Metallic Nanoparticles Applications and Therapies: Comparison
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Metallic-based nanoparticles present a unique set of physicochemical properties that support their application in different fields, such as electronics, medical diagnostics, and therapeutics. Particularly, in cancer therapy, the plasmonic resonance, magnetic behavior, X-ray attenuation, and radical oxygen species generation capacity displayed by metallic nanoparticles make them highly promising theragnostic solutions.

  • metallic nanoparticles
  • metal-polymer nanoconjugates
  • cancer

1. Introduction

The manipulation of matter at the nanoscale led to the development of various nanomaterials, based on polymers, lipids, ceramics, or metals, that exhibit exciting properties for improving the performance of electronics, medical diagnostics, and therapeutics [1,2][1][2]. Particularly, the application of nanoparticles for cancer therapy led to the development of new alternatives from therapeutics (i.e., drug delivery, photothermal and photodynamic effects) to diagnostic and imaging, leveraging the innate ability of these materials to accumulate in the tumor tissue [3,4,5][3][4][5].
In this field, the application of metallic-based nanomaterials (e.g., gold, iron, silver, and copper) has been capturing more attention in recent years due to their characteristic physical (e.g., magnetic behavior, plasmonic resonance, and imaging capacity) and chemical (e.g., radical oxygen species (ROS) generation, and catalytic activity enhancement) properties, which render them as platforms suitable for creating multifunctional cancer therapeutics [2,6,7,8,9][2][6][7][8][9]. Moreover, there are several methodologies described for the synthesis of metallic nanoparticles, such as physical or chemical vapor deposition, sol-gel methods, chemical reduction, hydrothermal methods, solvothermal method, laser ablation, and green synthesis processes, allowing the selection of the process most compatible with the available laboratory/industrial conditions and desired physicochemical properties [10,11,12,13][10][11][12][13]. Additionally, the surface functionalization of metallic nanomaterials, a strategy often used to refine the therapeutics pharmacokinetics, can be performed by well-known and defined methodologies [14]. Thus, the metallic nanomaterials’ theranostic potential provides an all-in-one solution for cancer diagnosis, therapy, and real-time monitoring, which ultimately can improve the therapeutic outcome of anticancer therapy [15,16][15][16]. This is the rationale behind various metallic-based nanomaterials under clinical trials, such as Aurolase®, Nanotherm®, and Magnablate®.
Nevertheless, despite the wide number of publications showing the appealing features of metallic-based nanomaterials, their translation into the clinic is still very limited [17]. Such is widely associated with some toxicological issues, lack of colloidal stability, and the establishment of off-target interactions [18]. Additionally, when subjected to high-energy radiations, the metallic nanoparticles often undergo reshaping processes or are even degraded leading to the loss of their therapeutic potential [19]. Therefore, researchers have been exploring the combination of metallic nanoparticles with other materials, inorganic (e.g., silica) and/or organic (e.g., polymers). Particularly, the combination of the metallic nanoparticles’ physicochemical properties with the superior biological performance of synthetic or natural polymers emerges as a valuable and straightforward approach to develop more effective anti-cancer therapeutics [16,20][16][20].

