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. 2014 Nov 5:9:5093-102.
doi: 10.2147/IJN.S60648. eCollection 2014.

A histological evaluation and in vivo assessment of intratumoral near infrared photothermal nanotherapy-induced tumor regression

Hadiyah N Green  1 , Stephanie D Crockett  2 , Dmitry V Martyshkin  3 , Karan P Singh  4 , William E Grizzle  5 , Eben L Rosenthal  6 , Sergey B Mirov  3
Affiliations

A histological evaluation and in vivo assessment of intratumoral near infrared photothermal nanotherapy-induced tumor regression

Hadiyah N Green et al. Int J Nanomedicine. .

Abstract

Purpose: Nanoparticle (NP)-enabled near infrared (NIR) photothermal therapy has realized limited success in in vivo studies as a potential localized cancer therapy. This is primarily due to a lack of successful methods that can prevent NP uptake by the reticuloendothelial system, especially the liver and kidney, and deliver sufficient quantities of intravenously injected NPs to the tumor site. Histological evaluation of photothermal therapy-induced tumor regression is also neglected in the current literature. This report demonstrates and histologically evaluates the in vivo potential of NIR photothermal therapy by circumventing the challenges of intravenous NP delivery and tumor targeting found in other photothermal therapy studies.

Methods: Subcutaneous Cal 27 squamous cell carcinoma xenografts received photothermal nanotherapy treatments, radial injections of polyethylene glycol (PEG)-ylated gold nanorods and one NIR 785 nm laser irradiation for 10 minutes at 9.5 W/cm(2). Tumor response was measured for 10-15 days, gross changes in tumor size were evaluated, and the remaining tumors or scar tissues were excised and histologically analyzed.

Results: The single treatment of intratumoral nanorod injections followed by a 10 minute NIR laser treatment also known as photothermal nanotherapy, resulted in ~100% tumor regression in ~90% of treated tumors, which was statistically significant in a comparison to the average of all three control groups over time (P<0.01).

Conclusion: Photothermal nanotherapy, or intratumoral nanorod injections followed by NIR laser irradiation of tumors and tumor margins, demonstrate the potential of NIR photothermal therapy as a viable localized treatment approach for primary and early stage tumors, and prevents NP uptake by the reticuloendothelial system.

Keywords: PEGylation; cancer treatment; gold nanorods; intratumoral; laser therapy; malignancy; nanoparticles; photothermal cancer therapy.

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Figures

Figure 1
Figure 1
Schematic representation of treatment platform. Notes: (A) PEGylated AuNRs, transmission electron microscope images, and 785 nm peak absorption spectra shown, were used in multiple radial intratumoral injections, followed by (B), a single 10 minute near infrared laser irradiation of tumor resulting in (C), tumor discoloration and eventual tumor regression. Abbreviations: PEG, polyethylene glycol; AuNRs, gold nanorods.
Figure 2
Figure 2
An in vitro (A–C) and in vivo (D) summary comparing the nanorod and laser combination treatment to the three controls: the no-treatment, laser-only, and nanorod-only groups. Notes: A cell viability assay using trypan blue staining (which causes dead cells to turn dark blue) for cells treated (A) with no nanorods, with (inside oval) and without (outside oval) laser irradiation and (B) with nanorods, with (inside oval) and without (outside oval) laser irradiation. The oval shape indicates laser contact area with the tumor. (C) An in vitro summary of the percentages of cell death due to each treatment. (D) An in vivo summary of the average changes in tumor volume over 10 days. Cell counts expressed as the mean value of triplicate observations. *Indicates a statistically significant difference between the combination treatment and the average of the other three control groups. The error bars are resolved from standard deviation calculations (± standard deviation).
Figure 3
Figure 3
Histology of representative tumors excised after 10 days of treatment. Notes: Comparing all four treatment groups: (A) no treatment presenting viable tumor, (B) laser-only treatment showing viable tumor, (C) nanorod-only treated tissue consisting of mostly viable tumor, and (D) combination nanorod and laser treatment with no definitely identifiable tumor, only reparative changes including fibrosis and inflammatory cells. Silver intensification demonstrated gold particles were present in the areas of damage (black arrows). Images on the right are insets of images on the left.
Figure 4
Figure 4
Photographic monitoring of tumor regression over 15 days in response to photothermal therapy, intratumoral injections of PEGylated AuNRs and a single 10-minute NIR laser irradiation. Notes: (A) Day 1 before treatment; (B) day 1 after treatment; (C) day 2, (D) day 3, (E) day 4, (F) day 5, (G) day 6, (H) day 7, (I) day 8, (J) day 9, (K) day 10, (L) day 11, (M) day 13, and (N) day 15. The width of all cropped pictures is 19.05 mm (0.75 in). Abbreviations: PEG, polyethylene glycol; in, inches; AuNRs, gold nanorods.
Figure 5
Figure 5
Histology of tumors excised at different time points after photothermal nanotherapy, treatment with directly injected PEGylated AuNRs and laser irradiation. Notes: (A) Day 2, (B) day 7, and (C) day 15. Black arrows indicate nanorods before and after uptake by a macrophage containing a pigment, probably hemosiderin stain. Images on the right (magnification 25×) are insets of images on the left (magnification 400×). Abbreviations: PEG, polyethylene glycol; AuNRs, gold nanorods.
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