Progress of Nanomaterials-Based Photothermal Therapy for Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) is one of the top 15 most prevalent cancers worldwide. However, the current treatment models for OSCC (e.g., surgery, chemotherapy, radiotherapy, and combination therapy) present several limitations: damage to adjacent healthy tissue, possible recurrence, low efficiency, and severe side effects. In this context, nanomaterial-based photothermal therapy (PTT) has attracted extensive research attention. This paper reviews the latest progress in the application of biological nanomaterials for PTT in OSCC. We divide photothermal nanomaterials into four categories (noble metal nanomaterials, carbon-based nanomaterials, metal compounds, and organic nanomaterials) and introduce each category in detail. We also mention in detail the drug delivery systems for PTT of OSCC and briefly summarize the applications of hydrogels, liposomes, and micelles. Finally, we note the challenges faced by the clinical application of PTT nanomaterials and the possibility of further improvement, providing direction for the future research of PTT in OSCC treatment.     

Light-Triggered Covalent Coupling of Gold Nanoparticles for Photothermal Cancer Therapy

Manipulating the cross-coupling of gold nanoparticles (AuNPs) to maximize the photothermal effect is a promising strategy for cancer therapy. Here, by taking advantage of the well-known tetrazole/alkene photoclick chemistry, we have demonstrated for the first time that small AuNPs (23 nm) decorated with both 2,5-diphenyltetrazole and methacrylic acid on their surfaces can form covalently crosslinked aggregates upon laser irradiation (λ=405 nm). In vitro studies indicated that the light-triggered assembling shifted the surface plasmon resonance of AuNPs significantly to near-infrared (NIR) regions, which as a consequence effectively enhanced the efficacy of photothermal therapy for 4T1 breast cancer cells. We thus believe that this new light-triggered cross-coupling approach might offer a valuable tool for cancer treatment.     

Self-Assembled BODIPY Derivative with A-D-A Structure as Organic Nanoparticles for Photodynamic/Photothermal Cancer Therapy

Organic nanomaterials have attracted considerable attention in the area of photodynamic and photothermal therapy, owing to their outstanding biocompatibility, potential biodegradability, well-defined chemical structure, and easy functionalization. However, it is still a challenge to develop a single organic molecule that obtains both photothermal and photodynamic effects. In this contribution, we synthesized a new boron-dipyrromethene (BODIPY)-based derivative (DPBDP) with an acceptor–donor–acceptor (A-D-A) structure by coupling 3,6-di(2-thienyl)-2,5-dihydropyrrolo [3,4-c] pyrrole-1,4-dione (DPP) and BODIPY. To enhance the hydrophilicity of the BODIPY derivative, the polyethylene glycol (PEG) chains were introduced to the meso- position of BODIPY core. The amphiphilic DPBDP was then self-assembled into related nanoparticles (DPBDP NPs) with improved hydrophilicity and enhanced absorbance in the NIR region. DPBDP NPs could simultaneously generate the singlet oxygen (¹O₂) and heat under the irradiation of a single laser (690 nm). The ¹O₂ quantum yield and photothermal conversion efficiency (PCE) of DPBDP NPs were calculated to be 14.2% and 26.1%, respectively. The biocompatibility and phototherapeutic effect of DPBDP NPs were evaluated through cell counting kit-8 (CCK-8) assay. Under irradiation of 690 nm laser (1.0 W/cm²), the half maximal inhibitory concentration (IC₅₀) of DPBDP NPs was calculated to be 16.47 µg/mL. Thus, the as-prepared DPBDP NPs could be acted as excellent candidates for synergistic photodynamic/photothermal therapy.     

