1. Please check and comment entries here.
Table of Contents

    Topic review

    Nanomaterials for Head/Neck Cancers

    View times: 2
    Submitted by: Sadanand Pandey


    Early diagnosis of head and neck cancer (HNC) is a significant clinical concern and, due to a lack of signs, just one-third of HNC patients are diagnosed at an early stage. Functional nanomaterials are appearing as versatile systems in nanomedicine, particularly in the field of biomedical imaging and treatment. Various surface chemistries, peculiar magnetic properties, tunable excitation and fluorescence properties, and recent developments in the design and synthesis of different nanoparticles indicate their high potential.

    1. Introduction

    It houses and protects important sense organs such as eyes, nose, ears, tongue, and related structures [1]. Besides the regular arrangement of different components between the head and neck, diseases produced in these vital structures and organs may threaten the health of a person [2]. Head and neck cancer (HNC) comprises a group of various malignant tumors that grow in the throat, larynx, mouth, sinuses, and nose [3]. HNC squamous cell carcinomas (HNSCCs), which arise from the mucosal surfaces of the oral cavity, oropharynx, and larynx, include 90% of head and neck cancers cases [4].

    Traditionally, tumors are classified by stage and anatomic site of origin. Within the head and neck, these sites are classified based on established anatomic parameters. Beyond the upper aerodigestive tract, the paranasal sinuses, skull base, salivary glands, endocrine glands, skin, ear, and temporal bones are other possible sites where primary HNSCCs may arise. While HNSCC has traditionally been categorized by its anatomic site of occurrence, other factors may also be important in determining prognosis.

    It was reported that consumption of alcohol and tobacco can increase the risk of this type of cancer by up to 80% [5]. Due to this, India, Bangladesh, and Pakistan are among the highest-risk countries. In the northern regions of America and Europe, HNSCCs include 5–10% of all new cancer cases. In the United States, 53,600 patients are diagnosed yearly and 11,500 deaths are recorded annually as associated with these types of cancer [6][7].

    Most of HNCs can be developed in the flat squamous cells that create a thin layer of tissue on the surface of the head and neck. So, the main methods for the treatment of HNC are surgery, radiation, chemotherapy, and antibody-blocking therapy [8][9][10]. Surgical methods are the standard route for patients diagnosed with early-stage disease. The majority of patients, however, face advanced-stage disease that precludes surgery.

    It is important to determine the stage of cancer and the resectability of the tumors for a better treatment approach. In many clinical outcome studies, stage remains one of the only valuable prognostic parameters. Intermediate-stage tumors, i.e., infiltrative tumors, poor-prognosis T2 tumors, or exophytic T3 N0–N1 tumors, may benefit from a combined-modality approach. Patients with locally advanced tumors are best treated with concurrent chemoradiation if the tumor is unresectable, or if it is resectable but organ preservation is desired, or else if patients are receiving postoperative adjuvant radiation with concurrent cisplatin [11][12].

    The molecular structures (receptors) and genetic change (biomarkers) that happen in head and neck cancer have allowed the detection of candidate routes for effective “targeted” approaches to therapy. Advances in the understanding of the molecular basis of HNC should help in the identification of new markers that could be used for the diagnosis, prognosis and treatment of the disease. Cancer is a genetic disease but does not imply inheritance; rather, the agents that bring about malignant transformation of a cell in the foundational step of tumorigenesis do so by inducing change in the tumor DNA. This may be by alteration in the base sequence (through mutation, deletion, insertion, or rearrangement), change in copy number of a chromosomal segment (through duplication, larger segment deletion, and loss of heterozygosity), alterations in the level at which a gene is transcribed through rearrangements that bring the gene into new association with promoter regions, or through epigenetic events including (hypermethylation of promoter regions) that block expression of mRNA into protein [13][14].

    Multiple signaling pathways involved in the invasion process are influenced by genetic alterations in the development of head and neck cancer. Conventionally available methods for HNC treatment suffer some major restrictions. The mainstays of medical imaging for detection of HNC patients are magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). Furthermore, interpretation of imaging results can be complicated by difficult anatomy, edema or inflammation, scarring from prior treatment, and loss of detail changes because of patient’s movement [15].

    Nanotechnology is expected to develop a wide range of instruments for detection and treatment of sickness in medicine [16][17][18][19][20][21]. Nanostructures with small particle size distributions are well applied to interact with biological molecules and diverse structures developed inside living cells [22][23][24][25]. The capacity to effectively control the nanosized nature of surface chemistry allows interacting at molecular levels [ 1displays the application of some nanostructured devices for the detection and treatment of HNC.

    Nanoporous materials also have appealing properties, including uniform pore morphology, high surface area, and small particle size distribution, and have been applied in different areas, such as medical applications [26][27][28][29][30]. Just to provide some examples, magnetic nanostructures were widely utilized due to their unique features such as magnetic susceptibility and stability. Li et al. developed methotrexate-conjugated and hyperbranched polyglycerol-grafted Fe3O4magnetic nanoparticles for targeted anticancer effects in HNC. used fibrous nanostructures with high physicochemical properties for cancer detection and treatment by local anticancer therapy.

    2. Metallic and Metal Oxide Nanoparticles

    Different metallic and metal oxide nanoparticles with a size of 1–100 nm have emerged as potential “weapons” for treating HNC, including cerium oxide, gadolinium, gold, iron oxide, and silver, which are synthetized mainly for amplifying radiation effects [31][32][33] due to their high X-ray absorption and ability to emit secondary energy in form of photoelectrons, auger electrons, and X-rays into the surrounding tissue [34][35][36][37]. Moreover, metallic and metal oxide nanoparticles provide a versatile platform for surface modification through covalent bonds, complexation, or coupling to the capping agents [38][39][40][41].

    Gold (Au) nanoparticles exhibit two main mechanisms for treating HNC: photothermal therapies of malignant tumors and radiosensitization of the cancer cells [42], based on their unique physicochemical properties, including biocompatibility, preferential accumulation in tumors, photostability, photothermal conversion, and optical and multifunctionalization features [43].

    Photothermal ablation is a mechanism for treating malignant tumors by using a photothermal agent to produce an intense and highly localized hyperthermic effect [44]. Au NPs exhibit unique surface plasmon resonance (SPR) properties, in which gold electrons resonate in response to incoming radiation, promoting the absorption and light scattering to obtain localized heating [33]. This efficient conversion of light is achieved at the near-infrared (NIR) wavelength range, 700–1000 nm, and is suitable because the electron–photon interaction at this wavelength presents low scattering and low absorption by blood and soft tissues [45][46]. It is worth highlighting that gold nanorods or gold nanostars are more convenient for photothermal therapies based on their higher efficiency in the absorption of near-infrared light [47].

