bond, thus liberating the drug; • Similar to the previous case, except the drug is noncovalently attached to the AuNP surface, usually through embedding the drug in a silica matrix. The local heating facilitates the liberation of the drug. Liberation of the drug from a polymer matrix
A thermoresponsive polymer corona can be easily introduced via different strategies [41–43] . The first application of photothermally modulated drug delivery with nanoparticles was performed by Sershen et al., who demonstrated that copolymers of N-isopropylacrylamide (NIPAM) and acrylic amide could be used to build a thermally responsive hydrogel that exhibits a lower critical solution temperature that is slightly above body temperature [25] . When the copolymer exceeds
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the lower critical solution temperature, the hydrogel collapses, causing a burst of any soluble material held within the hydrogel matrix. Nanoshells were incorporated into the hydrogel with the aim of initiating a temperature change by light irradiation at 1064 nm. Methylene blue and proteins of varying molecular weights were also included in the hydrogel in order to study their liberation. The nanoshell-composite hydrogels were demonstrated to release multiple bursts of protein in response to repeated NIR irradiation. Low clearance of nanoparticles in the body is a factor that limits their utility. For this reason, different strategies have been developed in order to make nanoparticles more biocompatible. To increase the efficiency of AuNPs for drug delivery, it is possible to incorporate biocompatible polymers, such as poly(lactic-co-glycolic acid) (PLGA) and PEG [44–48] . The use of these
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Gold nanoparticles for photothermally controlled drug release
polymers expands the possible applications of AuNPs. For example, several studies have been published in recent years that show the irradiation of AuNPs in the presence of biocompatible polymers, polymeric micelles and liposomes. Huang et al. synthesized AuNRs functionalized with multilayers of negatively charged polyelectrolytes (poly[acrylic acid sodium salt]) and positively charged polyelectrolytes (poly[allylamine hydrochloride]) in order to electrostatically absorb the model drug rhodamine 6G [49] . The modified and loaded AuNRs were exposed to laser irradiation at 785 nm for 5-min intervals from 0 to 60 min. After irradiation, the amount of rhodamine 6G in the supernatants was quantified by fluorescence spectroscopy. These results showed that the dye release was linear with the time of radiation. In addition, when more layers were added around the AuNRs, the release of the model drug decreased progressively until no released drug was detected. Choi et al. used photopolymerization to develop the polymer Pluronic® F-68 (Gibco®, NY, USA) and the chitosan-conjugated form of a Pluronic-based nanocarrier as carriers for AuNRs [50] . In this case, the vehicle was observed to be an excellent reservoir with a simple loading method that possessed a high loading capacity for large molecules. This system was also exposed to laser irradiation at a wavelength of 780 nm with different power densities for 4 min and had a photothermal effect in cancer cells. Liu et al. synthesized AuNRs functionalized with a thermoresponsive corona of poly(ethylene glycol)-bpoly(N-vinylcaprolactam) where internal heating was generated by laser irradiation [51] . This method induced the phase transition of the polymer, liberating the preloaded drug molecule. In this case, temperature variation was measured with an optical thermosensor. After 10 min of NIR irradiation (200 mW), the temperature increased by 19°C in comparison to the control experiment with phosphate buffered saline (PBS) instead of AuNRs, which only increased in temperature by 2°C under NIR-induced heating. Polyrotaxanes are another polymeric drug delivery system consisting of a PEG axis and cyclodextrin rings that are interconnected through noncovalent interactions. Because cyclodextrins have strong host–guest relationships, they can be used as biocompatible carriers. Adeli et al. formed pseudopolyrotaxanes through hydrophobic interactions between the end of the triazine groups of PEG (conjugated onto AuNRs) and the α-cyclodextrin cavity [52] . These pseudopolyrotaxanes interact noncovalently through the end functional groups of PEG with the citrate shell of the AuNPs, constituting a hybrid system. In this study, the photothermal properties of AuNRs were used to control the
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Review
Figure 3. Four scenarios for triggering drug delivery using the photothermal effect. (A) The drug (green capsules) is embedded in a polymeric matrix surrounding the nanoparticle. (B) The drug and the nanoparticle are embedded in liposomes. (C) The drug is covalently bonded to a spacer molecule (yellow diamonds), which is bound to the nanoparticle. (D) The drug is not covalently bound to the AuNPs.
release of a model drug incorporated into the cyclo dextrin matrix. Doxorubicin (Dox) was used in this case. Irradiation with a 512-nm laser demonstrated that the release of the drug depended on the molecular weight of the PEG due to the noncovalent interactions with AuNPs. For this reason, high-molecular-weight polymers (e.g., 10,000 and 20,000) will release the drug faster than systems with lower molecular weights due to their weaker interactions with gold. Several works have been published on the use of HGNs for NIR irradiation. For example, Campardelli et al. synthesized a biocompatible polylactic acid (PLA)–HGN composite in which NIR irradiation was used to determine the rate of drug release from this composite [53] . PLA was used as a polymeric matrix, and a dye – rhodamine B – was used as a model drug; the dye was dissolved in the aqueous phase of a water– oil–water emulsion, and the HGNs were incorporated in the polymeric organic phase. The authors obtained interesting results because the model drug, rhodamine B, was delivered in 10 days without NIR light influence and without the presence of HGN. These results are explained by the natural swelling of the polymer, allowing the delivery of the model drug. However, when the composite was exposed to a NIR light with different laser power intensities and with different HGN loading in the PLA carriers, the delivery of the drug was reduced from 10 days to 5 min. The temperature of the system can be increased by up to 6°C due to the presence of high concentrations of HGN (1.5 wt%). In the case of low-HGN concentrations (0.5 wt%), the temperature can increase by up to 3°C.
