Tumor Angiogenesis Targeted Radiosensitization Therapy Using Gold Nanoprobes Guided by MRI/SPECT Imaging

Abstract

Gold nanoparticles (AuNPs) have recently garnered great interest as potential radiosensitizers in tumor therapy. However, major challenges facing their application in this regard are further enhancement of tumor accumulation of the particles in addition to enhanced permeability retention (EPR) effect and an understanding of the optimal particle size and time for applying radiotherapy after the particle administration. In this study, we fabricated novel cyclic c(RGDyC)-peptide-conjugated, Gd- and 99 mTc-labeled AuNPs (RGD@AuNPs-Gd99 mTc) probes with different sizes (29, 51, and 80 nm) and evaluated their potential as radiosensitization therapy both in vitro and in vivo. We found that these probes have a high specificity for αvβ3 integrin positive cells, which resulted in their high cellular uptake and thereby enhanced radiosensitization. Imaging in vivo with MRI and SPECT/CT directly showed that the RGD@AuNPs-Gd99 mTc probes specifically target tumors and exhibit greater accumulation within tumors than the RAD@AuNPs-Gd99 mTc probes. Interestingly, we found that the 80 nm RGD@AuNPs-Gd99 mTc probes exhibit the greatest effects in vitro; however, the 29 nm RGD@AuNPs-Gd99 mTc probes were clearly most efficient in vivo. As a result, radiotherapy of tumors with the 29 nm probe was the most potent. Our study demonstrates that RGD@AuNPs-Gd99 mTc probes are highly useful radiosensitizers capable of guiding and enhancing radiation therapy of tumors.

Feasibility of USPIOs for T1-weighted MR molecular imaging of tumor receptors

“…99m Tc was labeled onto the USPIOs by complexing 99m Tc with DTPA. 33,36 The labeling efficiency, as veried by RTLC, was 95%. The procedure for preparation of the probe was shown in Scheme 1.…”

“…Stability of 99m Tc was expressed as a percentage of radioactivities retained on the particles to the radioactivity of the probes. 33 In addition, RGD peptide-conjugated, technetium (Tc)labeled USPIOs (RGD-Tc-PAA@USPIOs) were also prepared as a "cold" probe using NaTcO 4 as a precursor under the same conditions as those for 99m Tc labeling. At the same time, scramble peptide c(RADyC) (abbreviated RAD) conjugated-, 99m Tc-or Tc-labeled PAA@USPIOs were also prepared as control probes (RAD-99m Tc-PAA@USPIOs, RAD-Tc-PAA@USPIOs).…”

“…Cytotoxicity of the probes was evaluated by the typical 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assays using the cold probe (RGD-Tc-PAA@Fe 3 O 4 ). 33,34 For this purpose, the cells were seeded in a 96-well plate with 1 Â 10 4 cells per well and cultured with the media containing various concentrations of probes (0.15, 0.5 and 1.5 mM in iron) for different period of time. Aer incubation, the culture media were removed and the cells were washed with PBS (pH 7.4) three times.…”

Emerging Strategies of Nanomaterial‐Mediated Tumor Radiosensitization

“…Au‐based nanomaterials are the hottest researched radiosensitizers due to their unique advantages such as chemical inertness, highly biocompatibility, varied morphology for achieving optimum delivery and effect, multiform modification of targeting moieties for specifically delivering to the tumor tissue and longer systemic circulation for providing the material with enough time to be absorbed by tumor tissue . A large amount of articles about Au‐induced tumor radiosensitization can be searched . For example, Zhang et al prepared ultrasmall GSH‐Au nanomolecules for increasing the safety and efficacy of RT .…”

Molecular imaging of integrins in oncology

“…Additional functional modifications enabled 99m Tc-and Gd-labeling, and thus SPECT-and MR-based imaging. 28 So far, clinical applications of integrintargeted MR imaging for cancer diagnosis have not been reported. This is because the clinical use of nanoparticles is considered rather skeptical and numerous challenges have to be faced to introduce new nanoparticle-based compounds to the market and into routine clinical practice.…”