    On the other hand, Au NPs are very attractive radiosensitizers that intensify the radiation dosage through a strong X-ray absorption followed by the emission of secondary electrons [48] which stimulates the radiolysis of intracellular water, a high production of free radicals, a radiation-induced reactive oxygen species (ROS) generation, oxidative stress, DNA damage, and interferences in the cell cycle that are associated with increased necrotic and apoptotic cell death [49][50], triggering cytotoxic effects in tumoral cells [42].

    In addition, Au NPs can be coated with targeting ligands and surface-engineered with anticancer drugs for combining radiotherapy with chemotherapy [51], in order to improve the outcomes through a synergistic effect in which the nanoparticles act simultaneously as a radiosensitizer and as a targeted carrier of chemotherapeutic agents [34].

    Gadolinium (Gd) is a lanthanide whose potential radioenhancing properties have been widely explored, despite the fact that, unlike other metallic nanoparticles, Gd NPs are not metal-core particles, thus they typically refer to Gd chelates or Gd-based nanoparticles [52]. Therefore, Gd chelates or Gd-based nanoparticles are used for enhancing radiation dose during radiotherapy by inducing the activation of an autophagy pathway when the tumoral cells are exposed to X-rays, which improves the effectiveness of radiotherapy while reducing collateral damage [53]. In the same way, the radiosensitizing properties of Gd NPs stimulate photocytotoxic effects through the production of extra ROS and water radiolysis products [54]. Furthermore, Gd NPs exhibit some advantages during HNC treatments such as low toxicity, enabled renal elimination, and preferential uptake in tumors through an EPR effect [31].

    Iron oxide (Fe3O4) nanoparticles have been approved by FDA as a photothermal agent for application in cancer treatments due to their broad absorption in the near-infrared (NIR) range [55]. Moreover, superparamagnetic Fe3O4NPs can exhibit magnetic hyperthermia by converting an external high-frequency field energy into thermal energy, which produces thermal ablation when the temperature raises over 50 °C to cause irreversible cell damage, inhibition of tumor growth, and necrosis of tumoral cells in HNC [56][57]. Nonetheless, Fe3O4NPs are easily recognized by the innate immune system as invaders, so they are rapidly cleared from the systemic circulation by the reticuloendothelial system (RES) [58]. Another main problem during cancer treatments is the low targeting properties of superparamagnetic Fe3O4NPs, which results in lower efficacy and greater side effects [59].

    Different types of coating and surface functionalization have been studied for countering the rapid clearance of Fe3O4NPs and for stimulating their accumulation in cancer cells through the EPR effect [60]. The novel approaches for coating magnetic Fe3O4NPs include cell-membrane coating and anti-CD44 antibodies, both with the purpose of targeting the overexpressed CD44 receptors in cancer stem cells and the evasion of immune system [55][59] to their specific cell killing potential without damaging the surrounding healthy tissue [56].

    In addition, magnetic drug targeting has been explored for guiding and inducing the accumulation of superparamagnetic Fe3O4NPs into a specific site (commonly tumors) by strong external magnetic field gradient [61][56]. This approach is mainly used when superparamagnetic Fe3O4NPs are employed as nanocarriers by functionalizing their surface for delivering chemotherapeutic agents in order to increase the efficacy of cancer treatments [60]. However, superparamagnetic iron oxide NPs can also be crosslinked with different polymeric matrixes, such as cellulose nanocrystals, to form hierarchically organized networks similar to “nanocages” with the objective of capturing circulating tumor cells in the blood during HNC treatments [62].

    Silver (Ag) nanoparticles have demonstrated some antiproliferative properties against cancer cells by inducing cellular cytotoxicity in cancer cells through different mechanisms such as generating ROS and free radicals, genomic instability, DNA fragmentation, disruption of calcium (Ca2+) homeostasis, cytoskeletal weakening, damage of intracellular organelles, and interruption of some intracellular signal transduction pathways, which results in cancer cell apoptosis [63][64]. Therefore, Ag NPs show great potential for new therapeutic approaches by improving the sensitivity of current therapies [65]. Ag NPs can even act as cell sensitizers for photothermal therapy, whereas they provide different alternatives for delivery of chemotherapeutic drugs through their surface functionalization and conjugation in a clearly synergistic effect which can enhance the efficacy of the treatment [44]. Recent studies have demonstrated that Ag NPs ingestion is safe and could be associated with a complete and sustained regression of HNC, including metastases to other organs such as the liver or the lungs [66].

    Cerium oxide (CeO2) nanoparticles have attracted a special interest due to their dual radioenhancing and radioprotective properties based on their redox-modulatory activities, which are related to an antioxidant/pro-oxidant reversal property that is useful for sensitizing cancer cells and protecting normal cells from ROS during radiation therapy [52][67]. conditions, CeO2NPs adopt an enzymatic defense mechanism similar to superoxide dismutase, catalase, peroxidase, and oxidase activities [68], in which CeO2NPs mimic superoxide dismutase activity by converting Ce3+to Ce4+and diminishing the levels of superoxide and free radicals such as nitric oxide, hydroxyl, and hydrogen peroxide [69], followed by catalase activity stimulated by the reconversion of Ce4+into Ce3+, in which the hydrogen peroxide is decomposed into water and hydrogen molecules [70]. Otherwise, the antioxidant activity of CeO2NPs is significantly reduced at low pH, suggesting that under acidic environments of highly glycolytic tumors their catalase activity is reduced, inducing oxidative stress and cytotoxicity in cancer cells that results in apoptosis of cancer cells and inhibition of tumor metastasis [71].

    3. Polymeric Nanoparticles

    Polymeric nanoparticles are colloidal particles with a mean diameter between 100 and 300 nm that are prepared with biocompatible polymers for controlled and targeted transport of drugs [72][73]. They represent a great and versatile platform for improving HNC therapy due to their high encapsulation efficiency of hydrophobic anticancer drugs, which usually exhibit poor pharmacokinetics and inappropriate biodistribution [74]. Furthermore, polymeric nanoparticles promote the accumulation of encapsulated drugs inside tumor tissues through the EPR effect [75][76] with a subsequent controlled release to increase its antitumoral efficacy [77][78]. In the same way, polymeric nanoparticles can be loaded with radiosensitizing drugs for countering radiotherapy resistance and reducing side effects [79].

    Additionally, polymeric nanoparticles allow the delivery of a combination of therapeutic agents with a reduced intensity of side effects. The surface of polymeric nanoparticles can be modified for triggering an efficient cell-membrane penetration and cellular internalization in the acidic environment of tumoral cells, as compared to the neutral pH of healthy cells [80].

    Otherwise, polymeric nanoparticles are divided into nanocapsules and nanospheres, based on their morphology. A nanocapsule refers to a polymeric shell that surrounds an aqueous or oily core in which the active compound is confined (usually dissolved), whereas nanospheres are a polymeric network in which the active compound and the polymer are uniformly dispersed [73][81].

