Ablation of Venous Malformations by Photothermal Therapy with Intravenous Gold Nanoshells.

Venous malformations (VMs) consist of hugely enlarged and dysmorphic veins. These lesions cause significant disfigurement, pain, and complications such as bleeding and coagulopathy. Pharmacotherapy for the treatment of VMs has limited efficacy and potentially limiting toxicity. Current treatment for patients with VMs entails life-long pharmacotherapy or surgical procedures. Here we explored whether intravenously administered agents can be used to destroy VMs by photothermal therapy (PTT), using gold nanoshells (AuNSs) that generated heat following irradiation with near-infrared (NIR) light. In a murine model of VMs, intravenous AuNSs accumulated within the VMs. Irradiation of the VMs induced marked regression and even elimination. Nanoparticle-based photothermal therapy can provide effective therapy for VMs, which are otherwise relatively refractory to treatment.

Biomimetic Gold Nanoshell-Loaded Macrophage for Photothermal Biomedicine.

The purpose of this study was to investigate the effect of photothermal treatment (PTT) with gold nanoshell (ANS) using a macrophage-mediated delivery system in a head and neck squamous cell carcinoma (HNSCC) cell line. To achieve this, ANS-loaded rat macrophages (ANS-MAs) were prepared via the coculture method with ANS. The human HNSCC (FaDu cell) and macrophage (rat macrophage; NR8383 cell) hybrid spheroid models were generated by the centrifugation method to determine the possibility of using ANS-MAs as a cancer therapy. These ANS-MAs were set into the tumor and macrophage hybrid spheroid model to measure PTT efficacy. Kinetic analysis of the spheroid growth pattern revealed that this PTT process caused a decreasing pattern in the volume of the hybrid model containing ANS-MAs (p < 0.001). Comparison with empty macrophages showed harmony between ANS and laser irradiation for the generation of PTT. An annexin V/dead cell marker assay indicated that the PTT-treated hybrid model induced increasing apoptosis and dead cells. Further studies on the toxicity of ANS-MAs are needed to reveal whether it can be considered biocompatible. In summary, the ANS was prepared with a macrophage as the delivery method and protective carrier. The ANS was successfully localized to the macrophages, and their photoabsorption property was stationary. This strategy showed significant growth inhibition of the tumor and macrophage spheroid model under NIR laser irradiation. In vivo toxicology results suggest that ANS-MA is a promising candidate for a biocompatible strategy to overcome the limitations of fabricated nanomaterials. This ANS-MA delivery and PTT strategy may potentially lead to improvements in the quality of life of patients with HNSCC by providing a biocompatible, minimally invasive modality for cancer treatment.

Selective radiofrequency ablation of tumor by magnetically targeting of multifunctional iron oxide-gold nanohybrid.

PURPOSE: Radiofrequency (RF) ablation therapy is of great interest in cancer therapy as it is non-ionizing radiation and can effectively penetrate into the tissue. However, the current RF ablation technique is invasive that requires RF probe insertion into the tissue and generates a non-specific heating. Recently, RF-responsive nanomaterials such as gold nanoparticles (AuNPs) and iron oxide nanoparticles (IONPs) have led to tremendous progress in this area. They have been found to be able to absorb the RF field and induce a localized heating within the target, thereby affording a non-invasive and tumor-specific RF ablation strategy. In the present study, for the first time, we used a hybrid core-shell nanostructure comprising IONPs as the core and AuNPs as the shell (IO@Au) for targeted RF ablation therapy. Due to the magnetic core, the nanohybrid can be directed toward the tumor through a magnet. Moreover, IONPs enable the nanohybrid to be used as a magnetic resonance imaging (MRI) contrast agent. RESULTS: In vitro cytotoxicity experiment showed that the combination of IO@Au and 13.56-MHz RF field significantly reduced the viability of cancer cells. Next, during an in vivo experiment, we demonstrated that magnetically targeting of IO@Au to the tumor and subsequent RF exposure dramatically suppressed the tumor growth. CONCLUSION: Therefore, the integration of targeting, imaging, and therapeutic performances into IO@Au nanohybrid could afford the promise to improve the effectiveness of RF ablation therapy.