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Review Guerrero, Hassan, Escobar, Albericio, Kogan & Araya In the case of laser power intensities of the maximum value, the temperature of the composite increases by 9°C over the 5-min irradiation period, showing that the heat evolution and consequent delivery of the drug increases with HGN concentration and laser intensity. Another drug delivery strategy uses branched AuNSs. Topete et al. combined three different properties in one multifunctional nanoparticle that includes chemo-, photo- and thermo-therapies [54] . This was achieved by loading PLGA nanoparticles with Dox and covering them with porous gold shells, which allows for NIR light absorption. The porous AuNPs in this nanoplatform use NIR light irradiation to produce localized heat, accelerating the drug release. Several works have been published with Dox loaded as a model drug [55] . Another approach using thermally responsive, biocompatible hydrogel-coated AuNPs has been developed by Kim et al. [56] . In this case, a thermally responsive hydrogel overlayer (20–90 nm thick) consisting of a crosslinked copolymer of N-isopropylacrylamide and acrylic acid was designed to show swelling/contracting behavior. These reversible volume transitions are dependent on the lower critical solution temperature and would lead to drug release. Because NIR light can be used to excite the plasmon resonance of the hydrogel-coated AuNPs, it is assumed that the heat generated by the infrared excitation could be used in the future to collapse a drug-impregnated hydrogel overlayer, thus liberating the drug. You et al. prepared HGNs (35 nm in diameter) to be used as photothermal agents mediated by NIR light, and they included them into biodegradable and biocompatible microspheres of poly(lactide-co-glycolide) copolymer (1–15 μm) containing the anticancer drug paclitaxel [57] . They evaluated the drug release properties of paclitaxel from the HGN-loaded microspheres, mediated by NIR laser irradiation (808 nm). They found that paclitaxel release was insignificant under no irradiation, and the controlled release was dependent on the output power, duration of irradiation and frequency and concentration of the gold nanospheres embedded inside the microspheres. It was also shown that paclitaxel-loaded microspheres and nanospheres display significantly greater cytotoxic effects in in vitro cancer cells (human breast carcinoma and human glioma) under irradiation than in cells incubated with the microspheres alone or cells irradiated with NIR light alone. For the treatment of rheumatoid arthritis, Lee et al. developed a methotrexate-loaded PLGA gold halfshell nanoparticle system [58] . A HS–PEG–COOH linker was also attached through Au–S bonds, and a cyclic RGD peptide (i.e., an arginine–glycine–aspartic acid tripeptide, which is a targeting moiety for inflammation) was conjugated to the linker. The
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nanoparticles were injected intravenously into collagen-induced arthritic mice. In vivo NIR absorbance images revealed that the nanoparticles selectively accumulated in the inflamed region or in tumors due to the enhanced permeability and retention (EPR) effect [59–62] , which is caused by the abnormal irrigation that favors the retention of AuNPs in the affected zone. Upon NIR irradiation (1.59 W/cm2, 10 min), the temperature of the inflamed paw increased to 48°C, leading to the burst release of methotrexate from the nanoparticles (Figure 4) . An implantable reservoir capped by a nanocomposite membrane whose permeability was modulated by irradiation with a NIR laser was developed by Timko et al. [63] . The device is able to provide on-demand, repeated, reproducible and titratable drug delivery over extended periods. HGNs were used to accomplish the task because they are less likely to deform than AuNRs. The key feature of this system is an impermeable membrane that becomes porous when irradiated with NIR light. The membrane consists of a hydrophobic ethylcellulose matrix containing HGNs that heat under NIR irradiation, causing a network of interconnected polymer nanoparticles to reversibly collapse when heated beyond a critical temperature. The particles contracted to approximately a tenth of their original diameter, the polymer became hydrophobic and the material was dewetted. Membranesealed devices loaded with aspart, a fast-acting insulin analog, were tested on diabetic rats with the aim of depressing the blood sugar to normal levels. Repeated dosing was demonstrated using 30-min dosing cycles triggered by laser irradiation twice per day for a 5-day period (Figure 5) . Liposomes
Liposomes (or lipid vesicles) are spherical particles with small central volumes separated from their surroundings by one or more lipid bilayers. These elements are a class of nanoparticles that can encapsulate drugs or other therapeutic agents and can act as biomimetic compartments with membranes that closely resemble those of living cells [64–67] . Rengan et al. coated liposomes with gold nanospheres that, in an aggregated state, are able to absorb NIR light at approximately 750 nm [68] . This increases the temperature to the phase transition temperature (43°C) and causes changes in the membrane structure, thereby releasing the drug. Calcein was used as a model drug in these experiments, and within 5 min of NIR irradiation, almost 50% was released. In the previous example, AuNPs were coating the liposome. AuNPs can also be incorporated between the bilayers of the liposomes, as in the work of An et al.