    Natural (e.g., chitosan and hyaluronic acid) and synthetic ( e.g., poly(lactide-co-glycolide) and polyethylene glycol) polymers have been studied for administering chemotherapeutic drugs and radiosensitizers based on their biocompatibility and biodegradability [38][72]. After drug release, the polymeric matrix is usually degraded into innocuous molecules such as water and hydrogen-

    However, natural polymeric systems present variability between batches, irregular release kinetics, and mild immunogenicity, which sometimes restrict their use as vehicles for anticancer molecules [38] in comparison with synthetic polymers that offer the additional advantages of high purity, reproducibility, and well-known chemical composition [82].

    Chitosan is a natural cationic polymer that exhibits high biocompatibility, biodegradability, reduced toxicity, low cost of preparation, high encapsulation rate, controllable drug release kinetics, and targeting properties at specific tissues [83]. In addition, chitosan NPs provide drug stability, reduce adverse reactions, present facilitated transmucosal drug delivery, and have mucoadhesive features, which make them appropriate nanocarriers for delivering entrapped chemotherapeutic agents during HNC treatments [84]. For instance, oxaliplatin (OXPt) has been successfully incorporated in chitosan NPs to interact with the mucosa for a prolonged time, leading to an initial drug burst effect followed by a long-term sustained release with the opportunity to accumulate in the tumor tissue in a more concentrated way, thus increasing the rate of apoptosis in oral tumors [85]. Moreover, the controlled release from chitosan nanovehicles is associated with reduced kidney toxicity and decreased inflammatory response, without affecting their anticancer activity [86].

    In the same way, chitosan has a pKa value around 6.5, which plays a key role in its drug-releasing and mucoadhesive properties, with a positive charge at low pH due to amino group protonation that allows interaction with negatively charged components of mucus [82]. Therefore, chitosan NPs can be engineered to develop a pH-sensitive tumor-targeting property under the acidic conditions of the tumor microenvironment, followed by an enhanced mucoadhesive activity that stimulates NP internalization by endocytosis to reduce chemotherapy-induced damage in healthy tissues [83]. For that reason, chitosan NPs are used in novel mucoadhesive topical formulations to deliver anticancer agents through iontophoresis, in which a small electric current is applied to transport hydrophilic anticancer molecules (i.e., drug-loaded chitosan NPs) for treating oral tumors through rapid penetration of the NPs into the mucosa [85].

    Otherwise, the functional groups on the surface of chitosan, i.e., hydroxyl (-OH) and amine (-NH2), are highly reactive, allowing the easy modification of their surface through different chemical reactions [82], which make it an appropriate compound to administer drugs such as cisplatin, by coordinating bonds between the carboxylic moieties available in the polymer backbone and the center of the drug [86]. Moreover, specialized ligands can be conjugated with chitosan functional groups for interacting with specific cell surface receptors leading to NP endocytosis. The most common targeted receptors in cancer cells are the folate receptor, CD44 receptor, EGFR, low-density lipoprotein receptors, and integrins [84].

    Hyaluronic acid (HA) is a natural glycosaminoglycan polysaccharide that has been extensively studied as a safe carrier or coating material for the delivery of anticancer agents, based on its unique properties [87]. Since HA represents an extracellular matrix constituent of connective tissues, it exhibits biodegradability, biocompatibility, nonimmunogenic properties, and specific binding ability with the overexpressed surface receptors in tumoral cells: CD44 and receptor for hyaluronan mediated motility (RHAMM) [88][89].

    For these reasons, HA is not commonly used alone for preparing nanoparticles, but it can be applied as a protective layer with the capability of improving drug pharmacokinetic properties [90]. Nevertheless, HA conjugation has been demonstrated to increase drug solubility, stability under biological conditions, a prolonged time in blood circulation that leads to a higher passive targeting, and a specific affinity for some overexpressed cellular receptors [91]. Therefore, HA is usually conjugated with hydrophobic and amphiphilic chemotherapeutical drugs that are required to overcome multidrug resistance (MDR) by actively targeting CD44 receptors, facilitating antitumor drug entrance into the tumor cells via receptor-mediated endocytosis with reduced toxic side effects and an enhanced efficacy at lower doses [92]. For example, HA–cisplatin nanoconjugates have been developed for local therapies of HNC, in which the conjugate stabilizes the cisplatin in the bloodstream and targets CD44 receptors of tumoral cells, followed by an accumulation of drug at tumor area based on an EPR effect to improve their therapeutic effect [88].

    On the other hand, HA can be conjugated on the surface of metallic NPs through covalent amide bonds to improve their targeting and stability properties with the purpose of maximizing their anticancer effects in radio- and phototherapies. For instance, HA-coated Fe3O4NPs represent a promising multifunctional platform for magnetic hyperthermia therapy due to their good colloidal stability, biocompatibility, high heating efficacy, and specific interaction with overexpressed receptors in HNC cells [89]. Furthermore, HA offers interesting coating features for mesoporous NPs, such as mesoporous silica, in three main aspects: (1) acting as a barrier that prevents drug release through the NP pores, (2) protecting drugs from the harsh conditions in the bloodstream, and (3) targeting specific receptors to promote an effective internalization of mesoporous NPs [90].

    (PLGA) is a biocompatible copolymer approved by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) and is widely used in the fabrication of nanoparticles for encapsulating and enhancing the properties of hydrophobic chemotherapeutic drugs, which results in a controlled drug release, lower dosage requirement, and reduced side effects [93]. PLGA properties can be tuned by modifying the molecular weight and changing the ratio of lactic to glycolic acid, in order to control the release rate of a drug or the biodegradability of the nanoparticle [94]. Another significant advantage of PLGA NPs as drug delivery vehicles is their property of being easily endocytosed by tumor cells, where they are transported into acidic endolysosomal compartments. These attractive features of PLGA-based NPs make them promising delivery vehicles for chemotherapeutic drugs such as docetaxel (DTX), which has shown a localized in situ delivery to the tumor site and an increased antiproliferative efficiency compared with free DTX in a dose-dependent manner [95].

    Furthermore, PLGA NPs have been developed for the successful encapsulation and administration of photosensitizers, considering that most of them are hydrophobic and need to maintain their stability for a prolonged circulation in the blood in order to reach an appropriate accumulation in tumor tissues. One good example is the encapsulation of pheophorbide (Pba), which has shown stability after one week, prolonged blood circulation, and a faster uptake on cancer cell lines, with an effective killing of tumoral cells in mice by photodynamic effect [96]. However, PLGA NPs show some disadvantages, such as initial burst, incomplete release, and limited surface functionalization. It is worth highlighting that PLGA exhibits some angiogenic properties that could interfere with the anticancer effects of the therapeutical molecules or, in the case of diabetic patients, accelerate wound healing [97].