2. Metallic Nanoparticles Applications and Therapies

Nanosized metals present optical and electrical properties that differentiate them from other nanomaterials, supporting their application in biomedicine, such as the development of biosensors (e.g., diagnosis of viruses using colloidal gold nanoparticles), bioimaging agents (e.g., iron oxide-based contrast agents), catalysts, mechanical reinforcement, and drug delivery system or other therapeutics. Moreover, these unique characteristics can be explored to create more effective antitumoral nanomedicines. The high density and X-ray attenuation capacity of metallic nanoparticles allow them the intrinsic capacity to be applied as contrast agents for bioimaging applications [21]. Up to now, several studies available in the literature have already shown that metallic nanoparticles provide a higher contrast enhancement in X-ray computed tomography (CT) imaging than the iodine-based contrast agents conventionally used in the clinic [22,23,24,25,26][22][23][24][25][26]. On the other hand, nanosized metals, such as gold, silver, and copper, show a pronounced plasmonic resonance phenomenon, i.e., the collective oscillation of the conduction band electrons in metal-based nanomaterials in response to the incident photons [27]. This interaction can lead to light absorption or scattering and is dependent on the size, morphology, distance, and dielectric constant of the metallic nanoparticles and surrounding medium [28,29,30][28][29][30]. In turn, the excited surface electrons can decay to the ground state via different processes (e.g., electron-to-photon, electron-to-electron, and electron-to-phonon energy conversion), the two most common events being the release of the absorbed energy in the form of light or heat [31]. The former is often explored to enhance the quantum efficiency and photostability of fluorophores, allowing the detection of lower quantities of biomarkers used in biosensing or bioimaging [32]. The latter is the foundation stone for the application of metallic nanoparticles in cancer hyperthermia/photothermal therapy [33]. However, it is essential to tailor the nanomaterials to interact specifically with near-infrared (NIR) radiation, a region of the spectra where the major biological components (e.g., collagen, hemoglobin, and water) have the lowest or insignificant absorption [34]. This will reduce the off-target interactions and guarantee a site-specific activation of the metallic nanomaterials. Then, the heat generated by the light-nanoparticles interaction can mediate the destruction of the cancer cells [35,36][35][36]. The elevation of the tumor temperature to values superior to 45 °C provokes irreversible damage to cancer cells (e.g., DNA degradation, cell membrane disruption, and protein denaturation), leading to cell death (i.e., tumor ablation). Otherwise, if mild temperature increases are achieved (i.e., between 40 and 45 °C), the cell damage is less pronounced and often reversed by the cell repair mechanisms [5,37,38][5][37][38]. Nevertheless, this creates a time window during which the cancer cells are more sensitive to the action of other therapeutic modalities such as chemotherapy [39]. Furthermore, metallic nanomaterials, such as those composed of iron, nickel, and cobalt, can also present magnetic properties, also allowing their application as contrast agents (magnetic resonance imaging (MRI)) and in tumor magnetic hyperthermia [40]. This capacity to be magnetically manipulated by external magnetic fields is also explored to guide these metallic nanomaterials in the human body and promote a tumor-specific accumulation [41,42][41][42]. At the tumor site, the utilization of alternating magnetic fields will promote the nanoparticles’ vibration and consequently a localized temperature increase will be obtained [43]. Metallic nanomaterials have also shown the capacity to mediate the formation of ROS [18]. This oxidative stress can influence several cellular processes/structures, e.g., intracellular calcium concentrations, activate transcription factors, induce DNA damage, and lipid peroxidation (cell membrane disruption), and increased amounts of ROS are highly cytotoxic [18]. The mechanism of ROS generation by metallic nanomaterials is influenced by their physicochemical properties (e.g., size, chemical structure, surface area, and charge) [44]. Generally, metallic nanomaterials act as the reactant or catalyst for the reduction of molecular oxygen to water, which yields the production of ROS, such as superoxide radicals and hydroxyl radicals [45]. The ROS generation of metallic nanomaterials can be further boosted by light absorption [46]. During this process, the electrons transit to higher energy bands, facilitating the reaction with water or molecular oxygen and consequently the ROS generation, a process denominated by photodynamic effect [47,48][47][48]. Despite the imaging and therapeutic potential of metallic nanoparticles, the in vivo application and translation to the clinic are severely hindered by their low colloidal stability, high reactivity, the formation of the protein corona, and high cytotoxicity [49,50,51][49][50][51]. Therefore, to overcome these limitations, researchers have been combining the superior physicochemical features of metallic nanoparticles with the increased biological properties (e.g., biocompatibility, enhanced blood circulation time, targeting capacity) of synthetic and natural polymers, often referred to as metal-polymer nanocomplexes or nanohybrids.

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