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Gold nanoparticles for photothermally controlled drug release
Review
Au Half Shell
PLGA Au deposition
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Figure 4. Fabrication process of RGD–methotrexate–PLGA–gold nanoparticles. First, MTX-loaded PLGA nanoparticles were prepared, then Au (15 nm) was deposited onto the MTX–PLGA nanoparticle monolayers, resulting in a half-shell structure. MTX–PLGA–Au nanoparticles were conjugated with HS–PEG–COOH (α-mercapto-ω-carboxy-PEG) in order to functionalize the structure with the cyclic RGD peptide. MTX: Methotrexate; PLGA: Poly(lactic-co-glycolic acid). Reproduced from [58] © 2012 American Chemical Society. [69] .
This group prepared a vehicle in which the drug was encapsulated in the central aqueous compartment of the liposome, while AuNPs were incorporated into the bilayer. AuNPs strongly absorb light energy, converting this energy to heat. The drug release is controlled by the timing of irradiation and the concentration of AuNPs in the AuNP–liposome composite. The photothermal effect induces the phase transition of the liposome, disrupting the layers and releasing the drug. Hybrid nanocomposite materials have also been used as drug delivery systems. Nanocomposite sponges composed of amphiphilic micelles within a porous chitosan-based matrix that includes AuNPs have been studied by Matteini et al. [70] . The temperature generated inside the sponge was regulated by the laser intensity and the irradiation time. A linear relationship within the temperature range of interest for the activation of the release mechanism was found. This control can activate the micelles contained inside the chitosan scaffold, exploiting the potential stimulus-responsive implants.
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More examples have been published, including liposomes with pegylated nanoparticles (Agarwal et al. [71]), giant vesicles (Lei et al. [72]) and liposomes with plasmonic nanobubbles using a short-pulsed laser (Anderson et al. [73]). Molecular rupture
The next strategy to analyze is when a covalent bond is broken in order to release a drug. Notably, there are a few studies in which this strategy has been explored. One example is the binding of the Diels–Alder adduct to the AuNP, such that when the complex is irradiated, the photothermal effect causes a temperature rise that shifts the equilibrium of the Diels–Alder reaction from the adduct (the product in a normal, ‘forward’ Diels–Alder) to the precursors, the diene and the dienophile. This effect is employed to release a drug. Bakhtiari et al. have developed a method to harness the local heat dissipated from AuNPs when they are stimulated with visible light without significantly increasing the temperature of the surrounding environment
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Review Guerrero, Hassan, Escobar, Albericio, Kogan & Araya
hv
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Figure 5. Nanocomposites with nanogels that include hollow gold nanospheres.The permeability of nanocomposites can be modulated for the controlled release of an insulin analog after irradiation with a laser. The photothermal effect leads to changes in the phase of the ethylcellulose matrix (note that in the original image from [63] , hollow gold nanospheres are represented as ‘AuNS’). AuNS: Hollow gold nanosphere; hv: Photon of light. Reproduced from [63] © National Academy of Sciences, USA.
(i.e., without cell damage) [74] . To this end, the retroDiels–Alder reaction of the 7-oxa-bicyclo[2.2.1]-hepta5-ene-2,3-dicarboxylic imide was selected. Upon heating in the range of 25–60°C, this compound releases both a furan and a maleimide moiety. The AuNPs and the Diels–Alder adduct were linked together through an n-decane linker attached to the AuNPs through a sulfur atom and to the maleimide moiety through the nitrogen atom. To test the usefulness of the AuNP– linker–maleimide adduct as a drug delivery system, a fluorescein furfuryl ester was attached to the maleimide side of the nanoparticle–linker–maleimide adduct. The photothermal release of the fluorescein dye was induced by irradiation with a 532-nm pulsed laser. Yamashita et al. prepared a Diels–Alder adduct consisting of a 7-oxa-bicyclo-[2.2.1]hept-5-ene-2,3-dicarboxylic imide core functionalized with a methylenethiol at the furan side and with a long-chain PEG at the maleimide side [75] . AuNRs were functionalized by attaching the thiol side to the nanoparticle. When the modified AuNRs were irradiated by NIR light, the maleimide–PEG chains were released from the AuNRs due to the retro-Diels–Alder reaction induced by the photothermal effect (Figure 6) . Another technique that differs from a retro-Diels– Alder reaction was developed by Pandey et al., who prepared a blend of carbon dots and AuNRs for the controlled release of Dox under ideal physiological conditions [76] . Using a modified protocol, they were able to introduce purified carbon dots into
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the AuNR-growing solution and obtain a carbon dot–AuNR complex, where the dots were attached to the rods via weak interactions. This complex was used for anchoring Dox via covalent and noncovalent pHsensitive chemical bonds. Under physiological conditions, the drug load capacity was estimated to be in the order of 94%. After 2 h of irradiation, a rapid release of the Dox (
Gold nanoparticles for photothermally controlled drug release
In this article, we describe how nanoparticles work in photothermally triggered drug delivery, starting with a description of the plasmon resonance and the photothermal effect, and how this is used to release a drug. Then, we describe the four major functionalization strategies and each of their different applications. Finally, we discuss the biodistribution and toxicity of these systems and the necessary requirements for the use of gold nanoparticles for spatially and temporally controlling drug release through the photothermal effect. Keywords: cancer • drug delivery • near-infrared irradiation • photothermal release • spatial and temporal release