    Polyethylene glycol (PEG) is an amphiphilic, nontoxic, biodegradable polymer that offers biocompatibility, stability, and prolonged blood circulation time for different drugs while promoting the accumulation at tumor sites, which results in the introduction of a therapeutic agent with a minimally invasive approach [98]. PEG incorporation into an NP structure promotes water solubility of poorly soluble drugs, inhibits aggregation, decreases serum protein adsorption, and reduces capture rate by the reticuloendothelial system. However, PEG concentration is fundamental for determining the therapeutic effect of drugs because an increasing PEG concentration decreases the drug release rate that could increase the therapeutic effect and minimize the drug side effects. Moreover, PEG can diminish the initial burst that triggers an overmedication in conventional drug delivery systems [99].

    Cationic nanocomplexes can be PEGylated for improving their stability by shielding their charge in order to prevent protein adhesion, aggregation with red blood cells, or activation of the immune system, which limits their potential clinical applications [100]. In the same way, polymer–lipid–PEG hybrid nanoparticle systems have emerged as a novel design for encapsulating anticancer drugs and photosensitizers to exhibit higher cytotoxicity in tumor tissues due to an increased drug loading and a reduced aggregation of the photosensitizer in aqueous solution, which promotes a faster cellular uptake [101]. PEG can be mixed with other polymers to prepare nanoparticles that reduce undesirable toxicity to healthy tissues and improve the pharmacokinetic properties of loaded anticancer molecules, such as PLA–PEG NPs [102].

    Additionally, PEG can be modified to be pH-sensitive for promoting nanoparticle permeability in tumoral cells with the objective of decreasing noncancerous cellular uptake by releasing the radiosensitizer or chemotherapeutic drug inside the low-pH microenvironment of HNC cells [103]. Moreover, PEG can be conjugated with specific antibodies such as low-density lipoprotein receptor (LDLR) to target the tumor hypoxic region, which is the main contributor to chemoresistance. Thus, PEG could represent a useful nanocarrier for treating cancer by co-delivering a chemotherapeutic (cisplatin) and a chemosensitizer (metformin) into the hypoxia core area of tumors in a very promising strategy for treating HNC [104].

