Tumor uptake of hollow gold nanospheres after intravenous and intra-arterial injection: PET/CT study in a rabbit VX2 liver cancer model

Abstract

Purpose: This study was designed to investigate the intratumoral uptake of hollow gold nanospheres (HAuNS) after hepatic intra-arterial (IA) and intravenous (IV) injection in a liver tumor model.

Materials and methods: Fifteen VX2 tumor-bearing rabbits were randomized into five groups (n = 3 in each group) that received either IV (64)Cu-labeled PEG-HAuNS (IV-PEG-HAuNS), IA (64)Cu-labeled PEG-HAuNS (IA-PEG-HAuNS), IV cyclic peptide (RGD)-conjugated (64)Cu-labeled PEG-HAuNS (IV-RGD-PEG-HAuNS), IA RGD-conjugated (64)Cu-labeled PEG-HAuNS (IA-RGD-PEG-HAuNS), or IA (64)Cu-labeled PEG-HAuNS with lipiodol (IA-PEG-HAuNS-lipiodol). The animals underwent PET/CT 1 h after injection, and uptake expressed as percentage of injected dose per gram of tissue (%ID/g) was measured in tumor and major organs. The animals were euthanized 24 h after injection, and tissues were evaluated for radioactivity.

Results: At 1 h after injection, animals in the IA-PEG-HAuNS-lipiodol group showed significantly higher tumor uptake (P < 0.001) and higher ratios of tumor-to-normal liver uptake (P < 0.001) than those in all other groups. The biodistribution of radioactivity 24 h after injection showed that IA delivery of PEG-HAuNS with lipiodol resulted in the highest tumor uptake (0.33 %ID/g; P < 0.001) and tumor-to-normal liver ratio (P < 0.001) among all delivery methods. At 24 h, the IA-RGD-PEG-HAuNS group showed higher tumor uptake than the IA-PEG-HAuNS group (0.20 vs. 0.099 %ID/g; P < 0.001).

Conclusion: Adding iodized oil to IA-PEG-HAuNS maximizes nanoparticle delivery to hepatic tumors and therefore may be useful in targeted chemotherapy and photoablative therapy. PET/CT can be used to noninvasively monitor the biodistribution of radiolabeled HAuNS after IV or IA injection.

Figure 1

(A) Scheme for synthesis of SATA-PEG₅₀₀₀-RGD. Reagents and conditions: (a) Pd⁰[P(C₆H₅)₃]₄ (3 eq), CHCl₃/AcOH/NMM (37/2/1, v/v/v); (b) 20% piperidine in DMF; (c) PyBOP/HOBt/DIPEA (3/3/6 eq) in DMF; (d) TFA/DCM/TES (1/97/2, v/v/v). (B) Structure of 1,4,7,10-tetraazacyclododecane-1,4,7-tris(acetic acid)-10-[acetic acid-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-lipoic acid mono amide] (DOTA-LA). (C) Transmission electron microscopy image of RGD-PEG-HAuNS. Bar, 20 nm.

Figure 2

Representative whole-body PET/CT images of rabbits bearing hepatic VX2 tumors at 1 hour after injection of each ⁶⁴Cu-labeled PEG-HAuNS.

Figure 3

Representative axial PET/CT images of rabbits bearing hepatic VX2 tumors at 1 hour after injection of ⁶⁴Cu-labeled PEG-HAuNS in different groups.

Figure 4

(A) In vivo biodistribution in rabbits bearing hepatic VX2 tumors at 1 hour after injection of each ⁶⁴Cu-labeled PEG-HAuNS. (B–E) Time-activity curves of heart (B), muscle (C), normal liver (D), and tumor (E) from hepatic VX2 tumor-bearing rabbits over a 60-minute period after intravenous injection. The data are presented as mean ± SD.

Figure 4

(A) In vivo biodistribution in rabbits bearing hepatic VX2 tumors at 1 hour after injection of each ⁶⁴Cu-labeled PEG-HAuNS. (B–E) Time-activity curves of heart (B), muscle (C), normal liver (D), and tumor (E) from hepatic VX2 tumor-bearing rabbits over a 60-minute period after intravenous injection. The data are presented as mean ± SD.

Figure 5

(A) Biodistribution analysis of selected tissues from rabbits injected with ⁶⁴Cu-labeled PEG-HAuNS and sacrificed at 24 hours after IA or IV injection. Data are presented as mean ± SD of %ID/g. (B) Tumor-to-liver uptake ratio of the %ID/g values 24 hours after IV or IA injection of PEG-HAuNS. Data are expressed as mean ± SD.

Figure 5

(A) Biodistribution analysis of selected tissues from rabbits injected with ⁶⁴Cu-labeled PEG-HAuNS and sacrificed at 24 hours after IA or IV injection. Data are presented as mean ± SD of %ID/g. (B) Tumor-to-liver uptake ratio of the %ID/g values 24 hours after IV or IA injection of PEG-HAuNS. Data are expressed as mean ± SD.

Figure 6

Representative images of intratumoral distribution of ⁶⁴Cu-labeled PEG-HAuNS 24 hours after IV or IA injection. Cell nuclei were stained with 4′,6-diamidino-2-phenylindole (DAPI, blue). The scattering signal of PEG-HAuNS (green pseudocolor) was observed under a dark-field condenser. Tumor vessels were immunostained with mouse anti-human CD31 monoclonal antibody (red). Bar, 20 μm.