Comprehensive Evaluation of Degradable and Cost-Effective Plasmonic Nanoshells for Localized Photothermolysis of Cancer Cells.

Integrating the concept of biodegradation and light-triggered localized therapy in a functional nanoformulation is the current approach in onco-nanomedicine. Morphology control with an enhanced photothermal response, minimal toxicity, and X-ray attenuation of polymer-based nanoparticles is a critical concern for image-guided photothermal therapy. Herein, we describe the simple design of cost-effective and degradable polycaprolactone-based plasmonic nanoshells for the integrated photothermolysis as well as localized imaging of cancer cells. The gold-deposited polycaprolactone-based plasmonic nanoshells (AuPCL NS) are synthesized in a scalable and facile way under ambient conditions. The synthesized nanoshells are monodisperse, fairly stable, and highly inert even at five times (250 µg/mL) the therapeutic concentration in a week-long test. AuPCL NS are capable of delivering standalone photothermal therapy for the complete ablation of cancer cells without using any anticancerous drugs and causing toxicity. It delivers the same therapeutic efficacy to different cancer cell lines, irrespective of their chemorefractory status and also works as a potential computed tomography contrast agent for the integrated imaging-directed photothermal cancer therapy. High biocompatibility, degradability, and promising photothermal efficacy of AuPCL NS are attractive aspects of this report that could open new horizons of localized plasmonic photothermal therapy for healthcare applications.

Inorganic Nanoshell-Stabilized Liquid Metal for Targeted Photonanomedicine in NIR-II Biowindow.

Gallium and gallium-based alloys, typical types of liquid metals with unique physiochemical properties, are emerging as a next generation of functional materials in versatile biomedical applications. However, the exploration of their biomedical performance is currently insufficient, and their intrinsic low oxidative resistance is a key factor blocking their further clinical translation. Herein, we report on the surface engineering of liquid metal-based nanoplatforms by an inorganic silica nanoshell based on a novel but facile sonochemical synthesis for highly efficient, targeted, and near-infrared (NIR)-triggered photothermal tumor hyperthermia in the NIR-II biowindow. The inorganic silica-shell engineering of liquid metal significantly enhances the photothermal performance of the liquid metal core as reflected by enhanced NIR absorption, improved photothermal stability by oxidation protection, and abundant surface chemistry for surface-targeted engineering to achieve enhanced tumor accumulation. Systematic in vitro cell-level evaluation and in vivo tumor xenograft assessment demonstrate that (Arg-Gly-Asp) RGD-targeted and silica-coated nanoscale liquid metal substantially induces phototriggered cancer-cell death and photothermal tumor eradication, accompanied by high in vivo biocompatibility and easy excretion out of the body. This work provides the first paradigm for surface-inorganic engineering of liquid metal-based nanoplatforms for achieving multiple desirable therapeutic performances, especially for combating cancer.

Rodlike MSN@Au Nanohybrid-Modified Supermolecular Photosensitizer for NIRF/MSOT/CT/MR Quadmodal Imaging-Guided Photothermal/Photodynamic Cancer Therapy.