    The entry is from 10.3390/ma14133706


    1. Castilho, R.M.; Squarize, C.H.; Almeida, L.O. Epigenetic modifications and head and neck cancer: Implications for tumor progression and resistance to therapy. Int. J. Mol. Sci. 2017, 18, 1506.
    2. Fiuza-Luces, C.; Santos-Lozano, A.; Joyner, M.; Carrera-Bastos, P.; Picazo, O.; Zugaza, J.L.; Izquierdo, M.; Ruilope, L.M.; Lucia, A. Exercise benefits in cardiovascular disease: Beyond attenuation of traditional risk factors. Nat. Rev. Cardiol. 2018, 15, 731–743.
    3. Argiris, A.; Karamouzis, M.V.; Raben, D.; Ferris, R.L. Head and neck cancer. Lancet 2008, 371, 1695–1709.
    4. Patterson, R.H.; Fischman, V.G.; Wasserman, I.; Siu, J.; Shrime, M.G.; Fagan, J.J.; Koch, W.; Alkire, B.C. Global burden of head and neck cancer: Economic consequences, health, and the role of surgery. Otolaryngol. Head Neck Surg. 2020, 162, 296–303.
    5. Larsson, S.C.; Carter, P.; Kar, S.; Vithayathil, M.; Mason, A.M.; Michaëlsson, K.; Burgess, S. Smoking, alcohol consumption, and cancer: A mendelian randomisation study in UK Biobank and international genetic consortia participants. PLoS Med. 2020, 17, 1003178–1003193.
    6. Ferlay, J.; Colombet, M.; Soerjomataram, I.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Cancer statistics for the year 2020: An overview. Int. J. Cancer 2021, 149, 778–789.
    7. Sheth, S.H.; Johnson, D.E.; Kensler, T.W.; Bauman, J.E. Chemoprevention targets for tobacco-related head and neck cancer: Past lessons and future directions. Oral Oncol. 2015, 51, 557–564.
    8. Fang, F.M.; Tsai, W.L.; Chen, H.C.; Hsu, H.C.; Hsiung, C.Y.; Chien, C.Y.; Ko, S.F. Intensity-modulated or conformal radiotherapy improves the quality of life of patients with nasopharyngeal carcinoma: Comparisons of four radiotherapy techniques. Cancer 2007, 109, 313–321.
    9. Nyst, H.J.; Tan, I.B.; Stewart, F.A.; Balm, A.J. Is photodynamic therapy a good alternative to surgery and radiotherapy in the treatment of head and neck cancer? Photodiagnosis Photodyn. Ther. 2009, 6, 3–11.
    10. Day, K.V.; Li, D.; Liu, S.; Guo, M.; O’Malley Jr, B.W. Granulocyte-Macrophage Colony-Stimulating Factor in a Combination Gene Therapy Strategy for Head and Neck Cancer. Laryngoscope 2001, 111, 801–806.
    11. Olshan, A.F. Epidemiology, Pathogenesis, and Prevention of Head and Neck Cancer; Springer: Berlin/Heidelberg, Germany, 2010; pp. 1–21.
    12. D’Souza, G.; Gillison, M.L. Head and neck squamous cell cancers in the nonsmoker-nondrinker. In Squamous Cell Head and Neck Cancer; Humana Press: Totowa, NJ, USA, 2005; pp. 1–26.
    13. Williams, M.D. Integration of biomarkers including molecular targeted therapies in head and neck cancer. Head Neck Pathol. 2010, 4, 62–69.
    14. Kang, H.; Kiess, A.; Chung, C.H. Emerging biomarkers in head and neck cancer in the era of genomics. Nat. Rev. Clin. Oncol. 2015, 12, 11–26.
    15. Yasumatsu, R.; Nakashima, T.; Miyazaki, R.; Segawa, Y.; Komune, S. Diagnosis and management of extracranial head and neck schwannomas: A review of 27 cases. Int. J. Otolaryngol. 2013, 2013, 1–5.
    16. Sargazi, S.; Saravani, R. An Updated Review of Methods, Challenges, and Future Perspectives of Circulating Tumor Cell Isolation: Focusing on the Use of Nanomaterials. Gene Cell Tissue 2020, 7, 102074–102091.
    17. Sheervalilou, R.; Shirvaliloo, M.; Sargazi, S.; Ghaznavi, H.; Shakeri-Zadeh, A. Recent advances in iron oxide nanoparticles for brain cancer theranostics: From in vitro to clinical applications. Expert Opin. Drug Deliv. 2021, 1, 1–29.
    18. Sheervalilou, R.; Shirvaliloo, M.; Sargazi, S.; Shirvalilou, S.; Shahraki, O.; Pilehvar-Soltanahmadi, Y.; Sarhadi, A.; Nazarlou, Z.; Ghaznavi, H.; Khoei, S. Application of Nanobiotechnology for Early Diagnosis of SARS-CoV-2 Infection in the COVID-19 Pandemic. Appl. Microbiol. Biotechnol. 2021, 105, 2615–2624.
    19. Yang, M.; Li, C.; Luo, L.; Li, R.; Long, Y. Predictive model of convective heat transfer coefficient in bone micro-grinding using nanofluid aerosol cooling. Int. Commun. Heat Mass Transf. 2021, 125, 105317–105328.
    20. Chen, C.; Wang, X.; Wang, Y.; Yang, D.; Yao, F.; Zhang, W.; Wang, B.; Sewvandi, G.A.; Yang, D.; Hu, D. Additive Manufacturing of Piezoelectric Materials. Adv. Funct. Mater. 2020, 30, 2005141–2005162.
    21. Wu, P.; Gao, W.; Su, M.; Nice, E.C.; Zhang, W.; Lin, J.; Xie, N. Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment. Front. Cell Dev. Biol. 2021, 9, 357–378.
    22. Akbarzadeh, F.; Motaghi, M.; Chauhan, N.P.S.; Sargazi, G. A novel synthesis of new antibacterial nanostructures based on Zn-MOF compound: Design, characterization and a high performance application. Heliyon 2020, 6, 3231–3247.
    23. Badoei-Dalfard, A.; Malekabadi, S.; Karami, Z.; Sargazi, G. Magnetic cross-linked enzyme aggregates of Km12 lipase: A stable nanobiocatalyst for biodiesel synthesis from waste cooking oil. Renew. Energy 2019, 141, 874–882.
    24. Sargazi, G.; Afzali, D.; Mostafavi, A.; Ebrahimipour, S.Y. Ultrasound-assisted facile synthesis of a new tantalum (V) metal-organic framework nanostructure: Design, characterization, systematic study, and CO2 adsorption performance. J. Solid State Chem. 2017, 250, 32–48.
    25. Barani, M.; Mukhtar, M.; Rahdar, A.; Sargazi, G.; Thysiadou, A.; Kyzas, G.Z. Progress in the Application of Nanoparticles and Graphene as Drug Carriers and on the Diagnosis of Brain Infections. Molecules 2021, 26, 186.
    26. Alijani, H.Q.; Pourseyedi, S.; Mahani, M.T.; Khatami, M. Green synthesis of zinc sulfide (ZnS) nanoparticles using Stevia rebaudiana Bertoni and evaluation of its cytotoxic properties. J. Mol. Struct. 2019, 1175, 214–218.
    27. Alijani, H.Q.; Pourseyedi, S.; Torkzadeh-Mahani, M.; Seifalian, A.; Khatami, M. Bimetallic nickel-ferrite nanorod particles: Greener synthesis using rosemary and its biomedical efficiency. Artif. Cells Nanomed. Biotechnol. 2020, 48, 242–251.
