Plasmonic photothermal photodynamic therapy in mice with colorectal cancer

To assess the effectiveness of plasmonic photothermal therapy (PPT) multiple intravenous strategy of gold nanorods (GNRs) administration was used before laser exposure. The model of alveolar liver cancer PC-1 was used in male outbred albino rats, which were intravenously administrated by single and multiple injections of GNRs and then were treated by PPT. The gold dosage was 400 μg (single injection group), 800 μg (double injection group), 1200 μg (triple injection group), and absorption maximum of gold nanorods suspension was at the wavelength of 808 nm. 24 hours after last injection the tumors were irradiated by the 808-nm diode laser during 15 min at power density 2.3 W/cm2. Temperature control of the tumor heating was provided by IR imager. 24 hours after the PPT the half of animals from each group was withdrawn from the experiments and the sampling tumor tissue for morphological study was performed. In survived animals the growth of tumors was evaluated during 21 days after the PPT. The antitumor effects of PPT after triple intravenous injection were comparable with those obtained at direct intratumoral administration of similar total dose of GNRs. The effectiveness of PPT depended on gold accumulation in tumor, probably, due to sufficient vascularization of tumor tissue.

The goal of our research was to assess the vascularization degree of tumor to predict the efficiency of plasmonic photothermal therapy (PPT) and photodynamic therapy (PDT) in tumor-bearing rats. Before any treatment, 3D Doppler ultrasound imaging was used for assessment of the vascularization degree of transplanted rat cholangiocarcinoma. For PPT, the gold nanorods with aspect ratio of 4:1, functionalized with thiolated polyethylene glycol, were used. After multiple fractional intravenous (IV) injections in rats with cholangiocarcinoma, the tumours were irradiated through the skin by an 808-nm NIR diode laser at a power density of 2.3 W/cm2 for 15 min. For PDT, galactose – Luphthalocyanine, as a photosensitizer, was applied by intratumoural injection, in a dose of 2 mg/kg. Then, tumors were irradiated through the skin by 670 nm-diode laser source with power density 200 mW/cm2 applied for 1000 sec in three non-overlapping zones covering whole tumour surface to obtain a total irradiation dose of 200 J/cm2 for each lesion. The withdrawal of the animals from the experiment and sampling of tissues for morphological study were performed before and 72 hrs after PPT and PDT. The vascular microdensity in tumors was assessed on histological sections as vessel counts or vessel area per unit of assessed tumor area. It was shown that efficiency of PPT and PDT therapy was mostly due to the sufficient accumulation of photothermosensitizers in the tumor, therefore preliminary assessment of tumor vascularization degree was necessary before starting a therapy.

Plasmonic photothermal and photodynamic therapy (PPTT and PDT, respectively) are two cancer treatments that have the potential to be combined in a synergistic scheme. The aim of this study is to optimize the PPTT treatment part, in order to account for the PDT lack of coverage in the hypoxic tumor volume and in cancer areas laying in deep sites. For the needs of this study, a mouse was modeled, subjected to PDT and its necrotic area was estimated by using the MATLAB software. The same procedure was repeated for PPTT, using COMSOL Multiphysics. PPTT treatment parameters, namely laser power and irradiation time, were optimized in order to achieve the optimum therapeutic effect of the combined scheme. The PDT alone resulted in 54.8% tumor necrosis, covering the upper cancer layers. When the PPTT was also applied, the total necrosis percentage raised up to 99.3%, while all of the surrounding studied organs (skin, heart, lungs and trachea, ribs, liver and spleen) were spared. The optimized values of the PPTT parameters were 550 mW of laser power and 70 s of irradiation time. Hence, the PPTT–PDT combination shows great potential in achieving high levels of tumor necrosis while sparing the healthy tissues.