Tumor Targeting with Methotrexate-Conjugated Zwitterionic Near-Infrared Fluorophore for Precise Photothermal Therapy

Targeted tumor imaging can effectively enable image-guided surgery and precise cancer therapy. Finding the right combination of anticancer drugs and near-infrared (NIR) fluorophores is the key to targeted photothermal cancer treatment. In this study, a tumor-targetable NIR fluorophore conjugate with rapid body clearance was developed for accurate tumor imaging and effective photothermal therapy (PTT). The methotrexate (MTX) and zwitterionic NIR fluorophore conjugate (MTX-ZW) were prepared by conjugating a folate antagonist MTX with an aminated ZW800-1 analog to increase the tumor targetability for NIR laser-based PTT of cancer. The MTX, known as a poor tumor-selective drug, showed high tumor accumulation and rapid background clearance after conjugation with the highly water-soluble zwitterionic NIR fluorophore up to 4 h post-injection. The photothermal energy was generated from the MTX-ZW conjugate to induce necrotic cell death in the targeted tumor site under 808 nm laser irradiation. Compared with the previously reported MTX conjugates, the MTX-ZW conjugate can be a great candidate for targeted tumor imaging and fluorescence-guided photothermal cancer therapy. Therefore, these results provide a strategy for the design of drug-fluorophore conjugates and elaborate therapeutic platforms for cancer phototherapy.     

Optimization of Photothermal Therapy Treatment Effect under Various Laser Irradiation Conditions

The photothermal effect refers to a phenomenon in which light energy is converted into heat energy, and in the medical field, therapeutics based on this phenomenon are used for anticancer treatment. A new treatment technique called photothermal therapy kills tumor tissue through a temperature increase and has the advantages of no bleeding and fast recovery. In this study, the results of photothermal therapy for squamous cell carcinoma in the skin layer were analyzed numerically for different laser profiles, intensities, and radii and various concentrations of gold nanoparticles (AuNPs). According to the heat-transfer theory, the temperature distribution in the tissue was calculated for the conditions under which photothermal therapy was performed, and the therapeutic effect was quantitatively confirmed through three apoptotic variables. In addition, the laser intensity and the volume fraction of AuNPs were optimized, and the results provide useful criteria for optimizing the treatment effects in photothermal therapy.     

Biodegradable and Multifunctional Polymer Micro-Tubes for Targeting Photothermal Therapy

We describe an innovative form of polymer micro-tubes with diverse functions including biodegradation, magnetic manipulation, and photothermal effect that employs and activates photothermal therapy to target cancer cells. The micro-tube comprised soybean protein isolate, poly-l-glutamic acid, magnetite nanoparticles, plus gold nanoparticles. Through electrostatic force, these components, with opposite charges, formed pairs of layers in the pores of the template, various bilayers of soybean protein isolate and poly-l-glutamic acid served as the biodegradable building wall to each micro-tube. The layers of magnetite nanoparticle functionalized micro-tubes enabled the micro-tube manipulate to target the cancer cells by using an external magnetic field. The photo-thermal effect of the layer of gold nanoparticles on the outer surface of the micro-tubes, when under irradiation and when brought about by the near infrared radiation, elevated each sample’s temperature. In addition, and when under the exposure of the near infrared radiation, the elevated temperature of the suspension of the micro-tubes, likewise with a concentration of 0.2 mg/mL, and similarly with a power of 2 W and as well maintained for 10 min, elevated the temperature of the suspension beyond 42 °C. Such temperatures induced apoptosis of target cancer cells through the effect of photothermal therapy. The findings assert that structured micro-tubes have a promising application as a photothermal agent. From this assertion, the implications are that this multifunctional agent will significantly improve the methodology for cancer diagnosis and therapy.     

Conjugated-Polymer-Based Nanoparticles with Efficient NIR-II Fluorescent,Photoacoustic and Photothermal Performance

Fluorescence imaging (FI) and photoacoustic imaging (PA) play important roles in the real-time assessment of cell-based therapies. However, the limitations of conventional organic fluorescence contrast agents and the narrow range of the emission wavelength in the first near-infrared (NIR-I) window (750–900 nm) hamper applications of fluorescence imaging in living subjects. Herein, we report the design and synthesis of a short-wave infrared FI contrast agent and PA contrast agent based on a conjugated polymer—poly{2,5-bis[(5-thiophen-2-yl)methylene]-3,6-bis(2-octyldodecyl)-2,5-dihydropyrazine}—and its use to construct multifunctional nanoparticles to simplify photothermal therapy.     