    28. Alkasir, M.; Samadi, N.; Sabouri, Z.; Mardani, Z.; Khatami, M.; Darroudi, M. Evaluation cytotoxicity effects of biosynthesized zinc oxide nanoparticles using aqueous Linum Usitatissimum extract and investigation of their photocatalytic activityackn. Inorg. Chem. Commun. 2020, 119, 108066–108086.
    29. Heidari, M.R.; Varma, R.S.; Ahmadian, M.; Pourkhosravani, M.; Asadzadeh, S.N.; Karimi, P.; Khatami, M. Photo-fenton like catalyst system: Activated carbon/CoFe2O4 nanocomposite for reactive dye removal from textile wastewater. Appl. Sci. 2019, 9, 963.
    30. Mukhtar, M.; Bilal, M.; Rahdar, A.; Barani, M.; Arshad, R.; Behl, T.; Brisc, C.; Banica, F.; Bungau, S. Nanomaterials for Diagnosis and Treatment of Brain Cancer: Recent Updates. Chemosensors 2020, 8, 117.
    31. Simonet, S.; Rodriguez-Lafrasse, C.; Beal, D.; Gerbaud, S.; Malesys, C.; Tillement, O.; Lux, F.; Fayyad-Kazan, H.; Rachidi, W.; Ardail, D. Gadolinium-Based Nanoparticles Can Overcome the Radioresistance of Head and Neck Squamous Cell Carcinoma Through the Induction of Autophagy. J. Biomed. Nanotechnol. 2020, 16, 111–124.
    32. Evans, E.R.; Bugga, P.; Asthana, V.; Drezek, R. Metallic nanoparticles for cancer immunotherapy. Mater. Today 2018, 21, 673–685.
    33. Singh, P.; Pandit, S.; Mokkapati, V.; Garg, A.; Ravikumar, V.; Mijakovic, I. Gold Nanoparticles in Diagnostics and Therapeutics for Human Cancer. Int. J. Mol. Sci. 2018, 19, 1979.
    34. Davidi, E.S.; Dreifuss, T.; Motiei, M.; Shai, E.; Bragilovski, D.; Lubimov, L.; Kindler, M.J.J.; Popovtzer, A.; Don, J.; Popovtzer, R. Cisplatin-conjugated gold nanoparticles as a theranostic agent for head and neck cancer. Head Neck J. Sci. Spec. Head Neck 2018, 40, 70–78.
    35. Chugh, H.; Sood, D.; Chandra, I.; Tomar, V.; Dhawan, G.; Chandra, R. Role of gold and silver nanoparticles in cancer nano-medicine. Artif. Cells Nanomed. Biotechnol. 2018, 46, 1210–1220.
    36. Roghani, A. The Influence of Covid-19 Vaccine on Daily Cases, Hospitalization, and Death Rate in Tennessee: A Case Study in the United States. medRxiv 2021.
    37. Roghani, A.; Nyarko, S.H.; Potter, L. Smoking Cigarettes, Marijuana, and the Transition to Marriage among Cohabiters in the USA. Glob. Soc. Welf. 2021, 1, 1–8.
    38. Shrestha, B.; Tang, L.; Romero, G. Nanoparticles-Mediated Combination Therapies for Cancer Treatment. Adv. Ther. 2019, 2, 26–35.
    39. Zhang, Y.; Li, C.; Jia, D.; Zhang, D.; Zhang, X. Experimental evaluation of MoS2 nanoparticles in jet MQL grinding with different types of vegetable oil as base oil. J. Clean. Prod. 2015, 87, 930–940.
    40. Zhang, Y.; Li, C.; Jia, D.; Zhang, D.; Zhang, X. Experimental evaluation of the lubrication performance of MoS2/CNT nanofluid for minimal quantity lubrication in Ni-based alloy grinding. Int. J. Mach. Tools Manuf. 2015, 99, 19–33.
    41. Masoumnezhad, M.; Rajabi, M.; Chapnevis, A.; Dorofeev, A.; Shateyi, S.; Kargar, N.S.; Nik, H.S. An Approach for the Global Stability of Mathematical Model of an Infectious Disease. Symmetry 2020, 12, 1778.
    42. Borran, A.A.; Aghanejad, A.; Farajollahi, A.; Barar, J.; Omidi, Y. Gold nanoparticles for radiosensitizing and imaging of cancer cells. Radiat. Phys. Chem. 2018, 152, 137–144.
    43. Amendoeira, A.; Garcia, L.R.; Fernandes, A.R.; Baptista, P.V. Light Irradiation of Gold Nanoparticles Toward Advanced Cancer Therapeutics. Adv. Ther. 2020, 3, 11–24.
    44. Soica, C.; Pinzaru, I.; Trandafirescu, C.; Andrica, F.; Danciu, C.; Mioc, M.; Coricovac, D.; Sitaru, C.; Dehelean, C. Silver-, gold-, and iron-based metallic nanoparticles: Biomedical applications as theranostic agents for cancer. Des. Nanostruct. Theranostics Appl. 2018, 1, 161–242.
    45. Aminabad, N.S.; Farshbaf, M.; Akbarzadeh, A. Recent Advances of Gold Nanoparticles in Biomedical Applications: State of the Art. Cell Biochem. Biophys. 2019, 77, 123–137.
    46. Nouri, S.; Mohammadi, E.; Mehravi, B.; Majidi, F.; Ashtari, K.; Neshasteh-Riz, A.; Einali, S. NIR triggered glycosylated gold nanoshell as a photothermal agent on melanoma cancer cells. Artif. Cells Nanomed. Biotechnol. 2019, 47, 2316–2324.
    47. Bai, X.; Wang, Y.Y.; Song, Z.Y.; Feng, Y.M.; Chen, Y.Y.; Zhang, D.Y.; Feng, L. The Basic Properties of Gold Nanoparticles and their Applications in Tumor Diagnosis and Treatment. Int. J. Mol. Sci. 2020, 21, 2480.
    48. Shi, Y.L.; Xue, J.T.; Jia, L.Y.; Du, Q.; Niu, J.; Zhang, D.Y. Surface-modified PLGA nanoparticles with chitosan for oral delivery of tolbutamide. Colloids Surf. B Biointerfaces 2018, 161, 67–72.
    49. Beik, J.; Khateri, M.; Khosravi, Z.; Kamrava, S.K.; Kooranifar, S.; Ghaznavi, H.; Shakeri-Zadeh, A. Gold nanoparticles in combinatorial cancer therapy strategies. Coord. Chem. Rev. 2019, 387, 299–324.
    50. Kashin, M.; Kakei, Y.; Teraoka, S.; Hasegawa, T.; Yamaguchi, A.; Fukuoka, T.; Sasaki, R.; Akashi, M. Gold Nanoparticles Enhance EGFR Inhibition and Irradiation Effects in Head and Neck Squamous Carcinoma Cells. BioMed Res. Int. 2020, 2020, 10–17.
    51. Setua, S.; Ouberai, M.; Piccirillo, S.G.; Watts, C.; Welland, M. Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma. Nanoscale 2014, 6, 10865–10873.
    52. Kuncic, Z.; Lacombe, S. Nanoparticle radio-enhancement: Principles, progress and application to cancer treatment. Phys. Med. Biol. 2018, 63, 27–38.
    53. Li, H.; Zeng, Y.; Zhang, H.; Gu, Z.; Gong, Q.; Luo, K. Functional gadolinium-based nanoscale systems for cancer theranostics. J. Control. Release 2021, 329, 482–512.
    54. Tamanoi, F.; Matsumoto, K.; Doan, T.L.H.; Shiro, A.; Saitoh, H. Studies on the Exposure of Gadolinium Containing Nanoparticles with Monochromatic X-rays Drive Advances in Radiation Therapy. Nanomaterials 2020, 10, 1341.