Recently, rodlike nanomaterials with specific aspect ratio for efficient cellular uptake have received enormous attention. For functional nanomaterials, such as photothermal agents, large surface areas for their rod-shaped exterior that increase the amount of light absorbed would lead to a higher absorption coefficient as well as drug-loading property. In this project, we coated rodlike mesoporous silica with gold nanoshells (MSNR@Au hybrid), modifying them with ultrasmall gadolinium (Gd)-chelated supramolecular photosensitizers, TPPS4 (MSNR@Au-TPPS4(Gd)), which could be applied to near-infrared fluorescence/multispectral optoacoustic tomography/computed tomography/magnetic resonance imaging and imaging-guided remotely controlled photothermal (PTT)/photodynamic (PDT) combined antitumor therapy. Gold nanoshells, as a perfect PTT agent, were used to assemble the rodlike mesoporous silica nanoparticles with larger superficial area and higher drug loading, thus obtaining the MSNR@Au hybrid. HS-ß-CD, which was used as the host, was adsorbed on the gold nanoshell (MSNR@Au-ß-CD) to link TPPS4(Gd) through the host-guest reaction, thus forming CD-TPPS4 supramolecular photosensitizers (supraPSs). Compared with conventional PSs, supraPSs have host screens, which could reduce the self-aggregation of TPPS4, and consequently generate 1O2 with high efficiency. The in vivo quadmodal imaging of MSNR@Au-TPPS4(Gd) nanoparticles revealed an intensive tumor uptake effect after injection. The in vivo antitumor efficacy further testified that the synergistic therapy, which was more efficient than any other monotherapy, exhibited an excellent tumor inhibition therapeutic effect. As a result, this encourages to further explore multifunctional theranostic nanoparticles based on gold shells for combined cancer therapy.

Dual-template cascade synthesis of highly multi-branched Au nanoshells with ultrastrong NIR absorption and efficient photothermal therapeutic intervention.

With the rapid development of photothermal therapy (PTT) in cancer treatment, it is necessary to obtain effective plasma-responsive tunable photothermal transducing agents. Inspired by the peptide-directed hierarchical mineralized Ag nanocages (Ag NCs), scientists designed a new duel-template cascade preparation method, and novel unique multi-branched gold nanoshells (BGSs) were successfully prepared under mild conditions using green strategy. The length, density and diameter of the branches were tuned, which led to the adjustment of the surface plasma response of the nanostructure. Because of the hierarchical structure and anisotropic surface, an obvious red shift of the local surface plasmon resonance spectrum was observed for the branched Au nanoshells. The excellent photothermal conversion efficiency (70.9%) and photo-induced heating responsive curves proved the superior photothermal conversion performance and photothermal stability of BGSs. The in vitro and in vivo results indicated that the heat generated by the intense NIR absorption of BGSs can selectively destroy cancer cells under laser irradiation. The nanostructures with ultrastrong absorption have promising prospects in tumor therapy.

Total Aqueous Synthesis of Au@Cu2-x S Core-Shell Nanoparticles for In Vitro and In Vivo SERS/PA Imaging-Guided Photothermal Cancer Therapy.

Both accurate tumor navigation and nanostructures with high photothermal (PT) conversion efficiency are important but remain challenging to achieve in current biomedical applications. This study reports an anion exchange-based facile and green approach for synthesizing Au@Cu2-x S core-shell nanoparticles (NPs) in an aqueous system. In addition to the PT effect of the suggested NPs, the surface-enhanced Raman scattering (SERS) is also significantly improved due to the tailored localized surface plasmon resonance coupling between the Au metal core and the Cu2-x S semiconductor shell. Using an epitaxial strategy, Au@Cu2 O NPs are first obtained by the in situ reduction of cupric hydroxide on a cresyl violet acetate-coated Au core; then, Au@Cu2-x S NPs are obtained via anion exchange between the S2- and Cu2 O shell. Both the Cu/S atomic ratio and the Cu2-x S shell thickness can be adjusted conveniently. Hence, the ideal integration of the plasmonic Au core and Cu2-x S shell into a single unit is conducive not only to highly efficient PT conversion but also to the construction of a SERS-based navigator. This new type of SERS-guided NP, with enhanced photoacoustic signals, is an important candidate for both accurate tumor navigation and nondestructive PT treatment guided in vivo by two modes of optical imaging.

Multifunctional Porous Iron Oxide Nanoagents for MRI and Photothermal/Chemo Synergistic Therapy.