Although metallic nanoparticles have been used as new therapeutic agents since the turn of this century, their use has increased in the last few years. After the appearance of the first reviews on this topic in major scientific journals, interest in the field has become widespread and the number of published papers has surged. These new strategies attempt to reduce or eliminate the side effects of metallic nanoparticles, mostly by improving the targeting of the drugs through the spatial and temporal control of the nanoparticles. In particular, the systems described here liberate a drug when irradiated by light, usually in the near-infrared (NIR) region. The use of metallic nanoparticles has been developed to a great extent towards drug delivery and therapy in cancer treatment. Traditional chemotherapy drugs have well-known pernicious side effects; chemotherapy attacks healthy cells as well as sick cells, causing hair loss, GI tract problems, loss of bone marrow and general distress, all due to the lack of drug specificity. New therapies attempt to relieve some of these effects by improving drug targeting through dedicated drug delivery strategies. In this article, we discuss strategies that harness the power of the photothermal effect of plasmonic gold
10.2217/NNM.14.126 © 2014 Future Medicine Ltd
nanoparticles (AuNPs) to produce controlled drug delivery. Most of the efforts described here are cancer-related strategies, but other diseases can be targeted as well. Plasmon resonance All of the systems that we will describe in this article are composed of plasmonic nanoparticles, so it is best to start our discussion with the plasmon, which is the basis of photothermal applications. Nanoparticles made of metals, such as gold or silver, have what is termed a localized surface plasmon resonance (LSPR) [1,2] , which is usually shortened to ‘plasmon’. The plasmon is the collective oscillation of the electrons on the surface of the metal, and in the case of metallic nanoparticles, this plasmon is very well localized, hence the term ‘LSPR’. The LSPR confers properties that are absent in the bulk metal and are unique to the nanostructured form, and these properties are due to the interaction of light with the electrons on the surface of the nanoparticle. Bulk gold has the characteristic yellow–orange tones we commonly associate with the metal, but gold at the nanoscale, such as typical colloidal gold, is red colored. This finding was demonstrated in the first gold colloids prepared
Nanomedicine (Lond.) (2014) 9(13), 2023–2039
Ariel R Guerrero1,2, Natalia Hassan1, Carlos A Escobar3, Fernando Albericio4,5,6,7, Marcelo J Kogan*,‡,1,2 & Eyleen Araya*,‡,3 Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago, Chile 2 Advanced Center for Chronic Diseases (ACCDiS), Santos Dumont 964, Independencia, Santiago, Chile 3 Universidad Andres Bello, Facultad de Ciencias Exactas, Departamento de Ciencias Químicas, Av. República 275, Santiago, Chile 4 Institute for Research in Biomedicine (IRB) Barcelona & CIBER-BBN, Networking Centre on Bioengineering, Biomaterials & Nanomedicine, 08028 Barcelona, Spain 5 School of Chemistry & Physics, University of Kwazulu-Natal, Durban 4001, Kwa-Zulu Natal, South Africa 6 Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain 7 School of Chemistry, Yachay Tech, Yachay Cityof Knowledge, 100119-Urcuqui, Ecuador *Authors for correspondence: mkogan@ ciq.uchile.cl; eyleen.araya@ unab.cl ‡ Authors contributed equally 1
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ISSN 1743-5889
2023
Review Guerrero, Hassan, Escobar, Albericio, Kogan & Araya by Michael Faraday and in the typical citrate-reduced gold nanospheres originally developed by Turkevich et al. [3] . The surface plasmon in nanosized gold makes the particle absorb and scatter light very efficiently at certain wavelengths, which gives them their color. In addition, some of the absorbed light is dissipated as local heat in what is called the photothermal effect, which we will describe later. The position of the absorption maximum in the spectrum varies with the size of the particle. AuNPs between approximately 10 and 40 nm have an absorption peak that falls in the green region of the visible spectrum, which makes them red when they are viewed with the naked eye. The plasmons of larger particles, such as gold nanoshells (AuNSs) or gold nanorods (AuNRs), are further shifted towards red, making them appear bluer and even brownish when the plasmon absorption is well into the infrared region (as observed in larger rods). The scattering produced by the particles reaches a maximum slightly towards the red of the absorption peak. Light scattered by the nanoparticles amplifies Raman and fluorescence signals in the form of surface-enhanced Raman scattering and surface-enhanced fluorescence. Photothermal effect: how it works The goal of the photothermally controlled drug release strategy is to obtain a chemotherapy system that is spatially and temporally controlled. Ideally, the drug would not be released until the particles arrive at the site of action. This would reduce the toxic side effects of cancer chemotherapy by providing a more specific delivery that reduces the harming of healthy cells, as this comprises the major problem of classical chemotherapy methods. In plasmonic nanoparticles, the photothermal effect manifests as phonons, in which energy is transformed from light into vibration of the crystal structures. Absorbed photons are transformed into phonons in a process that involves a rapid electron–phonon relaxation, followed by a phonon–phonon relaxation, resulting in an increase of the temperature of the system and by conduction to its surroundings [4–6] , thus producing local heat (Figure 1) . Several papers and reviews have already described how this has been applied to directly kill a cancer cell by hyperthermia [6–10] . Thus, in this article, we will focus on the application of the photothermal effect in photothermally triggered drug delivery. It is also important to mention that because of the nature of this strategy, most of the nanostructures employed for this purpose need a plasmon absorption in the NIR region. This is because human tissue absorbs very little in this region of the spectrum (wave-