    55. Bu, L.L.; Rao, L.; Yu, G.T.; Chen, L.; Deng, W.W.; Liu, J.F.; Wu, H.; Meng, Q.F.; Guo, S.S.; Zhao, X.Z.; et al. Cancer Stem Cell-Platelet Hybrid Membrane-Coated Magnetic Nanoparticles for Enhanced Photothermal Therapy of Head and Neck Squamous Cell Carcinoma. Adv. Funct. Mater. 2019, 29, 11–18.
    56. Legge, C.J.; Colley, H.E.; Lawson, M.A.; Rawlings, A.E. Targeted magnetic nanoparticle hyperthermia for the treatment of oral cancer. J. Oral Pathol. Med. 2019, 48, 803–809.
    57. Zhu, L.; Zhou, Z.Y.; Mao, H.; Yang, L.L. Magnetic nanoparticles for precision oncology: Theranostic magnetic iron oxide nanoparticles for image-guided and targeted cancer therapy. Nanomedicine 2017, 12, 73–87.
    58. Meng, Q.F.; Rao, L.; Zan, M.H.; Chen, M.; Yu, G.T.; Wei, X.Y.; Wu, Z.H.; Sun, Y.; Guo, S.S.; Zhao, X.Z.; et al. Macrophage membrane-coated iron oxide nanoparticles for enhanced photothermal tumor therapy. Nanotechnology 2018, 29, 11–25.
    59. Su, Z.; Liu, D.Q.; Chen, L.Y.; Zhang, J.; Ru, L.; Chen, Z.Y.; Gao, Z.N.; Wang, X.X. CD44-Targeted Magnetic Nanoparticles Kill Head And Neck Squamous Cell Carcinoma Stem Cells In An Alternating Magnetic Field. Int. J. Nanomed. 2019, 14, 7549–7560.
    60. Li, K.; Nejadnik, H.; Daldrup-Link, H.E. Next-generation superparamagnetic iron oxide nanoparticles for cancer theranostics. Drug Discov. Today 2017, 22, 1421–1429.
    61. Zhang, Z.Q.; Zhuang, L.; Lin, Y.; Yan, M.D.; Lv, J.H.; Li, X.L.; Lin, H.; Zhu, P.; Lin, Q.P.; Xu, Y. Novel drug delivery system based on hollow mesoporous magnetic nanoparticles for head and neck cancers-targeted therapy in vitro and in vivo. Am. J. Cancer Res. 2020, 10, 350–364.
    62. Hazra, R.S.; Kale, N.; Aland, G.; Qayyumi, B.; Mitra, D.; Jiang, L.; Bajwa, D.; Khandare, J.; Chaturvedi, P.; Quadir, M. Cellulose Mediated Transferrin Nanocages for Enumeration of Circulating Tumor Cells for Head and Neck Cancer. Sci. Rep. 2020, 10, 14–23.
    63. Mittal, L.; Ranjani, S.; Ahmed, M.S.; Shree, T.J.; Akther, T.; Poompavai, S.; Camarillo, I.G.; GowriSree, V.; Sundararajan, R.; Hemalatha, S. Turmeric-silver-nanoparticles for effective treatment of breast cancer and to break CTX-M-15 mediated antibiotic resistance inEscherichia coli. Inorg. Nano-Met. Chem. 2020, 8, 1–11.
    64. Lee, S.H.; Jun, B.H. Silver Nanoparticles: Synthesis and Application for Nanomedicine. Int. J. Mol. Sci. 2019, 20, 865.
    65. Morais, M.; Teixeira, A.L.; Dias, F.; Machado, V.; Medeiros, R.; Prior, J.A.V. Cytotoxic Effect of Silver Nanoparticles Synthesized by Green Methods in Cancer. J. Med. Chem. 2020, 63, 14308–14335.
    66. Singh, J.; Moore, W.; Fattah, F.; Jiang, X.Y.; Zheng, J.; Kurian, P.; Beg, M.S.; Khan, S.A. Activity and pharmacology of homemade silver nanoparticles in refractory metastatic head and neck squamous cell cancer. Head Neck J. Sci. Spec. Head Neck 2019, 41, 11–15.
    67. Eriksson, P.; Tal, A.A.; Skallberg, A.; Brommesson, C.; Hu, Z.J.; Boyd, R.D.; Olovsson, W.; Fairley, N.; Abrikosov, I.A.; Zhang, X.J.; et al. Cerium oxide nanoparticles with antioxidant capabilities and gadolinium integration for MRI contrast enhancement. Sci. Rep. 2018, 8, 12–17.
    68. Inbaraj, B.S.; Chen, B.H. An overview on recent in vivo biological application of cerium oxide nanoparticles. Asian J. Pharm. Sci. 2020, 15, 558–575.
    69. Nourmohammadi, E.; Khoshdel-sarkarizi, H.; Nedaeinia, R.; Darroudi, M.; Oskuee, R.K. Cerium oxide nanoparticles: A promising tool for the treatment of fibrosarcoma in-vivo. Mater. Sci. Eng. C Mater. Biol. Appl. 2020, 109, 10–21.
    70. Pezzini, I.; Marino, A.; Del Turco, S.; Nesti, C.; Doccini, S.; Cappello, V.; Gemmi, M.; Parlanti, P.; Santorelli, F.M.; Mattoli, V.; et al. Cerium oxide nanoparticles: The regenerative redox machine in bioenergetic imbalance. Nanomedicine 2017, 12, 403–416.
    71. Ciccarese, F.; Raimondi, V.; Sharova, E.; Silic-Benussi, M.; Ciminale, V. Nanoparticles as Tools to Target Redox Homeostasis in Cancer Cells. Antioxidants 2020, 9, 211.
    72. Palazzoloa, S.; Bayda, S.; Hadla, M.; Caligiuri, I.; Corona, G.; Toffoli, G.; Rizzolio, F. The Clinical Translation of Organic Nanomaterials for Cancer Therapy: A Focus on Polymeric Nanoparticles, Micelles, Liposomes and Exosomes. Curr. Med. Chem. 2018, 25, 4224–4268.
    73. Zielinska, A.; Carreiro, F.; Oliveira, A.M.; Neves, A.; Pires, B.; Venkatesh, D.N.; Durazzo, A.; Lucarini, M.; Eder, P.; Silva, A.M. Polymeric nanoparticles: Production, characterization, toxicology and ecotoxicology. Molecules 2020, 25, 3731.
    74. Sarcan, E.T.; Silindir-Gunay, M.; Ozer, A.Y. Theranostic polymeric nanoparticles for NIR imaging and photodynamic therapy. Int. J. Pharm. 2018, 551, 329–338.
    75. Zhong, Y.A.; Meng, F.H.; Deng, C.; Zhong, Z.Y. Ligand-Directed Active Tumor-Targeting Polymeric Nanoparticles for Cancer Chemotherapy. Biomacromolecules 2014, 15, 1955–1969.
    76. Conte, C.; Maiolino, S.; Pellosi, D.S.; Miro, A.; Ungaro, F.; Quaglia, F. Polymeric nanoparticles for cancer photodynamic therapy. Light Responsive Nanostruct. Syst. Appl. Nanomed. 2016, 61–112.
    77. Wu, W.; Chen, M.; Luo, T.R.; Fan, Y.; Zhang, J.Q.; Zhang, Y.; Zhang, Q.Y.; Sapin-Minet, A.; Gaucher, C.; Xia, X.F. ROS and GSH-responsive S-nitrosoglutathione functionalized polymeric nanoparticles to overcome multidrug resistance in cancer. Acta Biomater. 2020, 103, 259–271.
    78. Hu, J.; Fua, S.Z.; Peng, Q.X.; Han, Y.W.; Xie, J.; Zan, N.; Chen, Y.; Fan, J. Paclitaxel-loaded polymeric nanoparticles combined with chronomodulated chemotherapy on lung cancer: In vitro and in vivo evaluation. Int. J. Pharm. 2017, 516, 313–322.
    79. Caster, J.M.; Yu, S.K.; Patel, A.N.; Newman, N.J.; Lee, Z.J.; Warner, S.B.; Wagner, K.T.; Roche, K.C.; Tian, X.; Min, Y.Z.; et al. Effect of particle size on the biodistribution, toxicity, and efficacy of drug-loaded polymeric nanoparticles in chemoradiotherapy. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 1673–1683.