Dopamine-Modified Zero-Valent Iron Nanoparticles for Dual-Modality Photothermal and Photodynamic Breast Cancer Therapy

Phototherapy has the advantages of minimal invasion, few side effects, and improved accuracy for cancer therapy. The application of a polydopamine (PDA)-modified nano zero-valent iron (nZVI@PDA) as a new synergistic agent in combination with photodynamic/photothermal (PD/PT) therapy to kill cancer cells is discussed here. The nZVI@PDA offered high light-to-heat conversion and ROS generation efficiency under near-infrared (NIR) irradiation (808 nm), thus leading to irreversible damage to nZVI@PDA-treated MCF-7 cells at low concentration, without inducing apoptosis in normal cells. Irradiation of nZVI@PDA using an NIR laser converted the energy of the photons to heat and ROS. Our results showed that modification of the PDA on the surface of nZVI can improve the biocompatibility of the nZVI@PDA. This work integrated the PD and PT effects into a single nanodevice to afford a highly efficient cancer treatment. Meanwhile, nZVI@PDA, which combines the advantages of PDA and nZVI, displayed excellent biocompatibility and tumoricidal ability, thus suggesting its huge potential for future clinical research in cancer therapy.     

Organic Semiconductors for Photothermal Therapy and Photoacoustic Imaging

In recent years, semiconducting polymer nanoparticles (SPNs) have been attracting considerable attention because of their outstanding characteristics such as higher light and thermal stability. They are widely used in fields of biomedicine such as photoacoustic (PA) imaging (PAI), photodynamic therapy (PDT), and photothermal therapy (PTT). PAI, a new imaging modality based on PA effects, shows great promise in biomedical applications. SPNs that display strong optical absorbance in the visible and near-infrared (NIR) regions can be promising candidates for in vivo PTT and PAI. Here we introduce the preparation of organic conjugated polymer fluorescent nanoparticles in the aqueous phase. We then discuss the application of water-dispersible conjugated polymer nanoparticles in PA and PTT. Finally, we discuss the opportunities and challenges for the development of organic conjugated polymer nanoparticles.     

Assessing the Efficiency of Triangular Gold Nanoparticles as NIR Photothermal Agents In Vitro and Melanoma Tumor Model

Photothermal therapy (PTT) is gaining a lot of interest as a cancer treatment option with minimal side effects due to the efficient photothermal agents employed. They are based on nanomaterials that, upon laser irradiation, absorb photon energy and convert it into heat to induce hyperthermia, which destroys the cancer cells. Here, the unique light-to-heat conversion features of three different gold nanotriangular nanoparticles (AuNTs) are evaluated with respect to their absorption properties to select the most efficient nanoheater with the highest potential to operate as an efficient photothermal agent. AuNTs with LSPR response in- and out- of resonance with the 785 nm near-infrared (NIR) excitation wavelength are investigated. Upon 15 min laser exposure, the AuNTs that exhibit a plasmonic response in resonance with the 785 nm laser line show the highest photothermal conversion efficacy of 80%, which correlates with a temperature increase of 22 °C. These photothermal properties are well-preserved in agarose-based skin biological phantoms that mimic the melanoma tumoral tissue and surrounding healthy tissue. Finally, in vitro studies on B16.F10 melanoma cells prove by fluorescence staining and MTT assay that the highest phototoxic effect after NIR laser exposure is induced by AuNTs with LSPR response in resonance with the employed laser line, thus demonstrating their potential implementation as efficient photothermal agents in PTT.     