Nanoagents of integrating multiple imaging and therapeutic modalities have attracted tremendous attention for biomedical applications. Herein, we synthesize porous hollow Fe3O4 as a theranostic agent for MRI and combined photothermal/chemo cancer therapy. The as-prepared porous iron oxide nanoagents allow for T2-weighted MR imaging. Interestingly, we demonstrate that the porous structure endows the nanoagents an outstanding photothermal property for cancer cell killing, in comparison with other types of iron oxide nanomaterials. Under the exposure of an NIR laser, the heat produced by porous Fe3O4 can accelerate the release of the loaded drug (e.g., DOX) to enhance chemotherapeutic efficacy, promoting the ablation of cancer cells with synergistic photothermal/chemotherapy.

Glycol chitosan assisted in situ reduction of gold on polymeric template for anti-cancer theranostics.

Multifunctional biodegradable nanomaterials that could be used for both imaging and therapy are being researched extensively. A simple technique to synthesize multifunctional nanoparticles without compromising on any of their functionality is a challenge. We have attempted to optimize a two-step procedure of gold coated polymeric template involving 1) Single pot synthesis of PLGA nanoparticles with cationic surface charge using glycol chitosan and 2) in situ gold coating for formation of gold coated PLGA nanoshell (AuPLGA-NS). These gold-coated PLGA nanoparticles were explored for photothermal therapy (PTT) and as X-ray/CT contrast agents. Biocompatibility and photothermal cytotoxicity of AuPLGA-NS were evaluated in-vitro and results confirmed the therapeutic efficacy of these particles resulting in 80% cancer cell death. Besides, it also showed potential X-ray/CT imaging ability with contrast equivalent to that of Iodine. The results demonstrated that these gold-coated PLGA nanoparticles synthesized by a simple approach could be used as a multifunctional nanosystem for cancer theranostics.

Rational Design of Branched Nanoporous Gold Nanoshells with Enhanced Physico-Optical Properties for Optical Imaging and Cancer Therapy.

Reported procedures on the synthesis of gold nanoshells with smooth surfaces have merely demonstrated efficient control of shell thickness and particle size, yet no branch and nanoporous features on the nanoshell have been implemented to date. Herein, we demonstrate the ability to control the roughness and nanoscale porosity of gold nanoshells by using redox-active polymer poly(vinylphenol)-b-(styrene) nanoparticles as reducing agent and template. The porosity and size of the branches on this branched nanoporous gold nanoshell (BAuNSP) material can be facilely adjusted by control of the reaction speed or the reaction time between the redox-active polymer nanoparticles and gold ions (Au3+). Due to the strong reduction ability of the redox-active polymer, the yield of BAuNSP was virtually 100%. By taking advantage of the sharp branches and nanoporous features, BAuNSP exhibited greatly enhanced physico-optical properties, including photothermal effect, surface-enhanced Raman scattering (SERS), and photoacoustic (PA) signals. The photothermal conversion efficiency can reach as high as 75.5%, which is greater than most gold nanocrystals. Furthermore, the nanoporous nature of the shells allows for effective drug loading and controlled drug release. The thermoresponsive polymer coated on the BAuNSP surface serves as a gate keeper, governing the drug release behavior through photothermal heating. Positron emission tomography imaging demonstrated a high passive tumor accumulation of 64Cu-labeled BAuNSP. The strong SERS signal generated by the SERS-active BAuNSP in vivo, accompanied by enhanced PA signals in the tumor region, provide significant tumor information, including size, morphology, position, and boundaries between tumor and healthy tissues. In vivo tumor therapy experiments demonstrated a highly synergistic chemo-photothermal therapy effect of drug-loaded BAuNSPs, guided by three modes of optical imaging.

Gold nanoshell-based betulinic acid liposomes for synergistic chemo-photothermal therapy.