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lengths between 700 and 1100 nm, the so-called physiologically transparent region or the NIR window due to its position in the spectrum), and therefore this radiation can penetrate very well without causing harm [9] . Gold is the most commonly employed metal in these approaches due to its low inherent toxicity, as demonstrated in many assays (see the ‘Toxicity & biodistribution’ section at the end of this article) and because it allows for the fabrication of nanostructures that have plasmon absorptions in this region. Typical citratereduced gold nanospheres have plasmon absorption peaks at 510–540 nm, which is outside of the transparent region. Therefore, these are less suitable for photothermal therapy, although several papers have been published in which these are employed. Notably, when AuNPs are confined in space (i.e., in a cell compartment), the plasmon resonance shifts to the NIR region. The best studied nanostructures for this purpose are AuNSs [12–14] , hollow gold nanospheres (HGNs), AuNRs [15–18] and gold nanocages (AuNCs) [19,20] , which are shown in Figure 2. These will be discussed in more detail in the next section. What nanostructures are used? It is not an accident that the first to envision the potential of nanoparticles as photothermal agents for the treatment of diseases, especially cancer, were groups with previous experience in the synthesis of plasmonic nanoparticles who collaborated with biomedical groups in the search for new nanostructure applications. The first paper published on the subject was written by the groups of Naomi Halas from Rice University (TX, USA) and Jennifer West from the University of Texas (TX, USA). In 2000, Halas and colleagues first demonstrated the use of their nanosystem as a platform for a more efficient drug delivery [25] . Later, in their 2003 paper, they demonstrated the use of nanoshells as direct photothermal therapy agents [12] . Halas’s group had developed the synthesis of AuNSs [13–14,26] for applications towards surface-enhanced Raman scattering [13] and surface-enhanced fluorescence [27] . AuNSs are sphere-like nanostructures in which the metallic part is only their outer shell, hence their name. The resulting nanostructures have a single plasmon absorption band in the red or NIR window, right in the region required for photothermal activity (Figure 2) . Similar to AuNSs are the so-called HGNs, which are also a shell-like spherical nanoparticle, but are actually hollow on the inside [28,29] . The plasmon of these particles is very similar to that of AuNSs. For both AuNSs and HGNs, the peak position of the surface plasmon depends on the ratio between the shell diameter and the thickness of the HGNs. These particles are very attractive for treatment through NIR light due to their
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Gold nanoparticles for photothermally controlled drug release
Review
Figure 1. The photothermal effect in gold nanoparticles. Upon irradiation (visible or near-infrared radiation according to the plasmonic band of the gold nanoparticle), the gold nanoparticle absorbs light (hν, left). The absorption of energy leads to an electronic transition of the surface electrons from a ground state (S0 ) to an excited state (S1). The energy is dissipated to the surroundings of the nanostructure as local heat (right) in all directions. hv: Photon of light. Adapted from [11] © Royal Society of Chemistry.
unique combination of small size, spherical shape and strong, narrow and tunable NIR plasmons. There has long been interest in the synthesis of nanostructures with nonspherical geometry. The first researchers to successfully achieve this goal were the group of Murphy for silver nanorods [30] and later AuNRs. Nikoobakht and El-Sayed later modified Murphy’s method for the synthesis of AuNRs of varying aspect ratios, which have become a standard in the literature due to their high yield and ease of use [16] . El-Sayed’s group published a thermal therapy application of their AuNRs in 2006 [15] . This application has subsequently been used by many groups to develop photothermally triggered therapy systems. AuNRs show structure-dependent optical properties due to their two absorption bands that represent the transverse and longitudinal modes of their LSPR. These are typically observed with a peak of approximately 520 nm and another in the red or NIR region (Figure 2E) [31–35] . The other type of nanostructure that has been well studied for photothermal applications is the AuNCs developed by Xia’s group [36,37] . AuNCs are synthesized by first obtaining silver nanocubes by chemical reduction in a relatively lengthy procedure developed by the same group. These cubes then act as templates, and gold is grown on top of the silver nanocubes while
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the silver is extracted from the system. The result is a set of particles that are similar to hollow cubes made of gold, which possess the advantage that their plasmon absorption can also be tuned to match the required frequencies in the NIR window by regulating the size of the silver nanocubes. Similar to AuNSs and AuNRs, AuNCs have also been employed for direct photothermal cell ablation and for drug delivery [38–40] . Photothermally triggered drug delivery strategies As schematized in Figure 3, we can envision four major pharmaceutical scenarios in which the photothermal process is employed to trigger drug delivery with nanoparticles: • The drug (green capsules in Figure 3A) is embedded in a polymeric matrix surrounding the nanoparticle. The local heat changes the structure of the polymer, allowing for drug release; • The drug and the nanoparticle are embedded in liposomes, and the local heat breaks the liposomes to allow for drug release; • The drug is covalently bonded to a spacer molecule (yellow diamonds in Figure 3C) bound to the
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2025
Review Guerrero, Hassan, Escobar, Albericio, Kogan & Araya
A
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Wavelength (nm) Figure 2. Nanoparticles typically employed for photothermally-controlled drug delivery. (A–D) Transmission electron microscopy images of the four gold nanostructures most typically employed for photothermal applications, taken from the cited references: (A) gold nanospheres (∼15 nm); (B) gold nanorods (∼20 × 45 nm); (C) gold nanoshells (∼100 nm); (D) gold nanocages (∼60 nm). (E) Extinction spectra and transmission electron microscopy images of gold nanorods of increasingly high aspect ratios from below to above (from aspect ratio width:length from 1:1 to 1:4, respectively), showing the redshift of the longitudinal absorption peak. This absorption can be tuned to reach the near-infrared window (700–1100 nm) and can therefore be employed for photothermal applications. This is also valid for gold nanoshells and nanocages. Copyrights of the images: (A & B) Reproduced with permission from [21] © 2010 Wiley–VCH Verlag GmbH & Co. KGaA, Weinheim; (C) [22] © 2007 American Chemical Society; (D) [23] © 2014 Ivyspring International Publisher; (E) [24] © 2013 American Chemical Society.
