Photothermal and Photodynamic Therapy of Tumors with Plasmonic Nanoparticles: Challenges and Prospects

Abstract

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.

Keywords: gold nanoparticles; oncology; photodynamic therapy; plasmonic photothermal therapy.

Scheme 1

Two-dimension mapping of the power-density $Q_V=q$ distribution in Au spheres under plasmon resonance excitation in the air (~510 nm). The sphere radii are 12 nm (A) and 32 nm (B), the incident intensity is 1 W/cm². The calculations were made by S. Zarkov (IBPPM RAS and IPMC RAS).

Figure 1

Typical TEM images and dimensions of silica(core)/Au nanoshells (AuNSHs), Au nanostars (AuNSTs), Au-Ag nanocages (AuNCGs), and Au nanorods (AuNRs). The PR wavelength varies across the Vis-NIR region from 600 to 1200 nm through the variation of the structure and shape of particles. The images were provided by Lab of Nanobiotechnology, IBPPM RAS.

Figure 2

(A) Scheme for the synthesis of AuNSHs with a silica core. (B) The extinction cross-sections of AuNSHs as predicted by Mie theory for silica core 100 nm. The Au shell thickness has the normal distribution with the average values 5, 7, 10, 15, and 20 nm and the normalized standard deviation of 0.1. The size correction for Au dielectric function in the shell was included in the calculations.

Figure 3

TEM images of AuNSTs fabricated with 3 nm (A), 15 nm (B), and 35 nm (B) seeds and the corresponding extinction spectra (D). The scale bars are 100 (A) and 200 nm (B,C). The insets show enlarged images with scale bars 20 (A), 50 (B), and 100 nm (C).

Figure 4

Two-step scheme for the synthesis of AuNCGs. The first step results in the formation of approximately 50 nm silver nanocubes with a characteristic plasmon resonance of about 450 nm. The second step gives the appearance of porous nanoparticles owing to the galvanic replacement process. The examples of TEM images of Ag nanocubes, changes in the colloid color, and extinction spectra in the process of synthesis are illustrated by the insets.

Figure 5

Overview (A) and enlarged ((B) and inset in (A)) TEM images of AuNCGs and the particle-size distribution (C). Various hollow and porous particles with a typical wall thickness of 4–5 nm are seen in the panel (B). During the galvanic replacement process, the plasmonic peaks progressively move from 420 nm to 800 nm (extinction and differential light scattering spectra in panels (D) and (E), respectively).

Figure 6

(A) Length-diameter distributions for the NR-830 sample, containing a major fraction of rods (97% from TEM images) and 3% of impurity particles. (B) The aspect ratio distributions for the rods (1) and impurities (2). (C) TEM image, the scale bar is 100 nm. (D) Experimental (circles) and T-matrix simulated spectra for the polydisperse ensemble of AuNRs (for details, the readers are referred to Ref. [80]).

Figure 7

TEM image of AuNRs with PR wavelength of 920 nm. (A). Panels (B,D) show experimental and simulated extinction spectra of 9 samples during the etching process. Panel (C) displays a linear dependence between PR wavelength and TEM-derived average aspect ratio. Data for independent runs are sown together with STD errors. The line shows the T-matrix dependence calculated for polydisperse TEM ensembles (for details, see Ref. [89]).

Figure 8

(A). Scheme of thermographic measurements with a diode laser at 810 nm and the particle suspensions placed in an Eppendorf tube. (B) The temperature distribution was recorded by a thermal infrared camera IRSYS 4010. (C) The kinetics of suspension heating for the three nanoparticle types. (D) The time dependences of heat production per weight unit of the metal normalized to the maximal value for the AuNCGs.

Figure 9

TEM images of Au nanoparticles prepared by femtosecond laser ablation in 0.1 mM (A), 1 mM (B), and 10 mM (C) β-CD. The average sizes are 10 ± 6.7 (A), 5.5 ± 3.7 (B), and 2.5 ± 1.5 nm (C). Copyright 2021 by American Chemical Society. Reprinted with permission from Ref. [128]. Panel (D) shows 10 nm particles synthesized by the method [129]. The scale bars are 10 nm (A–C), and 50 nm (D).

Figure 10

TEM images of AuNPs obtained after the first ((A), 55 ± 34 nm) and second ((B), 21 ± 6 nm) steps of ablation. Adapted from Ref. [131]. For comparison, panel (C) shows monodisperse spherical AuNPs (22.9 ± 0.4 nm) obtained by the method [129]. The scale bars are 50 nm.

Figure 11

TEM image of chain-like elongated particles obtained after laser ablation in water (A). Adapted from Ref. [146]. For comparison, an ideally cigar-like shape of Au nanorods (Lab of Nanobiotechnology, IBPPM RAS) is demonstrated in panel (B).

Figure 12

Antitumor activity of AuNRs coupled with laser-induced photo plasmonic thermal therapy in EACC solid tumor-bearing mice. EACC tumor-bearing mice were given gold NRs (1.5 mg/kg every three weeks) by I.V. (▲) and I.T. (■) administration compared to PBS-treated animals (●). Animals were exposed to a laser plasmonic beam (50 W/cm² for 2 min) every week. Tumor size was measured every three days and plotted (A). Representative tumors are shown in panel (B). Data are presented as mean ± SEM (n = 10) Reprinted by CC BY license from Ref. [185].

Figure 13

Cholangiocarcinoma PC-1–without any treatment (a), after only laser irradiation (b), after single IV administration of AuNRs and PPT (c), after double IV administration of AuNRs and PPT (d), after triple IV administration of AuNRs and PPT (e), and after intratumoral administration of AuNRs and PPT (f). H&E staining, magnification ×246.6. Copyright 2021 by Springer Nature. Reprinted with permission from Ref. [187].

Figure 14

US Doppler imaging of rat tumors. (A) B-mode scanning; (B) 3D ultrasound mode. The lumen of the vessel is uniformly filled with color. (C) Three-dimensional (3D) power Doppler sonography in tumor-bearing rats. (D) Histogram analysis of vascularization indices. Copyright 2021 by John Wiley and Sons. Reprinted with permission from Ref. [188].

Figure 15

H&E-stained tumor slices after different treatments: (A) Laser 808 nm 2.3 W/cm² treated only; (B) NCs injected and 633 nm 160 mW/cm² treated; (C) NCs injected and 808 nm 2.3 W/cm² treated; (D) NCs injected and simultaneously irradiated with two lasers. Tumor tissue specimens were obtained three days after treatment. Copyright 2021 by Springer Nature. Reprinted with permission from Ref. [212].