Effective Intratumoral Retention of [¹⁰³Pd]AuPd Alloy Nanoparticles Embedded in Gel‐Forming Liquids Paves the Way for New Nanobrachytherapy

Abstract

Local application of radioactive sources as brachytherapy is well established in oncology. This treatment is highly invasive however, due to the insertion of millimeter sized metal seeds. The authors report the development of a new concept for brachytherapy, based on gold-palladium (AuPd) alloy nanoparticles, intrinsically radiolabeled with 103 Pd. These are formulated in a carbohydrate-ester based liquid, capable of forming biodegradable gel-like implants upon injection. This allows for less invasive administration through small-gauge needles. [ 103 Pd]AuPd nanoparticles with sizes around 20 nm are prepared with radiolabeling efficiencies ranging from 79% to >99%. Coating with the hydrophobic polymer poly(N-isopropylacrylamide) leads to nanoparticle diameters below 40 nm. Dispersing the nanoparticles in ethanol with water insoluble carbohydrate esters gives "nanogels", a low viscosity liquid capable of solidifying upon injection into aqueous environments. Both nanoparticles and radioactivity are stably retained in the nanogel over 25 days (>99%) after formation in aqueous buffers. Animals bearing CT26 murine tumors are injected intratumorally with 25 MBq of the 103 Pd-nanogel, and display tumor growth delay and significantly increase median survival times compared with control groups. Excellent retention in the tumor of both the 103 Pd and the nanoparticle matrix itself is observed, demonstrating a potential for replacing currently used brachytherapy seeds.

Recent Advances in Brachytherapy Using Radioactive Nanoparticles: An Alternative to Seed-Based Brachytherapy

“…Fach et al. ( 38 ) doped [ 103 Pd]PdCl 2 in a solution of HAuCl 4 for co-reduction to produce AuPdNPs intrinsically labeled with 103 Pd ([ 103 Pd]AuPdNPs) with ≈20 nm, and then ethylenediaminetetraacetic acid (EDTA) was used to scavenge free Pd 2+ to avoid unspecific labeling of the nanoparticle surface resulting in radiolabeling efficiencies of 79% to >99%.…”

“…This is attributed to higher cytotoxicity caused by these low-energy electrons (less than 500 eV or a few keV) with short range in the biological tissues (a few nanometers) ( 5 , 54 , 55 ). 103 Pd, 111 In, and 125 I have been used as nanobrachytherapeutic agents in preclinical studies involving tumor-bearing xenograft models ( 38 , 45 , 52 ). These radionuclides decay by internal conversion (IC) and electron capture (EC) mode and emit Auger electrons.…”

“…Fach et al. ( 38 ) synthesized [ 103 Pd]AuPd radio-NPs using chelator-free radiolabeling technique. The [ 103 Pd]Pd 2+ was reduced in the presence of Au 3+ and citric acid to form [ 103 Pd]AuPd radio-NPs of 15-nm size and 23.5-nm hydrodynamic diameter.…”

Surface Adsorption of the Alpha-Emitter Astatine-211 to Gold Nanoparticles Is Stable In Vivo and Potentially Useful in Radionuclide Therapy

“…This differentiation was chosen to investigate whether stable surface labeling with 211 At could be achieved both before and after PEG coating. In Group C, an embedding procedure was attempted [22,29]. In this group, 211 At was added to the 1st gen citrate-stabilized AuNPs to give, followed by the addition of a 2nd layer of gold, as described above.…”

Radiolabeling of Nanomaterials: Advantages and Challenges

“…For example, Zhang et al (2011) almost, if not totally, the same physicochemical properties as the unlabeled NMs. Therefore, incorporation strategy is also called intrinsic radiolabeling method in some previous reports (Goel et al, 2014;Chakravarty et al, 2018;Fach et al, 2021), which could essentially guarantee an accurate reflection of NMs behavior by detecting the radioactive signals. In addition to radiochemical synthesis starting from the cold-hot precursors, radionuclide can be incorporated into the NMs through surface elemental exchange, or radionuclide deposition in cage-like/mesoporous NMs (Goel et al, 2014;Tang et al, 2019;Korany et al, 2020).…”