nanoparticle. The local heat causes the rupture of the bond, thus liberating the drug; • Similar to the previous case, except the drug is noncovalently attached to the AuNP surface, usually through embedding the drug in a silica matrix. The local heating facilitates the liberation of the drug. Liberation of the drug from a polymer matrix
A thermoresponsive polymer corona can be easily introduced via different strategies [41–43] . The first application of photothermally modulated drug delivery with nanoparticles was performed by Sershen et al., who demonstrated that copolymers of N-isopropylacrylamide (NIPAM) and acrylic amide could be used to build a thermally responsive hydrogel that exhibits a lower critical solution temperature that is slightly above body temperature [25] . When the copolymer exceeds
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the lower critical solution temperature, the hydrogel collapses, causing a burst of any soluble material held within the hydrogel matrix. Nanoshells were incorporated into the hydrogel with the aim of initiating a temperature change by light irradiation at 1064 nm. Methylene blue and proteins of varying molecular weights were also included in the hydrogel in order to study their liberation. The nanoshell-composite hydrogels were demonstrated to release multiple bursts of protein in response to repeated NIR irradiation. Low clearance of nanoparticles in the body is a factor that limits their utility. For this reason, different strategies have been developed in order to make nanoparticles more biocompatible. To increase the efficiency of AuNPs for drug delivery, it is possible to incorporate biocompatible polymers, such as poly(lactic-co-glycolic acid) (PLGA) and PEG [44–48] . The use of these
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Gold nanoparticles for photothermally controlled drug release
polymers expands the possible applications of AuNPs. For example, several studies have been published in recent years that show the irradiation of AuNPs in the presence of biocompatible polymers, polymeric micelles and liposomes. Huang et al. synthesized AuNRs functionalized with multilayers of negatively charged polyelectrolytes (poly[acrylic acid sodium salt]) and positively charged polyelectrolytes (poly[allylamine hydrochloride]) in order to electrostatically absorb the model drug rhodamine 6G [49] . The modified and loaded AuNRs were exposed to laser irradiation at 785 nm for 5-min intervals from 0 to 60 min. After irradiation, the amount of rhodamine 6G in the supernatants was quantified by fluorescence spectroscopy. These results showed that the dye release was linear with the time of radiation. In addition, when more layers were added around the AuNRs, the release of the model drug decreased progressively until no released drug was detected. Choi et al. used photopolymerization to develop the polymer Pluronic® F-68 (Gibco®, NY, USA) and the chitosan-conjugated form of a Pluronic-based nanocarrier as carriers for AuNRs [50] . In this case, the vehicle was observed to be an excellent reservoir with a simple loading method that possessed a high loading capacity for large molecules. This system was also exposed to laser irradiation at a wavelength of 780 nm with different power densities for 4 min and had a photothermal effect in cancer cells. Liu et al. synthesized AuNRs functionalized with a thermoresponsive corona of poly(ethylene glycol)-bpoly(N-vinylcaprolactam) where internal heating was generated by laser irradiation [51] . This method induced the phase transition of the polymer, liberating the preloaded drug molecule. In this case, temperature variation was measured with an optical thermosensor. After 10 min of NIR irradiation (200 mW), the temperature increased by 19°C in comparison to the control experiment with phosphate buffered saline (PBS) instead of AuNRs, which only increased in temperature by 2°C under NIR-induced heating. Polyrotaxanes are another polymeric drug delivery system consisting of a PEG axis and cyclodextrin rings that are interconnected through noncovalent interactions. Because cyclodextrins have strong host–guest relationships, they can be used as biocompatible carriers. Adeli et al. formed pseudopolyrotaxanes through hydrophobic interactions between the end of the triazine groups of PEG (conjugated onto AuNRs) and the α-cyclodextrin cavity [52] . These pseudopolyrotaxanes interact noncovalently through the end functional groups of PEG with the citrate shell of the AuNPs, constituting a hybrid system. In this study, the photothermal properties of AuNRs were used to control the
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Review
Figure 3. Four scenarios for triggering drug delivery using the photothermal effect. (A) The drug (green capsules) is embedded in a polymeric matrix surrounding the nanoparticle. (B) The drug and the nanoparticle are embedded in liposomes. (C) The drug is covalently bonded to a spacer molecule (yellow diamonds), which is bound to the nanoparticle. (D) The drug is not covalently bound to the AuNPs.