A novel synthesis approach is first developed to fabricate a multifunctional smart nanodrug delivery system: gold nanoshell-coated betulinic acid liposomes (AuNS-BA-Lips) mediated by a glutathione. The AuNS-BA-Lips exhibited good size distribution (149.4±2.4nm), preferable photothermal conversion ability and synergistic chemo-photothermal therapy. Additionally, the absorption wavelength of AuNS-BA-Lips showed a significantly red-shifted to near infrared (NIR) region, which can strongly absorbed NIR laser and efficiently convert it into localized heat, thus providing controlled drug release and antitumor thermotherapy. Moreover, the nanocarriers excited by NIR light significantly promoted cell uptake compared to those without irradiation, resulting in an enhanced intracellular drug accumulation. Upon NIR irradiation, the AuNS-BA-Lips showed highly efficient antitumor effects on tumor-bearing mice with an inhibition rate of 83.02%, thus demonstrating a remarkable synergistic therapeutic effect of chemotherapy and thermotherapy. Therefore, this work provides new insight into developing a multifunctional antitumor drug.

Numerical investigation of thermal response of laser-irradiated biological tissue phantoms embedded with gold nanoshells.

The work presented in this paper focuses on numerically investigating the thermal response of gold nanoshells-embedded biological tissue phantoms with potential applications into photo-thermal therapy wherein the interest is in destroying the cancerous cells with minimum damage to the surrounding healthy cells. The tissue phantom has been irradiated with a pico-second laser. Radiative transfer equation (RTE) has been employed to model the light-tissue interaction using discrete ordinate method (DOM). For determining the temperature distribution inside the tissue phantom, the RTE has been solved in combination with a generalized non-Fourier heat conduction model namely the dual phase lag bio-heat transfer model. The numerical code comprising the coupled RTE-bio-heat transfer equation, developed as a part of the current work, has been benchmarked against the experimental as well as the numerical results available in the literature. It has been demonstrated that the temperature of the optical inhomogeneity inside the biological tissue phantom embedded with gold nanoshells is relatively higher than that of the baseline case (no nanoshells) for the same laser power and operation time. The study clearly underlines the impact of nanoshell concentration and its size on the thermal response of the biological tissue sample. The comparative study concerned with the size and concentration of nanoshells showed that 60nm nanoshells with concentration of 5×1015mm-3 result into the temperature levels that are optimum for the irreversible destruction of cancer infected cells in the context of photo-thermal therapy. To the best of the knowledge of the authors, the present study is one of the first attempts to quantify the influence of gold nanoshells on the temperature distributions inside the biological tissue phantoms upon laser irradiation using the dual phase lag heat conduction model.

Aspect ratios of gold nanoshell capsules mediated melanoma ablation by synergistic photothermal therapy and chemotherapy.

Nanomaterial-mediated photothermal therapy has shown great potential to fulfill the unmet medical needs for treatment of tumors. In this study, a rod-like gold nanoshell capsule, which can offer both photothermal therapy and chemotherapy, is synthesized and applied for the treatment of melanoma. This nano-platform is made by developing a gold nanoshell on rod-like mesoporous silica nanoparticles with different aspect ratios, and it was found that the aspect ratio significantly influenced the cellular uptake and tumor distribution of the nanoparticles. The gold nanoshell capsules with a moderate aspect ratio are found to be efficiently taken up by melanoma cells and are able to penetrate tumor tissues, resulting in the effective ablation of highly malignant melanomas when used along with mild laser irradiation and a single treatment. This study demonstrates that the optimization of the aspect ratio is indispensable to further development of this nanoplatform for antitumor therapy. FROM THE CLINICAL EDITOR: The combination of hyperthermia and chemotherapeutic agents has been investigated as a new approach for the treatment of malignant melanoma. It appears that the aspect ratio may play an important role in the treatment efficacy. In this article, the authors studied how the AR influenced the cellular uptake and the optimal AR for antitumor effects.