Cancer remains one of the leading causes of death in the world. For a number of neoplasms, the efficiency of conventional chemo- and radiation therapies is insufficient because of drug resistance and marked toxicity. Plasmonic photothermal therapy (PPT) using local hyperthermia induced by gold nanoparticles (AuNPs) has recently been extensively explored in tumor treatment. However, despite attractive promises, the current PPT status is limited by laboratory experiments, academic papers, and only a few preclinical studies. Unfortunately, most nanoformulations still share a similar fate: great laboratory promises and fair preclinical trials. This review discusses the current challenges and prospects of plasmonic nanomedicine based on PPT and photodynamic therapy (PDT). We start with consideration of the fundamental principles underlying plasmonic properties of AuNPs to tune their plasmon resonance for the desired NIR-I, NIR-2, and SWIR optical windows. The basic principles for simulation of optical cross-sections and plasmonic heating under CW and pulsed irradiation are discussed. Then, we consider the state-of-the-art methods for wet chemical synthesis of the most popular PPPT AuNPs such as silica/gold nanoshells, Au nanostars, nanorods, and nanocages. The photothermal efficiencies of these nanoparticles are compared, and their applications to current nanomedicine are shortly discussed. In a separate section, we discuss the fabrication of gold and other nanoparticles by the pulsed laser ablation in liquid method. The second part of the review is devoted to our recent experimental results on laser-activated interaction of AuNPs with tumor and healthy tissues and current achievements of other research groups in this application area. The unresolved issues of PPT are the significant accumulation of AuNPs in the organs of the mononuclear phagocyte system, causing potential toxic effects of nanoparticles, and the possibility of tumor recurrence due to the presence of survived tumor cells. The prospective ways of solving these problems are discussed, including developing combined antitumor therapy based on combined PPT and PDT. In the conclusion section, we summarize the most urgent needs of current PPT-based nanomedicine.

Experimental investigation of photothermal conversion and thermal conductivity of broadband absorbing gold nanoblackbodies and graphene oxide nanoparticles for plasmonic photothermal cancer therapy

Plasmonic photo-thermal therapy (PPTT)

Recent developments in nanomaterials with programmable optical responses and their capacity to modulate the photothermal effect induced by an extrinsic source of light have elevated plasmonic photothermal therapy (PPTT) to the status of a favored treatment for a variety of malignancies. However, the low penetration depth of near-infrared-I (NIR-I) lights and the need to expose the human body to a high laser power density in PPTT have restricted its clinical translation for cancer therapy. Most nanostructures reported to date exhibit limited performance due to (i) activity only in the NIR-I region, (ii) the use of intense laser, (iii) need of large concentration of nanomaterials, or (iv) prolonged exposure times to achieve the optimal hyperthermia state for cancer phototherapy. To overcome these shortcomings in plasmonic nanomaterials, we report a bimetallic palladium nanocapsule (Pd Ncap)─with a solid gold bead as its core and a thin, perforated palladium shell─with extinction both in the NIR-I as well as the NIR-II region for PPTT applications toward cancer therapy. The Pd Ncap demonstrated exceptional photothermal stability with a photothermal conversion efficiency of ∼49% at the NIR-II (1064 nm) wavelength region at a very low laser power density of 0.5 W/cm2. The nanocapsules were further surface-functionalized with Herceptin (Pd Ncap-Her) to target the breast cancer cell line SK-BR-3 and exploited for in vitro PPTT applications using NIR-II light. Pd Ncap-Her caused more than 98% cell death at a concentration of just 50 μg/mL and a laser power density of 0.5 W/cm2 with an output power of only 100 mW. Flow cytometric and microscopic analyses revealed that Pd Ncap-Her-induced apoptosis in the treated cancer cells during PPTT. Additionally, Pd Ncaps were found to have reactive oxygen species (ROS) scavenging ability, which can potentially reduce the damage to cells or tissues from ROS produced during PPTT. Also, Pd Ncap demonstrated excellent in vivo biocompatibility and was highly efficient in photothermally ablating tumors in mice. With a high photothermal conversion and killing efficiency at very low nanoparticle concentrations and laser power densities, the current nanostructure can operate as an effective phototherapeutic agent for the treatment of different cancers with ROS-protecting ability.

Plasmonic photothermal therapy increases the tumor mass penetration of HPMA copolymers