release of a model drug incorporated into the cyclo dextrin matrix. Doxorubicin (Dox) was used in this case. Irradiation with a 512-nm laser demonstrated that the release of the drug depended on the molecular weight of the PEG due to the noncovalent interactions with AuNPs. For this reason, high-molecular-weight polymers (e.g., 10,000 and 20,000) will release the drug faster than systems with lower molecular weights due to their weaker interactions with gold. Several works have been published on the use of HGNs for NIR irradiation. For example, Campardelli et al. synthesized a biocompatible polylactic acid (PLA)–HGN composite in which NIR irradiation was used to determine the rate of drug release from this composite [53] . PLA was used as a polymeric matrix, and a dye – rhodamine B – was used as a model drug; the dye was dissolved in the aqueous phase of a water– oil–water emulsion, and the HGNs were incorporated in the polymeric organic phase. The authors obtained interesting results because the model drug, rhodamine B, was delivered in 10 days without NIR light influence and without the presence of HGN. These results are explained by the natural swelling of the polymer, allowing the delivery of the model drug. However, when the composite was exposed to a NIR light with different laser power intensities and with different HGN loading in the PLA carriers, the delivery of the drug was reduced from 10 days to 5 min. The temperature of the system can be increased by up to 6°C due to the presence of high concentrations of HGN (1.5 wt%). In the case of low-HGN concentrations (0.5 wt%), the temperature can increase by up to 3°C.
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2027
Review Guerrero, Hassan, Escobar, Albericio, Kogan & Araya In the case of laser power intensities of the maximum value, the temperature of the composite increases by 9°C over the 5-min irradiation period, showing that the heat evolution and consequent delivery of the drug increases with HGN concentration and laser intensity. Another drug delivery strategy uses branched AuNSs. Topete et al. combined three different properties in one multifunctional nanoparticle that includes chemo-, photo- and thermo-therapies [54] . This was achieved by loading PLGA nanoparticles with Dox and covering them with porous gold shells, which allows for NIR light absorption. The porous AuNPs in this nanoplatform use NIR light irradiation to produce localized heat, accelerating the drug release. Several works have been published with Dox loaded as a model drug [55] . Another approach using thermally responsive, biocompatible hydrogel-coated AuNPs has been developed by Kim et al. [56] . In this case, a thermally responsive hydrogel overlayer (20–90 nm thick) consisting of a crosslinked copolymer of N-isopropylacrylamide and acrylic acid was designed to show swelling/contracting behavior. These reversible volume transitions are dependent on the lower critical solution temperature and would lead to drug release. Because NIR light can be used to excite the plasmon resonance of the hydrogel-coated AuNPs, it is assumed that the heat generated by the infrared excitation could be used in the future to collapse a drug-impregnated hydrogel overlayer, thus liberating the drug. You et al. prepared HGNs (35 nm in diameter) to be used as photothermal agents mediated by NIR light, and they included them into biodegradable and biocompatible microspheres of poly(lactide-co-glycolide) copolymer (1–15 μm) containing the anticancer drug paclitaxel [57] . They evaluated the drug release properties of paclitaxel from the HGN-loaded microspheres, mediated by NIR laser irradiation (808 nm). They found that paclitaxel release was insignificant under no irradiation, and the controlled release was dependent on the output power, duration of irradiation and frequency and concentration of the gold nanospheres embedded inside the microspheres. It was also shown that paclitaxel-loaded microspheres and nanospheres display significantly greater cytotoxic effects in in vitro cancer cells (human breast carcinoma and human glioma) under irradiation than in cells incubated with the microspheres alone or cells irradiated with NIR light alone. For the treatment of rheumatoid arthritis, Lee et al. developed a methotrexate-loaded PLGA gold halfshell nanoparticle system [58] . A HS–PEG–COOH linker was also attached through Au–S bonds, and a cyclic RGD peptide (i.e., an arginine–glycine–aspartic acid tripeptide, which is a targeting moiety for inflammation) was conjugated to the linker. The
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nanoparticles were injected intravenously into collagen-induced arthritic mice. In vivo NIR absorbance images revealed that the nanoparticles selectively accumulated in the inflamed region or in tumors due to the enhanced permeability and retention (EPR) effect [59–62] , which is caused by the abnormal irrigation that favors the retention of AuNPs in the affected zone. Upon NIR irradiation (1.59 W/cm2, 10 min), the temperature of the inflamed paw increased to 48°C, leading to the burst release of methotrexate from the nanoparticles (Figure 4) . An implantable reservoir capped by a nanocomposite membrane whose permeability was modulated by irradiation with a NIR laser was developed by Timko et al. [63] . The device is able to provide on-demand, repeated, reproducible and titratable drug delivery over extended periods. HGNs were used to accomplish the task because they are less likely to deform than AuNRs. The key feature of this system is an impermeable membrane that becomes porous when irradiated with NIR light. The membrane consists of a hydrophobic ethylcellulose matrix containing HGNs that heat under NIR irradiation, causing a network of interconnected polymer nanoparticles to reversibly collapse when heated beyond a critical temperature. The particles contracted to approximately a tenth of their original diameter, the polymer became hydrophobic and the material was dewetted. Membranesealed devices loaded with aspart, a fast-acting insulin analog, were tested on diabetic rats with the aim of depressing the blood sugar to normal levels. Repeated dosing was demonstrated using 30-min dosing cycles triggered by laser irradiation twice per day for a 5-day period (Figure 5) . Liposomes
Liposomes (or lipid vesicles) are spherical particles with small central volumes separated from their surroundings by one or more lipid bilayers. These elements are a class of nanoparticles that can encapsulate drugs or other therapeutic agents and can act as biomimetic compartments with membranes that closely resemble those of living cells [64–67] . Rengan et al. coated liposomes with gold nanospheres that, in an aggregated state, are able to absorb NIR light at approximately 750 nm [68] . This increases the temperature to the phase transition temperature (43°C) and causes changes in the membrane structure, thereby releasing the drug. Calcein was used as a model drug in these experiments, and within 5 min of NIR irradiation, almost 50% was released. In the previous example, AuNPs were coating the liposome. AuNPs can also be incorporated between the bilayers of the liposomes, as in the work of An et al.