Ultrasonic delivery of silica-gold nanoshells for photothermolysis of sebaceous glands in humans: Nanotechnology from the bench to clinic.

Recent advances in nanotechnology have provided numerous opportunities to transform medical therapies for the treatment of diseases including cancer, atherosclerosis, and thrombosis. Here, we report, through in vitro studies and in vivo human pilot clinical studies, the use of inert, inorganic silica-gold nanoshells for the treatment of a widely prevalent and researched, yet poorly treated disease of acne. We use ~150nm silica-gold nanoshells, tuned to absorb near-IR light and near-IR laser irradiation to thermally disrupt overactive sebaceous glands in the skin which define the etiology of acne-related problems. Low-frequency ultrasound was used to facilitate deep glandular penetration of the nanoshells. Upon delivery of the nanoshells into the follicles and glands, followed by wiping of superficial nanoshells from skin surface and exposure of skin to near-infrared laser, nanoshells localized in the follicles absorb light, get heated, and induce focal thermolysis of sebaceous glands. Pilot human clinical studies confirmed the efficacy of ultrasonically-delivered silica-gold nanoshells in inducing photothermal disruption of sebaceous glands without damaging collateral skin.

Investigation of thermal distribution for pulsed laser radiation in cancer treatment with nanoparticle-mediated hyperthermia.

In this paper, we have simulated the efficacy of gold/gold sulfide (GGS) nanoshells in NIR laser hyperthermia to achieve effective targeting for tumor photothermal therapy. The problem statement takes into account the heat transfer with the blood perfusion through capillaries, and pulsed laser irradiation during the hyperthermia. Although previous researchers have used short laser pulses (nanosecond and less), in order to prevent heat leakage to the neighbor tissues, we have examined the effect of millisecond pulses, as the extent of the target volume to which hyperthermia is induced is usually larger and also the lasers with this specification are more available. A tumor with surrounding tissue was simulated in COMSOL software (a finite element analysis, solver and simulation software) and also in a phantom made of agarose and intralipid. The tumor was irradiated by 10, 20 and 30 laser pulses with durations of 15, 50 and 200ms and fluences of 20, 40 and 60J/cm(2). Experimental tests performed on a phantom prove the ability of the applied numerical model to capture the temperature distribution in the target tissue. We have shown that our simulation permits prediction of treatment outcome from computation of thermal distribution within the tumor during laser hyperthermia using GGS nanoshells and millisecond pulsed laser irradiation. The advantage of this simulation is its simplicity as well as its accuracy. Although, to develop the model completely for a given organ and application, all the parameters should be estimated based on a real vasculature of the organ, physiological conditions, and expected variation in those physiological conditions for that application in the organ.

Gold nanoparticle-mediated photothermal therapy: current status and future perspective.

Gold nanoparticles (AuNPs) are attractive photothermal agents for cancer therapy because they show efficient local heating upon excitation of surface plasmon oscillations. The strong absorption, efficient heat conversion, high photostability, inherent low toxicity and well-defined surface chemistry of AuNPs contribute to the growing interest in their photothermal therapy (PTT) applications. The facile tunability of gold nanostructures enables engineering of AuNPs for superior near-infrared photothermal efficacy and target selectivity, which guarantee efficient and deep tissue-penetrating PTT with mitigated concerns regarding side effects by nonspecific distributions. This article discusses the current research findings with representative near-infrared-active AuNPs, which include nanoshell, nanorod, nanocage, nanostar, nanopopcorn and nanoparticle assembly systems. AuNPs successfully demonstrate potential for use in PTT, but several hurdles to clinical applications remain, including long-term toxicity and a need for sophisticated control over biodistribution and clearance. Future research directions are discussed, especially regarding the clinical translation of AuNP photosensitizers.

Cancer theranostics with gold nanoshells.