Hybrid Gold Nanorod-Based Nanoplatform with Chemo and Photothermal Activities for Bimodal Cancer Therapy

Metal nanoparticles (NPs), particularly gold nanorods (AuNRs), appear as excellent platforms not only to transport and deliver bioactive cargoes but also to provide additional therapeutic responses for diseased cells and tissues and/or to complement the action of the carried molecules. In this manner, here, we optimized a previous developed metal-based nanoplatform composed of an AuNR core surrounded by a polymeric shell constructed by means of the layer-by-layer approach, and in which very large amounts of the antineoplasic drug doxorubicin (DOXO) in a single loading step and targeting capability thanks to an outer hyaluronic acid layer were incorporated by means of an optimized fabrication process (PSS/DOXO/PLL/HA-coated AuNRs). The platform retained its nanometer size with a negative surface charge and was colloidally stable in a range of physiological conditions, in which only in some of them some particle clustering was noted with no precipitation. In addition, the dual stimuli-responsiveness of the designed nanoplatform to both endogenous proteases and external applied light stimuli allows to perfectly manipulate the chemodrug release rates and profiles to achieve suitable pharmacodynamics. It was observed that the inherent active targeting abilities of the nanoplatfom allow the achievement of specific cell toxicity in tumoral cervical HeLa cells, whilst healthy ones such as 3T3-Balb fibroblast remain safe and alive in agreement with the detected levels of internalization in each cell line. In addition, the bimodal action of simultaneous chemo- and photothermal bioactivity provided by the platform largely enhances the therapeutic outcomes. Finally, it was observed that our PSS/DOXO/PLL/HA-coated AuNRs induced cell mortality mainly through apoptosis in HeLa cells even in the presence of NIR light irradiation, which agrees with the idea of the chemo-activity of DOXO predominating over the photothermal effect to induce cell death, favoring an apoptotic pathway over necrosis for cell death.     

Induction of Apoptotic Temperature in Photothermal Therapy under Various Heating Conditions in Multi-Layered Skin Structure

Recently, photothermal therapy has attracted attention as an alternative treatment to conventional surgical techniques because it does not lead to bleeding and patients quickly recover after treatment compared to incisional surgery. Photothermal therapy induces tumor cell death through an increase in the temperature using the photothermal effect, which converts light energy into thermal energy. This study was conducted to perform numerical analysis based on heat transfer to induce apoptosis of tumor tissue under various heating conditions in photothermal therapy. The Monte Carlo method was applied to evaluate a multi-layered skin structure containing squamous cell carcinoma. Tissue-equivalent phantom experiments verified the numerical model. Based on the effective apoptosis retention ratio, the numerical analysis results showed the quantitative correlation for the laser intensity, volume fraction of gold nanorods injected into the tumor, and cooling time. This study reveals optimal conditions for maximizing apoptosis within tumor tissue while minimizing thermal damage to surrounding tissues under various heating conditions. This approach may be useful as a standard treatment when performing photothermal therapy.     

Synthesis Mechanisms,Structural Models,and Photothermal Therapy Applications of Top-Down Carbon Dots from Carbon Powder,Graphite, Graphene,and Carbon Nanotubes

In this study, top-down syntheses of carbon dots (CDs) from four different carbon precursors, namely, carbon nano powders, graphite, graphene, and carbon nanotubes, were carried out. Systematic study demonstrated that the optical properties and surface functionalities of the CDs were quite similar and mainly influenced by the synthesis method, while the sizes, morphologies, chemical compositions, and core structures of the CDs were heavily influenced by the carbon precursors. On the basis of these studies, the formation processes and structural models of these four top-down CDs were proposed. The cell cytotoxicity and photothermal conversion efficiency of these CDs were also carefully evaluated, demonstrating their potential applications in photothermal therapy.     

A Novel D-A-D Photosensitizer for Efficient NIR Imaging and Photodynamic Therapy

Photodynamic therapy (PDT) has attracted great interest in cancer theranostics owing to its minimal invasiveness and low side effect. In PDT, photosensitizers are indispensable components that generate cytotoxic reactive oxygen species (ROS). Tremendous efforts have been devoted to optimizing the photosensitizer with enhanced ROS efficiency. However, to improve the precision and controllability for PDT, developing NIR imaging-guided photosensitizers are still urgent and challenging. Here, we have designed a novel photosensitizer 2Cz-BTZ which integrated with intense NIR emission and photoinduced singlet oxygen ¹O₂ generation capabilities. Moreover, after loading the photosensitizers 2Cz-BTZ into biocompatible amphiphilic polymers F127, the formed 2Cz-BTZ@F127 nanoparticles (NPs) exhibited good photoinduced therapy as well as long-term in vivo imaging capabilities. Under these merits, the 2Cz-BTZ@F127 NPs showed NIR imaging-guided PDT, which paves a promising way for spatiotemporally precise tumor theranostics.     