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Gold nanoparticles for photothermally controlled drug release
Review
Au Half Shell
PLGA Au deposition
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Figure 4. Fabrication process of RGD–methotrexate–PLGA–gold nanoparticles. First, MTX-loaded PLGA nanoparticles were prepared, then Au (15 nm) was deposited onto the MTX–PLGA nanoparticle monolayers, resulting in a half-shell structure. MTX–PLGA–Au nanoparticles were conjugated with HS–PEG–COOH (α-mercapto-ω-carboxy-PEG) in order to functionalize the structure with the cyclic RGD peptide. MTX: Methotrexate; PLGA: Poly(lactic-co-glycolic acid). Reproduced from [58] © 2012 American Chemical Society. [69] .
This group prepared a vehicle in which the drug was encapsulated in the central aqueous compartment of the liposome, while AuNPs were incorporated into the bilayer. AuNPs strongly absorb light energy, converting this energy to heat. The drug release is controlled by the timing of irradiation and the concentration of AuNPs in the AuNP–liposome composite. The photothermal effect induces the phase transition of the liposome, disrupting the layers and releasing the drug. Hybrid nanocomposite materials have also been used as drug delivery systems. Nanocomposite sponges composed of amphiphilic micelles within a porous chitosan-based matrix that includes AuNPs have been studied by Matteini et al. [70] . The temperature generated inside the sponge was regulated by the laser intensity and the irradiation time. A linear relationship within the temperature range of interest for the activation of the release mechanism was found. This control can activate the micelles contained inside the chitosan scaffold, exploiting the potential stimulus-responsive implants.
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More examples have been published, including liposomes with pegylated nanoparticles (Agarwal et al. [71]), giant vesicles (Lei et al. [72]) and liposomes with plasmonic nanobubbles using a short-pulsed laser (Anderson et al. [73]). Molecular rupture
The next strategy to analyze is when a covalent bond is broken in order to release a drug. Notably, there are a few studies in which this strategy has been explored. One example is the binding of the Diels–Alder adduct to the AuNP, such that when the complex is irradiated, the photothermal effect causes a temperature rise that shifts the equilibrium of the Diels–Alder reaction from the adduct (the product in a normal, ‘forward’ Diels–Alder) to the precursors, the diene and the dienophile. This effect is employed to release a drug. Bakhtiari et al. have developed a method to harness the local heat dissipated from AuNPs when they are stimulated with visible light without significantly increasing the temperature of the surrounding environment
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2029
Review Guerrero, Hassan, Escobar, Albericio, Kogan & Araya
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Figure 5. Nanocomposites with nanogels that include hollow gold nanospheres.The permeability of nanocomposites can be modulated for the controlled release of an insulin analog after irradiation with a laser. The photothermal effect leads to changes in the phase of the ethylcellulose matrix (note that in the original image from [63] , hollow gold nanospheres are represented as ‘AuNS’). AuNS: Hollow gold nanosphere; hv: Photon of light. Reproduced from [63] © National Academy of Sciences, USA.
(i.e., without cell damage) [74] . To this end, the retroDiels–Alder reaction of the 7-oxa-bicyclo[2.2.1]-hepta5-ene-2,3-dicarboxylic imide was selected. Upon heating in the range of 25–60°C, this compound releases both a furan and a maleimide moiety. The AuNPs and the Diels–Alder adduct were linked together through an n-decane linker attached to the AuNPs through a sulfur atom and to the maleimide moiety through the nitrogen atom. To test the usefulness of the AuNP– linker–maleimide adduct as a drug delivery system, a fluorescein furfuryl ester was attached to the maleimide side of the nanoparticle–linker–maleimide adduct. The photothermal release of the fluorescein dye was induced by irradiation with a 532-nm pulsed laser. Yamashita et al. prepared a Diels–Alder adduct consisting of a 7-oxa-bicyclo-[2.2.1]hept-5-ene-2,3-dicarboxylic imide core functionalized with a methylenethiol at the furan side and with a long-chain PEG at the maleimide side [75] . AuNRs were functionalized by attaching the thiol side to the nanoparticle. When the modified AuNRs were irradiated by NIR light, the maleimide–PEG chains were released from the AuNRs due to the retro-Diels–Alder reaction induced by the photothermal effect (Figure 6) . Another technique that differs from a retro-Diels– Alder reaction was developed by Pandey et al., who prepared a blend of carbon dots and AuNRs for the controlled release of Dox under ideal physiological conditions [76] . Using a modified protocol, they were able to introduce purified carbon dots into
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the AuNR-growing solution and obtain a carbon dot–AuNR complex, where the dots were attached to the rods via weak interactions. This complex was used for anchoring Dox via covalent and noncovalent pHsensitive chemical bonds. Under physiological conditions, the drug load capacity was estimated to be in the order of 94%. After 2 h of irradiation, a rapid release of the Dox (
