Lessons Learned from the Thyroid: Use
of Nis for Non-Thyroideal Pathologies
Ana Redrado Osta1*, Belén Azanza-Hernández2* and Pilar Martin Duque1,2,3*
1Instituto de Investigación Sanitaria (IIS) de Aragón, Avenida San Juan Bosco, Zaragoza, Spain
2Surgery and Chemical and Environmental Engineering departments; University of Zaragoza, Spain
3Networking Research Center in Biomaterials, Bioengineering and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Spain
Submission: June 20, 2023; Published: July 19, 2023
*Corresponding author: Ana Redrado Osta, Belén Azanza Hernández, Pilar Martin Duque, Instituto de Investigación Sanitaria (IIS) de Aragón, Avenida San Juan Bosco, 13, 50009. Zaragoza, Spain, Surgery and Chemical and Environmental Engineering departments; University of Zaragoza. 50009 Zaragoza, Spain, Networking Research Center in Biomaterials, Bioengineering and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III; 28029 Madrid, Spain. Email: [email protected]
How to cite this article: Ana Redrado Osta*, Belén Azanza-Hernández* and Pilar Martin Duque*. Lessons Learned from the Thyroid: Use
of Nis for Non-Thyroideal Pathologies. J Endocrinol Thyroid Res. 2023; 7(3): 555712. DOI:10.19080/JETR.2023.07.555712
Over the years, sodium iodine symporter. (NIS) has been studied and exploited for thyroid cancer (and other thyroidal pathologies) diagnosis and treatment. Thanks to the cDNA cloning of the NIS gene and the many advances in gene transfer strategies, NIS has become a powerful tool to monitor and treat numerous non-thyroidal cancer types.
Nowadays, the sodium iodide symporter (NIS) is known to be key in the mechanism of iodide for the thyroid hormones synthesis process. NIS is a transmembrane protein expressed on the basolateral surface of thyroid follicular cells and is responsible for the active transport of iodine thanks to the sodium transport following the concentration gradient . There have been many crucial advances to establish the current clinical scenario regarding thyroid pathologies. In 1940, 131I was administered for the first time as a hyperthyroidism treatment and in 1946 it was employed to treat thyroid cancer . Moreover, over the years, NIS transporter has gained importance as a valuable imaging tool . The choice of imaging modality employed in thyroid cancer varies upon the expression of sodium iodide symporter (NIS) in tumor cells and the availability of specific radioisotopes. Consequently, the selection varies depending on the specific radioisotope utilized. In DTC (Differentiated thyroid cancer), non-invasive single-photon emission computed tomography (SPECT) imaging technique can be utilized to detect photon-emitting radionuclides, including 123/125/131I and 99mTcO4, which are transported intracellularly by NIS for medical diagnostic purposes.123I exhibits suitability as
a radioisotope for SPECT imaging, like 99mTcO4. Nevertheless, 99mTcO4 possesses a short half-life, yet it is not abundantly available. Within the context of SPECT imaging, the utilization of a radioisotope with a short half-life is advantageous. The sodium/iodide symporter (NIS), it exhibits the capability to transport radioisotopes for medical-clinical purposes, such as 124I and [18F]-tetrafluoroborate (18F-BF4-).
But besides their radiotherapeutic effect it was demonstrated that these radioisotopes can be effectively detected utilizing the highly sensitive non-invasive imaging technique known as positron emission tomography (PET). The utilization of 124I for PET imaging entails enhanced sensitivity in comparison to single-photon emission computed tomography (SPECT). However, it is worth noting that 124I emits both positrons and gamma radiation, thereby potentially compromising the quality of the acquired images. Consequently, significant attention has been devoted to the radioisotope 18F-BF4 as it stands out as the most promising candidate for imaging purposes. Its substantial positron emission capacity coupled with its low energy characteristics allows for the acquisition of high-quality three-dimensional PET images .
NIS is also involved in the success of RAI therapy (Radioactive
Iodine Therapy). 131I emits both beta particles and photons with
higher energy levels compared to the radioisotopes, thereby
resulting in inferior image quality when contrasted with other
radioisotopes but a great effect as radiotherapy against the
In relation to 131I, it harnesses high-energy nuclear electron
emissions that possess the capacity to effectively eliminate target
cells. Nevertheless, this radiation exerts detrimental effects on
DNA integrity, impacting not only the intended target cells but also
the surrounding cellular milieu, culminating in the formation of
DNA cross-links, breaks, and base lesions .
The introduction of NIS as a diagnostic treatment and/or
monitoring tool in thyroid pathologies has entailed a magnificent
advance in clinical practice. The idea of making use of this approach
in non-thyroidal tissues offers the opportunity of applying all the
expertise acquired over the years to numerous pathologies .
Considerable efforts were dedicated to the study and validation
of different strategies to transfer functional NIS to other tissues.
Herein, we provide a summary of some.
