Innovation Delivered

Iodine‑124 PET quantification of organ‑specific delivery and expression of NIS‑encoding RNA

Matthias Miederer¹, Stefanie Pektor¹, Isabelle Miederer¹, Nicole Bausbacher¹, Isabell Sofia Keil²,

Hossam Hefesha³, Heinrich Haas³, Ugur Sahin^2,3 and Mustafa Diken^2,3

¹ Department of Nuclear Medicine, University Medical Center of Johannes Gutenberg University, Mainz, Germany

² TRON - Translational Oncology at the University Medical Center, Johannes Gutenberg University Mainz GmbH, Mainz, Germany

³ Biopharmaceutical New Technologies (BioNTech) SE, Mainz, Germany

https://doi.org/10.1186/s13550-021-00753-2

Summary

There has been increased interest in the development of mRNA-based vaccines for protection against various infectious diseases and also for cancer immunotherapies since lipid-based nanoparticles opened the possibility to deliver RNA to specific sites within the body, overcoming the limitation of rapid degradation in the bloodstream. In the present study, RNA-lipoplex nanoparticles were assembled by complexing sodium-iodide-symporter (NIS) coding mRNA with liposomes at different charge ratios. Two kinds of RNA-lipoplex systems were used: one system with net anionic charge mediating translation primarily within the spleen, and the other with net positive charge yielding translation primarily within the lungs. After in vitro analysis of the expression kinetics, mice were iv. injected with the mRNA-lipoplexes then 6h later with ¹²⁴Iodine. Functional NIS protein translation was investigated by PET/MRI imaging. Results revealed rapid increase of ¹²⁴Iodine uptake in the spleen or lung compared to control-RNA-lipoplexes (containing non-coding RNA) with minimal background in other organs except from thyroid, stomach and salivary gland (where NIS is physiologically expressed). The strong organ selectivity and high target-to-background acquisition of NIS-RNA lipoplexes indicate the feasibility of small animal PET/MRI to quantify organ-specific delivery of RNA.

Results from nanoScan PET/MRI

Female BALB/c mice were intravenously injected with RNA-lipoplexes containing 20μg NIS RNA. Six hours later 6.64±0.66MBq ¹²⁴Iodine was injected intravenously. Three hours after ¹²⁴Iodine injection, mice were anesthetized and static imaging was performed over 20min by nanoScan PET/MRI. Additionally, one animal per group was imaged dynamically for one hour.

• PET/MRI of anionic NIS-RNA lipoplexes showed a visually detectable increase of ¹²⁴Iodine uptake in the spleen compared to control-RNA lipoplexes. Due to the high physiological NIS expression in the adjacent gastric wall, this increase was only visually clear with anatomical correlation by MRI. On PET imaging, spleen uptake appeared as an irregularity of the gastric wall which is not detected in control animals
• Lung uptake of NIS-RNA transported by cationic RNA-lipoplexes was depicted more clearly due to larger organ size and no adjacent physiological NIS uptake
• The quantified radioactivity from imaging matched well with the extent of uptake as measured in organs ex vivo, showing enhanced uptake of NIS-RNA and expression of functional NIS-protein in lung or spleen compared to the control RNA
• The uptake in lung was rapid and remained high over the first hour of dynamic acquisition

Blood-triggered generation of platinum nanoparticle functions as an anti-cancer agent

 Xin Zeng, Jie Sun, Suping Li, Jiyun Shi, Han Gao, Wei Sun Leong, Yiqi Wu, Minghui Li, Chengxin Liu, Ping Li, Jing Kong, Yi-Zhou Wu, Guangjun Nie, Yuming Fu, Gen Zhang

  https://doi.org/10.1038/s41467-019-14131-z 

Summary

Despite the large amount of research on the effects of metal nanoparticles (NPs) in nature and medicine, there has been very limited application in the clinic due to their potential toxicity, cost, and ethical hurdles of research in humans.

In this Nature Communications article, the authors have discovered that platinum (Pt) nanoparticles (NPs) are generated in vivo in human blood when a patient is treated with cisplatin, a powerful anti-cancer agent. They have shown that the self-assembled Pt NPs form rapidly, accumulate in tumors, and remain in the body for an extended period. Furthermore, the Pt NPs by themselves act as anti-cancer agent, but the tumor inhibitory activity is greatly increased when the nanoparticles are loaded with a chemotherapeutic drug, daunorubicin (DNR). The Daunorubicin loaded nanoparticles appeared to be effective even in daunorubicin-resistant models.

 The authors proposed that in vivo-generated metal NPs represent a biocompatible drug delivery platform for chemotherapy resistant tumor treatment. 

Results from nanoScan SPECT/CT

Authors have used nanoScan SPECT/CT to create high resolution images to track the tumor targeting dynamics of the nanoparticles in vivo.

Human-derived Pt NPs were labeled with 125-I and 500 μCi 125I-Pt NPs was directly injected into DNR-resistant K562-xenografted nude mice. The images were acquired for 30 min at 1, 4, 24 and 48 h time point.

The radioactive signal accumulated in the tumor regions, peaking at 24 h and remaining apparent at 48 h P.I. (Fig. 4f), indicating that the Pt NPs were efficiently taken up by the tumors.

Figure 4. f NanoScan SPECT/CT imaging of 125I-Pt NPs in DNR-resistant K562 cell-xenografted nude mice (n = 5) at 1, 4, 24 and 48 h after intravenous injection of the NPs. The arrows and dotted circles indicate the tumors. MIP: Maximum Intensity Projection.