    80. Sun, L.; Wu, Q.; Peng, F.; Liu, L.; Gong, C. Strategies of polymeric nanoparticles for enhanced internalization in cancer therapy. Colloids Surf. B Biointerfaces 2015, 135, 56–72.
    81. Crucho, C.I.; Barros, M.T. Polymeric nanoparticles: A study on the preparation variables and characterization methods. Mater. Sci. Eng. C 2017, 80, 771–784.
    82. Ruiz-Pulido, G.; Medina, D.I. An overview of gastrointestinal mucus rheology under different pH conditions and introduction to pH-dependent rheological interactions with PLGA and chitosan nanoparticles. Eur. J. Pharm. Biopharm. 2021, 159, 123–136.
    83. Chu, X.Y.; Huang, W.; Wang, Y.L.; Meng, L.W.; Chen, L.Q.; Jin, M.J.; Chen, L.; Gao, C.H.; Ge, C.; Gao, Z.G.; et al. Improving antitumor outcomes for palliative intratumoral injection therapy through lecithin-chitosan nanoparticles loading paclitaxel-cholesterol complex. Int. J. Nanomed. 2019, 14, 689–705.
    84. Shafabakhsh, R.; Youse, B.; Asemi, Z.; Nikfar, B.; Mansournia, M.A.; Hallajzadeh, J. Chitosan: A compound for drug delivery system in gastric cancer-a review. Carbohydr. Polym. 2020, 242, 6–15.
    85. Matos, B.N.; Pereira, M.N.; Bravo, M.D.; Cunha, M.; Saldanha-Araujo, F.; Gratieri, T.; Gelfuso, G.M. Chitosan nanoparticles loading oxaliplatin as a mucoadhesive topical treatment of oral tumors: Iontophoresis further enhances drug delivery ex vivo. Int. J. Biol. Macromol. 2020, 154, 1265–1275.
    86. Trummer, R.; Rangsimawong, W.; Sajomsang, W.; Kumpugdee-Vollrath, M.; Opanasopit, P.; Tonglairoum, P. Chitosan-based self-assembled nanocarriers coordinated to cisplatin for cancer treatment. RSC Adv. 2018, 8, 22967–22973.
    87. Huang, G.; Huang, H. Application of hyaluronic acid as carriers in drug delivery. Drug Deliv. 2018, 25, 766–772.
    88. Gotov, O.; Battogtokh, G.; Shin, D.; Ko, Y.T. Hyaluronic acid-coated cisplatin conjugated gold nanoparticles for combined cancer treatment. J. Ind. Eng. Chem. 2018, 65, 236–243.
    89. Soleymani, M.; Velashjerdi, M.; Shaterabadi, Z.; Barati, A. One-pot preparation of hyaluronic acid-coated iron oxide nanoparticles for magnetic hyperthermia therapy and targeting CD44-overexpressing cancer cells. Carbohydr. Polym. 2020, 237, 9–15.
    90. Shi, X.L.; Li, Y.; Zhao, L.M.; Su, L.W.; Ding, G. Delivery of MTH1 inhibitor (TH287) and MDR1 siRNA via hyaluronic acid-based mesoporous silica nanoparticles for oral cancers treatment. Colloids Surf. B Biointerfaces 2019, 173, 599–606.
    91. Spadea, A.; de la Rosa, J.M.R.; Tirella, A.; Ashford, M.B.; Williams, K.J.; Stratford, I.J.; Tirelli, N.; Mehibel, M. Evaluating the Efficiency of Hyaluronic Acid for Tumor Targeting via CD44. Mol. Pharm. 2019, 16, 2481–2493.
    92. Edelman, R.; Assaraf, Y.G.; Levitzky, I.; Shahar, T.; Livney, Y.D. Hyaluronic acid-serum albumin conjugate-based nanoparticles for targeted cancer therapy. Oncotarget 2017, 8, 24337–24353.
    93. Ribeiro, S.B.; de Araujo, A.A.; Oliveira, M.M.B.; Silva, A.M.D.; da Silva-Junior, A.A.; Guerra, G.C.B.; Brito, G.A.D.; Leitao, R.F.D.; Junior, R.F.D.; Garcia, V.B.; et al. Effect of Dexamethasone-Loaded PLGA Nanoparticles on Oral Mucositis Induced by 5-Fluorouracil. Pharmaceutics 2021, 13, 53.
    94. Haider, M.; Elsherbeny, A.; Jagal, J.; Hubatova-Vackova, A.; Ahmed, I.S. Optimization and Evaluation of Poly(lactide-co-glycolide) Nanoparticles for Enhanced Cellular Uptake and Efficacy of Paclitaxel in the Treatment of Head and Neck Cancer. Pharmaceutics 2020, 12, 828.
    95. Gupta, P.; Singh, M.; Kumar, R.; Belz, J.; Shanker, R.; Dwivedi, P.D.; Sridhar, S.; Singh, S.P. Synthesis and in vitro studies of PLGA-DTX nanoconjugate as potential drug delivery vehicle for oral cancer. Int. J. Nanomed. 2018, 13, 67–73.
    96. Son, J.; Yang, S.M.; Yi, G.; Roh, Y.J.; Park, H.; Park, J.M.; Choi, M.G.; Koo, H. Folate-modified PLGA nanoparticles for tumor-targeted delivery of pheophorbide a in vivo. Biochem. Biophys. Res. Commun. 2018, 498, 523–528.
    97. Chereddy, K.K.; Payen, V.L.; Preat, V. PLGA: From a classic drug carrier to a novel therapeutic activity contributor. J. Control. Release 2018, 289, 10–13.
    98. Rahimi-Moghaddam, F.; Azarpira, N.; Sattarahmady, N. Evaluation of a nanocomposite of PEG-curcumin-gold nanoparticles as a near-infrared photothermal agent: An in vitro and animal model investigation. Lasers Med. Sci. 2018, 33, 1769–1779.
    99. Alavi, S.E.; Al Harthi, S.M.; Shahmabadi, H.E.; Akbarzadeh, A. Cisplatin-Loaded Polybutylcyanoacrylate Nanoparticles with Improved Properties as an Anticancer Agent. Int. J. Mol. Sci. 2019, 20, 1531.
    100. Yang, C.X.; Gao, S.; Dagnaes-Hansen, F.; Jakobsen, M.; Kjems, J. Impact of PEG Chain Length on the Physical Properties and Bioactivity of PEGylated Chitosan/siRNA Nanoparticles in Vitro and in Vivo. ACS Appl. Mater. Interfaces 2017, 9, 12203–12216.
    101. Pramual, S.; Lirdprapamongkol, K.; Svasti, J.; Bergkvist, M.; Jouan-Hureaux, V.; Amoux, P.; Frochot, C.; Barberi-Heyob, M.; Niamsiri, N. Polymer-lipid-PEG hybrid nanoparticles as photosensitizer carrier for photodynamic therapy. J. Photochem. Photobiol. B Biol. 2017, 173, 12–22.
    102. Dobrzynska, M.; Napierala, M.; Florek, E. Flavonoid Nanoparticles: A Promising Approach for Cancer Therapy. Biomolecules 2020, 10, 1268.
    103. Lo, Y.L.; Chang, C.H.; Wang, C.S.; Yang, M.H.; Lin, A.M.Y.; Hong, C.J.; Tseng, W.H. PEG-coated nanoparticles detachable in acidic microenvironments for the tumor-directed delivery of chemo- and gene therapies for head and neck cancer. Theranostics 2020, 10, 6695–6714.
    104. Song, C.H.; Tang, C.C.; Xu, W.G.; Ran, J.C.; Wei, Z.; Wang, Y.F.; Zou, H.H.; Cheng, W.; Cai, Y.; Han, W. Hypoxia-Targeting Multifunctional Nanoparticles for Sensitized Chemotherapy and Phototherapy in Head and Neck Squamous Cell Carcinoma. Int. J. Nanomed. 2020, 15, 347–361.