The use of viruses as viral vectors represents a highly
promising strategy for antitumor therapy, transferred the desired
therapeutic gene. A novel approach involves the targeted transfer
of the NIS gene to non-thyroidal tumours, enabling the utilization
of both NIS-guided imaging techniques and the therapeutic
application of radioisotopes. On the one hand, in many cases,
replication-defective vectors were used. For those cases, even
though they are unable to induce cell lysis, they allow for the
insertion of therapeutic genes into the cellular genome. On the
other hand, oncolytic viruses are highly promising as they possess
distinct characteristics that enables the implementation of
radio virotherapy, besides to the cell death induced by the viral
One of the most widely studied oncolytic viruses for NIS gene
transfer therapy strategies is measles virus (MV). An attenuated
MV vaccine strain has been proven to have an extraordinary safety
profile. Tumour selectivity of this virus is achieved through the
CD46 specific binding to tumour cells . The utilization of MVNIS
as a reporter/therapy strategy has been successfully validated
across several types of cancers. In a multiple myeloma xenograft
mouse model, Russell’s team showed tumoral regression upon
a single i.v. injection of MV-NIS when 131I was administered .
Moreover, prostate cancer xenografts derived from the LNCaP
cell line were shown to be destroyed when MV-NIS was locally or
systemically administered, and the therapeutic effect could also
be enhanced with 131I administration . Finally, for pancreatic
cancer, the capacity of single-photon emission computed
tomography/computed tomography (SPECT/CT) to determine the
distribution pattern within the tumour and monitor the infection
of oncolytic MV-NIS viruses .
MV is not the sole virus employed for NIS gene transfer, other
oncolytic viruses have been explored with a similar approach.
Vaccinia virus in combination with NIS (VV-NIS) and iodide
administration has been shown to be effective in different cancer
models such as in endometrial cancer  or gastric cancer .
Moreover, VV-NIS could be used as an imaging tool to detect
remaining cancer cells in the margins of resected breast cancer
tumours in murine models . Other two oncolytic viruses
which have been employed are poxvirus and vesicular stomatitis
virus; those approaches have demonstrated to have positive
effects in an HCT116 colon cancer xenograft mouse model 
and in hematological malignancies as in immunocompetent mice
with syngeneic 5TGM1 myeloma tumours , respectively.
Noteworthy are the viruses based on conditionally replicating
adenoviruses (CRAds). NIS has been widely used for NIS transfer
on CRAds for imaging and therapy. Vassaux’s group described
several viruses [17, 18] under several promoters driving the viral
replication on different populations and type of tumors. NIS-Ads
were also used to track stem cells on their migration to the tumors
 with promising results.
The relationship between the sodium/iodide symporter
(NIS) and nanoparticles is based on their potential applications
for medicine and imaging. Consequently, researchers have
investigated the utilization of the NIS transporter in conjunction
with nanoparticles to facilitate targeted drug delivery . This
approach involves attaching nanoparticles to specific ligands
capable of binding to the NIS transporter, enabling the direct
administration of radioisotopes to cells expressing this transporter
. Urnauer’s team  conducted in vitro and in vivo studies
to assess the capability of the B6 ligand in NIS gene delivery. In
conjunction with LPEI-PEG/NIS polyplexes (specifically LPEIPEG-
B6/NIS), they successfully demonstrated enhanced iodide
uptake in the tumor and significant accumulation of radioiodine
in tissues expressing NIS physiologically, thereby confirming its
high tumor specificity and ligand-dependent uptake. The study
conducted by Le Goas and colleagues aimed to evaluate the capacity
to radiosensitizer neoplasms using nano therapy in combination
with standard systemic radioiodine therapy . For this purpose,
gold nanoparticles (AuNPs) were chosen and administered in
conjunction with standard systemic radioiodine therapy, with
a perspective towards clinical translation. Gold nanoparticles
(AuNPs) were selected to enhance the lethal efficacy of iodine-131
in two types of tumor cells genetically modified to express NIS
. In the case of colorectal cancer cells (DHD-NIS), the analyses
indicated a higher concentration of gold compared to the B16-
NIS melanoma cells, significantly decreasing the 50% lethal dose
in DHD-NIS cells. Furthermore, the enrichment of tumors with
PMAA-AuNPs prior to 131I therapy led to a more effective inhibition of tumor growth , creating new perspectives for the use of
metallic nanoparticles in molecular radiation therapy, not only in
131I-based treatment but also in other radiotherapeutic therapies.
Finally, the use of dendrimers bound to a DNA plasmid carrying NIS
showed promising results both for diagnostic and therapy .
The fusion of the NIS transporter with nanoparticles offers
numerous advantages, including targeted drug delivery, enhanced
therapeutic effectiveness, diminished systemic side effects, and
the ability to non-invasively image specific tissues. However, it
is important to note that this field is still evolving, with ongoing
research shaping the application of the NIS transporter and
nanoparticles in medicine and imaging. Consequently, the specific
details and advancements in this area may vary as new studies
and discoveries emerge.
The examination of the NIS transporter in conjunction with
viral and non-viral vectors for cancer therapy and diagnostic
in unrelated non-thyroid pathologies represents a relatively
underexplored area of research harboring significant prospect. The
application of these vectors and their subsequent implementation
of radiotherapy signifies a remarkable advancement for the
treatment of diverse pathologies, marking a pivotal milestone in
P.M-D´s lab is funded by Instituto de Salud Carlos III (ISCIII)
(PI19/01007 and DTS21/00130) and AECC and ASPANOA. We also
thank CIBER-BBN, an initiative funded by the VI National R&D&i
Plan 2008–2011 financed by the Instituto de Salud Carlos III
(ISCIII) with the assistance of the European Regional Development
Fund. A. R-O is funded by the Aragon Government Ph.D. Grant and
cofounded by Aragon/FEDER 2014–2020 “Building Europe from
Aragon” and B. A-H by INVESTIGO program.