Photothermal and photodynamic therapy of tumors with plasmonic nanoparticles: challenges and prospects

Cancer remains one of the leading causes of death in the world. For a number of neo-plasms, 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

The morphological changes in transplanted tumors of rats at plasmonic photothermal therapy

The aim of work was to study the morphological changes in transplanted liver tumors of rats after plasmonic photothermal therapy (PPTT). The gold nanorods functionalized with thiolated polyethylene glycol were injected intravenously to rats with transplanted liver cancer PC-1. A day after injection the tumors were irradiated by the infrared 808-nm diode laser. The withdrawal of the animals from the experiment and sampling of tumor tissue for morphological study were performed 24 hours after the laser exposure. The standard histological and immunohistochemical staining with antibodies to proliferation marker Ki-67 and apoptosis marker BAX were used for morphological study of transplanted tumors. The plasmonic photothermal therapy had pronounced damaging effect in rats with transplanted liver tumors expressed in degenerative and necrotic changes in the tumor cells. The decrease of proliferation marker Ki-67 and increase of expression of apoptosis marker BAX were observed in tumor cells after PPTT

The inflammation markers in serum of tumor-bearing rats after plasmonic photothermal therapy

We report on plasmonic photothermal therapy of rats with inoculated cholangiocarcinoma through the intratumoral injection of PEG-coated gold nanorods followed by CW laser light irradiation. The length and diameter of gold nanorods were 41±8 nm and 10±2 nm, respectively; the particle mass-volume concentration was 400 μg/mL, which corresponds to the optical density of 20 at the wavelength 808 nm. The tumor-bearing rats were randomly divided into three groups: (1) without any treatment (control); (2) with only laser irradiation of tumor; (3) with intratumoral administration of gold nanorods and laser irradiation of tumors. An hour before laser irradiation, the animals were injected intratumorally with gold nanorod solutions in the amount of 30% of the tumor volume. The infrared 808-nm laser with power density of 2.3 W/cm2 was used for plasmonic photothermal therapy (PTT). The withdraw of animals from the experiment was performed 24 h after laser exposure. The content of lipid peroxidation products and molecular markers of inflammation (TNF-α, IGF-1, VEGF-C) was determined by ELISA test in serum of rats. The standard histological techniques with hematoxylin and eosin staining were used for morphological examination of tumor tissues. It was revealed that the significant necrotic changes were noted in tumor tissue after plasmonic photothermal therapy, which were accompanied by formation of inflammatory reaction with release of proinflammatory cytokines and lipid peroxidation products into the bloodstream

The effects of prolonged oral administration of gold nanoparticles on the morphology of hematopoietic and lymphoid organs

Currently, the usage of gold nanoparticles as photosensitizers and immunomodulators for plasmonic photothermal therapy has attracted a great attention of researches and end-users. In our work, the influence of prolonged peroral administration of gold nanoparticles (GNPs) with different sizes on the morphological changes of hematopoietic and lymphoid organs was investigated. The 24 white outbred male rats weighing 180-220 g were randomly divided into groups and administered orally for 30 days the suspension of gold nanospheres with diameters of 2, 15 and 50 nm at a dosage of 190 μg/kg of animal body weight. To prevent GNPs aggregation in a tissue and enhance biocompatibility, they were functionalized with thiolated polyethylene glycol. The withdrawal of the animals from the experiment and sampling of spleen, lymph nodes and bone marrow tissues for morphological study were performed a day after the last administration. In the spleen the boundary between the red and white pulp was not clearly differ in all experimental groups, lymphoid follicles were significantly increased in size, containing bright germinative centers represented by large blast cells. The stimulation of lymphocyte and myelocytic series of hematopoiesis was recorded at morphological study of the bone marrow. The number of immunoblasts and large lymphocytes was increased in all structural zones of lymph nodes. The more pronounced changes were found in the group with administration of 15 nm nanoparticles. Thus, the morphological changes of cellular components of hematopoietic organs have size-dependent character and indicate the activation of the migration, proliferation and differentiation of immune cells after prolonged oral administration of GNPs

Investigation of the change of tumor optical properties after laser-induced plasmon-resonant photothermal treatment of transplanted tumors in rats

The paper presents the investigation of change of tumor optical properties of the rat tumor doped by gold nanoparticles after laser-induced plasmon-resonant photothermal treatment. To obtain the model tumors the rats have been implanted by suspension of alveolar kidney cancer cells. An hour before the experiment the animals have been injected by the suspension of gold nanorods intratumorally. For irradiation a diode laser with wavelength 808 nm has been used. After the irradiation the tumor has been removed and sliced. Spectra of total and collimated transmission and diffuse reflectance of the samples of different layers of the tumors have been measured in the wavelength range 350-2500 nm. Absorption, scattering, reduced scattering coefficients and scattering anisotropy factor of tumor tissues have been calculated with inverse adding-doubling method. The results of the experiment have shown that after doping the tumor tissue by the plasmon resonant nanoparticles and NIR laser irradiating, there is the decreases of absorption as well as scattering properties of the tumor and surrounding tissues. However, despite the sufficiently high temperature on the surface (about 80°C), the changes in the center of the tumor are insignificant

Concave Plasmonic Particles: Broad-Band Geometrical Tunability in the Near Infra-Red

Optical resonances spanning the Near and Short Infra-Red spectral regime were exhibited experimentally by arrays of plasmonic nano-particles with concave cross-section. The concavity of the particle was shown to be the key ingredient for enabling the broad band tunability of the resonance frequency, even for particles with dimensional aspect ratios of order unity. The atypical flexibility of setting the resonance wavelength is shown to stem from a unique interplay of local geometry with surface charge distributions

Resonances On-Demand for Plasmonic Nano-Particles

A method for designing plasmonic particles with desired resonance spectra is presented. The method is based on repetitive perturbations of an initial particle shape while calculating the eigenvalues of the various quasistatic resonances. The method is rigorously proved, assuring a solution exists for any required spectral resonance location. Resonances spanning the visible and the near-infrared regimes, as designed by our method, are verified using finite-difference time-domain simulations. A novel family of particles with collocated dipole-quadrupole resonances is designed, demonstrating the unique power of the method. Such on-demand engineering enables strict realization of nano-antennas and metamaterials for various applications requiring specific spectral functions

Improved Cellular Specificity of Plasmonic Nanobubbles versus Nanoparticles in Heterogeneous Cell Systems

The limited specificity of nanoparticle (NP) uptake by target cells associated with a disease is one of the principal challenges of nanomedicine. Using the threshold mechanism of plasmonic nanobubble (PNB) generation and enhanced accumulation and clustering of gold nanoparticles in target cells, we increased the specificity of PNB generation and detection in target versus non-target cells by more than one order of magnitude compared to the specificity of NP uptake by the same cells. This improved cellular specificity of PNBs was demonstrated in six different cell models representing diverse molecular targets such as epidermal growth factor receptor, CD3 receptor, prostate specific membrane antigen and mucin molecule MUC1. Thus PNBs may be a universal method and nano-agent that overcome the problem of non-specific uptake of NPs by non-target cells and improve the specificity of NP-based diagnostics, therapeutics and theranostics at the cell level