A Step Forward in Breast Cancer Research: From a Natural-Like Experimental Model to a Preliminary Photothermal Approach

Breast cancer is one of the most frequently diagnosed malignancies and common causes of cancer death in women. Recent studies suggest that environmental exposures to certain chemicals, such as 7,12-Dimethylbenzanthracene (DMBA), a chemical present in tobacco, may increase the risk of developing breast cancer later in life. The first-line treatments for breast cancer (surgery, chemotherapy or a combination of both) are generally invasive and frequently associated with severe side effects and high comorbidity. Consequently, novel approaches are strongly required to find more natural-like experimental models that better reflect the tumors’ etiology, physiopathology and response to treatments, as well as to find more targeted, efficient and minimally invasive treatments. This study proposes the development and an in deep biological characterization of an experimental model using DMBA-tumor-induction in Sprague-Dawley female rats. Moreover, a photothermal therapy approach using a near-infrared laser coupled with gold nanoparticles was preliminarily assessed. The gold nanoparticles were functionalized with Epidermal Growth Factor, and their physicochemical properties and in vitro effects were characterized. DMBA proved to be a very good and selective inductor of breast cancer, with 100% incidence and inducing an average of 4.7 tumors per animal. Epigenetic analysis showed that tumors classified with worst prognosis were hypomethylated. The tumor-induced rats were then subjected to a preliminary treatment using functionalized gold nanoparticles and its activation by laser (650–900 nm). The treatment outcomes presented very promising alterations in terms of tumor histology, confirming the presence of necrosis in most of the cases. Although this study revealed encouraging results as a breast cancer therapy, it is important to define tumor eligibility and specific efficiency criteria to further assess its application in breast cancer treatment on other species.     

Study on the Optimal Treatment Condition Control of Photothermal Therapy under Various Cooling Time Ratios of Lasers

Photothermal therapy is a treatment technique that has attracted attention as an alternative to conventional surgical techniques. It is based on the photothermal effect, wherein light energy is converted into thermal energy, and facilitates rapid recovery after treatment. This study employed various laser irradiation conditions and presented conditions with the optimal treatment effects through a numerical analysis based on heat transfer. A skin layer comprising four stages containing squamous cell carcinoma was targeted, and the treatment effect was confirmed by varying the heating conditions of the laser and volume fraction of gold nanoparticles. The therapeutic effect was confirmed through both the apoptosis retention ratio, which quantitatively estimated the degree of maintenance of the apoptosis temperature range within the tumor, and the thermal hazard retention value, which quantitatively calculates the amount of thermal damage to the surrounding normal tissues. Finally, the optimal treatment conditions were determined based on the laser intensity, cooling time ratio, and volume fraction of injected gold nanoparticles through numerical analysis.     

Biocompatible PEGylated Fe3O4 Nanoparticles as Photothermal Agents for Near-Infrared Light Modulated Cancer Therapy

In accordance with the World Cancer Report, cancer has become the leading cause of mortality worldwide, and various therapeutic strategies have been developed at the same time. In the present study, biocompatible magnetic nanoparticles were designed and synthesized as high-performance photothermal agents for near-infrared light mediated cancer therapy in vitro. Via a facile one-pot solvothermal method, well-defined PEGylated magnetic nanoparticles (PEG–Fe₃O₄) were prepared with cheap inhesion as a first step. Due to the successful coating of PEG molecules on the surface of PEG–Fe₃O₄, these nanoparticles exhibited excellent dispersibility and dissolvability in physiological condition. Cytotoxicity based on MTT assays indicated these nanoparticles revealed high biocompatibility and low toxicity towards both Hela cells and C6 cells. After near-infrared (NIR) laser irradiation, the viabilities of C6 cells were effectively suppressed when incubated with the NIR laser activated PEG–Fe₃O₄. In addition, detailed photothermal anti-cancer efficacy was evaluated via visual microscope images, demonstrating that our PEG–Fe₃O₄ were promising for photothermal therapy of cancer cells.     