In this study, we report the biosynthesis of Silver (Ag), Selenium (Se), Silver Selenium (AgSe) and 5FU AgSe nanoparticles by using Litchi chinensis (Sonn) seed extracts and cytotoxicity response of respective nanoparticles in combination with Plasmonic Photo Thermal Therapy (PTT). Biogenic nanoparticles formation was characterized by UV-visible spectrophotometry, scanning electron microscopy with energy dispersive X-ray spectroscopy and thermogravimetric analysis. The cytotoxic effect of biogenic nanoparticles with and without photothermal effects was studied by CCK8 antineoplastic assay. The apoptotic inducing ability of the biogenic nanoparticles and/or PTT was investigated by Propidium Iodide (PI) staining, Bax/Bcl-2 gene expression analysis using RT-PCR and western blotting. The mean particle size of biosynthesized nanoparticles was found 18–78 nm with polydispersity. TGA demonstrated that lychee seed extracts existed on the surface of biogenic nanoparticles. These results clearly indicate the successful formation of biogenic NPs for cellular uptake. Mitochondrial damage and intracellular ROS production were observed upon treatment with biogenic nanoparticles and PTT (1.0 W cm−1) showed significant cell death, expression of Bax and suppression of Bcl-2. Significantly, biosynthesized nanoparticles showed a broad-spectrum anticancer activity with PTT therapy and therefore represent promoting ROS generation by modulating mitochondrial apoptosis induction in PANC-1 cancer cells.

The present study aimed to investigate the effects of photothermal therapy with gold nanorods (AuNRs) or epidermal growth factor receptor monoclonal antibody‑conjugated AuNRs (EGFRmAb‑AuNRs) on hypopharyngeal carcinoma(HC) in nude mice. In addition, the associated signaling pathways were explored. Briefly, a subcutaneous transplantable hypopharyngeal tumor model was established in nude mice injected with FaDu human HC cells. A total of 70nude mice were randomly divided into seven groups, each of which received a different treatment. Mice were treated with AuNRs, locally or through intravenous injection, whereas EGFRmAb or EGFRmAb‑AuNRs were only administered locally. Near infrared spectroscopy (NIR) was also applied for plasmonic photothermal therapy (PPTT). The growth curve and the inhibitoryratefor tumor growth were used to evaluate the effects of each treatment. Flow cytometry and the terminal‑deoxynucleotidyl transferase dUTP nick end labeling assay were adopted to detect apoptosis of cells in thetransplantedtumors. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to determine the mRNA and protein expression levels of target genes, respectively. Local treatment with AuNRs+NIR or EGFRmAb significantly inhibited tumor growth, and EGFRmAb conjugation further increased the inhibitory effects. Furthermore, there was a significant increase in apoptosis of tumor cells in the AuNRs+NIR, EGFRmAb and EGFRmAb‑AuNRs+NIR groups; treatment with EGFRmAb‑AuNRs+NIR induced the highest apoptotic effect. Mechanistic studies indicated that EGFRmAb‑AuNRs+NIR may inhibit tumors through the AKT serine/threonine kinase (Akt) and DNA damage signaling pathways. In the AKT pathway, the mRNA and protein expression levels of phosphatase and tensin homolog were increased, whereas the expression levels of Akt and glycogen synthase kinase 3β were decreased. In the DNA damage signaling pathway, the mRNA and protein expression levels of ATR serine/threonine kinase, checkpoint kinase 1 and p53 were enhanced, whereas phosphorylated‑p53 protein expression was reduced. The present findings indicated that AuNRs+NIR inhibited HC tumor growth, and conjugating EGFRmAb to AuNRs further enhanced the inhibitory effects. EGFRmAb conjugation may increase the antitumor effects of AuNRs‑induced PPTT by downregulating the phosphatidylinositol‑3‑kinase/Akt pathway and upregulating the DNA damage pathway. These findings may provide novel insights into tumor‑targeting PPTT invivo.

The heating degree of the inner layers of tumor tissue is an important parameter required to optimize plasmonic photothermal therapy (PPT). This study reports the optical properties of tissue layers of transplanted cholangiocarcinoma and covering tissues in rats without treatment (control group) and after PPT using gold nanorods (experimental group). PPT was carried out for 15 min, and the temperature on the skin surface reached 54.8 ± 1.6 °C. The following samples were cut out ex vivo and studied: skin, subcutaneous connective tissue, tumor capsule, top, center, and bottom part of the tumor. The samples’ absorption and reduced scattering coefficients were calculated using the inverse adding–doubling method at 350–2250 nm wavelength. Diffuse reflectance spectra of skin surface above tumors were measured in vivo in the control and experimental groups before and immediately after PPT in the wavelength range of 350–2150 nm. Our results indicate significant differences between the optical properties of the tissues before and after PPT. The differences are attributed to edema and hemorrhage in the surface layers, tissue dehydration of the deep tumor layers, and morphological changes during the heating.