Gold nanoshells (AuNSs) present a vivid example of integrating nanoscience in order to solve a biomedical problem. AuNSs exhibit tunable surface plasmon resonance, which can be tuned to the near-infrared region in order to realize optimal tissue penetration. The highly efficient light-to-heat transformation by AuNSs during laser irradiation causes thermal damage to the tumor without damaging healthy organs. Transient nanobubbles can form around AuNSs during laser treatment and induce mechanical stress specifically in tumor cells. AuNSs also serve as a versatile platform for the delivery of various diagnostic and therapeutic agents. In this article, we describe the physicochemical properties of AuNSs in the context of their design, preparation and application in cancer theranostics. Ultimately, we look beyond the current research on AuNSs and discussed future challenges to their successful translation into clinical use.

Doxorubicin-loaded magnetic gold nanoshells for a combination therapy of hyperthermia and drug delivery.

In the present work, nanohybrid of an anticancer drug, doxorubicin (Dox) loaded gold-coated superparamagnetic iron oxide nanoparticles (SPIONs@Au) were prepared for a combination therapy of cancer by means of both hyperthermia and drug delivery. The Dox molecules were conjugated to SPIONs@Au nanoparticles with the help of cysteamine (Cyst) as a non-covalent space linker and the Dox loading efficiency was investigated to be as high as 0.32 mg/mg. Thus synthesized particles were characterized by HRTEM, UV-Vis, FT-IR, SQUID magnetic studies and further tested for heat and drug release at low frequency oscillatory magnetic fields. The hyperthermia studies investigated to be strongly influenced by the applied frequency and the solvents used. The Dox delivery studies indicated that the drug release efficacy is strongly improved by maintaining the acidic pH conditions and the oscillatory magnetic fields, i.e. an enhancement in the Dox release was observed from the oscillation of particles due to the applied frequency, and is not effected by heating of the solution. Finally, the in vitro cell viability and proliferation studies were conducted using two different immortalized cell lines containing a cancerous (MCF-7 breast cancer) and non-cancerous H9c2 cardiac cell type.

Combined concurrent photodynamic and gold nanoshell loaded macrophage-mediated photothermal therapies: an in vitro study on squamous cell head and neck carcinoma.

BACKGROUND AND OBJECTIVE: Treatment modalities, such as hyperthermia and photodynamic therapy (PDT) have been used in the treatment of a variety of head and neck squamous cell carcinoma (HNSCC), either alone or as an adjuvant therapy. Macrophages loaded with gold nanoshells, which convert near-infrared light to heat, can be used as transport vectors for photothermal hyperthermia of tumors. The purpose of this study was to investigate the effects of combined macrophage mediated photothermal therapy (PTT) and PDT on HNSCC cells. STUDY DESIGN/MATERIALS AND METHODS: Gold nanoshell loaded rat macrophages either alone or combined with human FaDu squamous cells in hybrid monolayers were subjected to PTT, PDT, or a simultaneous combination of the two light treatments. Therapies were given concurrently employing two laser light sources of λ = 670 nm (PDT) and λ = 810 nm (PTT), respectively. RESULTS: Significant uptake of gold nanospheres (AuNS) by rat alveolar macrophages was observed thus providing the rationale for their use as delivery vectors. Viability of the AuNS-loaded Ma was reduced to 35 and 12% of control values at an irradiance of 14 or 28 W/cm(2) administered over a 5 minute period respectively. No significant cytotoxicity was observed for empty Ma for similar PTT exposure. AlPcS2a mediated PDT at a fluence level of 0.25 J/cm(2) and PTT at 14 W/cm(2) irradiance had little effect on cell viability for the FaDu/Ma (ratio 2:1) hybrid monolayers. In contrast, combined treatment reduced the cell viability to less than 40% at these same laser power settings. CONCLUSIONS: The results of this study provide proof of concept for the use of macrophages as a delivery vector of AuNS for photothermal enhancement of the effects of PDT on squamous cell carcinoma. A significant synergy was demonstrated with combined PDT and PTT compared to each modality applied separately.