Towards Effective Photothermal/Photodynamic Treatment Using Plasmonic Gold Nanoparticles

Gold nanoparticles (AuNPs) of different size and shape are widely used as photosensitizers for cancer diagnostics and plasmonic photothermal (PPT)/photodynamic (PDT) therapy, as nanocarriers for drug delivery and laser-mediated pathogen killing, even the underlying mechanisms of treatment effects remain poorly understood. There is a need in analyzing and improving the ways to increase accumulation of AuNP in tumors and other crucial steps in interaction of AuNPs with laser light and tissues. In this review, we summarize our recent theoretical, experimental, and pre-clinical results on light activated interaction of AuNPs with tissues and cells. Specifically, we discuss a combined PPT/PDT treatment of tumors and killing of pathogen bacteria with gold-based nanocomposites and atomic clusters, cell optoporation, and theoretical simulations of nanoparticle-mediated laser heating of tissues and cells.     

The Functions and Applications of RGD in Tumor Therapy and Tissue Engineering

Arginine-Glycine-Aspartic (RGD), is the specific recognition site of integrins with theirs ligands, and regulates cell-cell and cell-extracellular matrix interactions. The RGD motif can be combined with integrins overexpressed on the tumor neovasculature and tumor cells with a certain affinity, becoming the new target for imaging agents, and drugs, and gene delivery for tumor treatment. Further, RGD as a biomimetic peptide can also promote cell adherence to the matrix, prevent cell apoptosis and accelerate new tissue regeneration. Functionalizing material surfaces with RGD can improve cell/biomaterial interactions, which facilitates the generation of tissue-engineered constructs. This paper reviews the main functions and advantages of RGD, describes the applications of RGD in imaging agents, drugs, gene delivery for tumor therapy, and highlights the role of RGD in promoting the development of tissue engineering (bone regeneration, cornea repair, artificial neovascularization) in recent years.     

INSIDIA 2.0 High-Throughput Analysis of 3D Cancer Models: Multiparametric Quantification of Graphene Quantum Dots Photothermal Therapy for Glioblastoma and Pancreatic Cancer

Cancer spheroids are in vitro 3D models that became crucial in nanomaterials science thanks to the possibility of performing high throughput screening of nanoparticles and combined nanoparticle-drug therapies on in vitro models. However, most of the current spheroid analysis methods involve manual steps. This is a time-consuming process and is extremely liable to the variability of individual operators. For this reason, rapid, user-friendly, ready-to-use, high-throughput image analysis software is necessary. In this work, we report the INSIDIA 2.0 macro, which offers researchers high-throughput and high content quantitative analysis of in vitro 3D cancer cell spheroids and allows advanced parametrization of the expanding and invading cancer cellular mass. INSIDIA has been implemented to provide in-depth morphologic analysis and has been used for the analysis of the effect of graphene quantum dots photothermal therapy on glioblastoma (U87) and pancreatic cancer (PANC-1) spheroids. Thanks to INSIDIA 2.0 analysis, two types of effects have been observed: In U87 spheroids, death is accompanied by a decrease in area of the entire spheroid, with a decrease in entropy due to the generation of a high uniform density spheroid core. On the other hand, PANC-1 spheroids’ death caused by nanoparticle photothermal disruption is accompanied with an overall increase in area and entropy due to the progressive loss of integrity and increase in variability of spheroid texture. We have summarized these effects in a quantitative parameter of spheroid disruption demonstrating that INSIDIA 2.0 multiparametric analysis can be used to quantify cell death in a non-invasive, fast, and high-throughput fashion.