The analysis of recent studies on plasmonic photothermal therapy (PPT) after intravenous administration of gold nanorods (GNRs) has demonstrated that the effectiveness of nanoparticle-assisted laser hyperthermia depends on a correct dosage strategy of nanoparticle administration. Accumulation of GNRs in tumor tissue dramatically increases the local heating of the tumor without damage to healthy tissues. However, the optimal doses of GNR intravenous injections (IVIs) for effective accumulation in tumors, and optimal protocols of PPT are not designed yet. The current study aims to improve the efficacy of PPT in tumor-bearing rats using multiple fractional intravenous administration of GNRs. For PPT experiments, the GNRs with aspect ratio of 4.1 were functionalized with thiolated polyethylene glycol (PEG) and their suspensions were used for multiple fractional intravenous administration in outbred albino male rats with experimental model of rat liver cancer (cholangiocarcinoma line PC-1). Doppler ultrasonography was performed to characterize the vascularity of transplanted rat tumors before any treatment. After a final injection of GNRs, tumor was irradiated during 15 minutes by 808-nm NIR diode laser at a power density 2.3 W/cm2 . The animals were withdrawn from the experiment and sampling of tissues for morphological study and gold accumulation was performed 24 hours and 3 weeks after PPT. The multiple IVIs of gold nanorods and further PPT of transplanted cholangiocarcinoma provided significant damage to tumor tissue resulting in pronounced necrotic mass and retardation of the tumor growth. More importantly, the proposed PPT protocol had low toxicity as evidenced by histological examination of internal organs. The efficiency of PPT depends on the presence of newly formed vasculature as revealed by the Doppler ultrasound investigation. The repeatable IVIs promote greater of GNR accumulation within the tumor thus resulting in higher PPT efficacy. Accompanying ultrasonography can be useful for prognosis and monitoring of treatment. Lasers Surg. Med. 50:1025-1033, 2018. © 2018 Wiley Periodicals, Inc.

Feline mammary carcinoma (FMC) shows great similarities to human breast cancer in the cellular and molecular levels. So, in cats as in humans, the role of immune responses is indicated to detect and follow up the development of tumors. As a new breast cancer therapeutic approach, Plasmonic Photothermal Therapy (PPTT) is an effective localized treatment for canine and feline mammary-carcinoma. Its systemic effect has not been inquired yet and needs many studies to hypothesis how the PPTT eradicates tumor cells. In this study, it is the first time to detect (P53, PCNA, MUC-1, and C-MYC) feline autoantibodies (AAbs), study the relationship between PCNA AAbs and mammary-tumors, and investigate the effect of PPTT on the humoral immune response of cats with mammary-carcinoma through detection of AAbs level before, during, and after the treatment. The four-AAbs panel was evaluated in serum of normal and clinically diagnosed cats with mammary tumors using Enzyme-Linked Immunosorbent Assay. The panel showed 100% specificity and 93.7% sensitivity to mammary tumors. The panel was evaluated in PPTT monotherapy, mastectomy monotherapy, and combination therapy. PPTT monotherapy decreased AAbs level significantly while mastectomy monotherapy and combination therapy had a nonsignificant effect on AAbs level.

For localized tumors, gold nanorod (AuNR)-assisted plasmonic photothermal therapy (PPTT) is a potentially effective alternative to traditional surgery, in which AuNRs absorb near-infrared light and convert it to heat in order to kill cancer cells. However, for large tumors (volume ≥ 20 cm3), an uneven distribution of AuNRs might cause inhomogeneity of the heat distribution inside the tumor. Surgery is frequently recommended for removing large tumors, but it is associated with a high risk of cancer recurrence and metastasis. Here, we applied PPTT before surgery, which showed improved treatment for large tumors. We divided the animals (eight cats/dogs) into two groups: Group I (control), where three cases were solely treated with surgery, laser, or AuNRs alone, resulting in recurrence and metastasis; and Group II, where animals were treated with PPTT before surgery. In Group II, four out of the five cases had tumor regression without any recurrence or metastasis. Interestingly, we observed that applying PPTT before surgery displayed reduced bleeding during tumor removal, supported by histopathology that showed altered blood vessels. In conclusion, our study showed that applying AuNR-assisted PPTT (AuNRs-PPTT) before surgery could significantly affect blood vessels inside the tumor, leading to a decreased amount of bleeding during surgery, which can potentially decrease the risk of metastasis and blood loss during surgery.

Utilizing gold nanoparticles in plasmonic photothermal therapy for cancer treatment.