**4. Newly introduced I-131 labeled radiopharmaceutical therapy agents**

Radiopharmaceutical therapy (RPT) is emerging as a safe and effective targeted approach to treating many types of cancer. In RPT, radiation is systemically or locally delivered using pharmaceuticals that either bind preferentially to cancer cells or accumulate by physiological mechanisms. Almost all radionuclides used in RPT emit photons that can be imaged, enabling non-invasive visualization of the biodistribution of the therapeutic agent. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal toxicity. With the recent FDA approval of several RPT agents, the remarkable potential of this treatment is now being recognized [6]. We will mention a few emerging clinical development of radioiodine labeled RPT agents newly available or still under development at the present time. RPT development is a multidisciplinary endeavor, requiring expertise in radiochemistry, radiobiology, oncology, pharmacology, medical physics and radionuclide imaging and dosimetry.

Theranostic is the general concept of using a radionuclide- labeled agent that may be imaged to guide radiopharmaceutical therapy; a radionuclide that may be used for both imaging and therapy, and it is the new trend in RPT.

I-131 meta- iodobenzylguanidine (mIBG)**:** for Adrenergic receptor tumors; the active uptake mechanism via the adrenaline transporter and storage in presynaptic neurosecretory granules. FDA approved but clinical trials are ongoing. This radiopharmaceutical can be used to treat patients with neuroblastomas [19].

mIBG radiolabelled with high- specific- activity iodine-131 was recently approved by the FDA for the treatment of adult and pediatric patients aged 12 years or older with unresectable metastatic phaeochromocytoma or paraganglioma.

I-131- labeled CLR131 for Pediatric cancer, head and neck cancer, multiple myeloma, leukemia, lymphoma. The radio-labeled phospholipid ether analogue targeting cancer cell- specific lipid raft microdomains. It is still undergoing the phase of clinical trials and testing.

I-131- labeled CLR1404 for unresponsive solid tumor, multiple myeloma. The radio-labeled phospholipid ether analogue targeting cancer cell-specific lipid raft microdomains. It is still undergoing the phase of clinical trials and testing.

#### **4.1 Antibody based radionuclide therapy**

Radiolabeled sdAbs prove to be promising vehicles for molecular imaging and targeted radionuclide therapy of metastatic lesions in the brain. Administration of [I-131]-2Rs15d and [Ac-225]-2Rs15d alone and in combination with trastuzumab showed a significant increase in median survival in 2 tumor models that remained largely unresponsive to trastuzumab treatment alone [20]. Puttemans et al. [21] have described the use of the anti-HER2 sdAb 2Rs15d, coupled to 111In or 131I for detection via PECT/CT, and coupled to 131I or 225Ac for targeted radionuclide therapy (TRNT) of HER2pos brain lesions and compare its therapeutic efficacy and systemic toxicity to that of trastuzumab, a clinically-approved anti-HER2 treatment. They have demonstrated that radiolabeled sdAbs are ideal vehicles for targeted radionuclide therapy and molecular imaging, not only for systemic disease, but also for metastatic lesions in the brain. Moreover, histopathological analysis after therapy revealed no significant early toxicity. Dosimetry based on ex vivo biodistribution data confirmed most activity is retained within the kidneys until 48 h after administration, however after extrapolation to therapeutic activities the cumulative absorbed dose (25 Gy) remains close to the considered toxicity threshold of 23 Gy to kidneys [21].

The amount of 131I- tositumomab prescribed to patients was determined by assessing the whole- body clearance rate, so that the amount administered was adjusted to deliver the same whole- body absorbed dose in all treated patients [21], making it the first RPT agent whose package insert specified an absorbed dose- based treatment planning procedure. Such an approach was, in part, necessitated because the radioiodine in iodine-131- labeled antibodies is cleaved (due to dehalogenation) from the antibody if the radiolabelled antibody construct is internalized.

#### **4.2 Iodine-131 labeled Metuximab**

Radioimmunotherpy using antibodies injection is another application of I-131 in oncology. Administered to patients suffering from hepatocellular carcinoma (HCC), the product will target the hepatic cancer cells while sparing other adjacent tissues. The whole body biodistribution is required in order to perform radiation dosimetry, evaluate the risk from the treatment and to ensure patient safety.

#### **4.3 I-131 - labeled a CD45**

I-131 - labeled a CD45 for Bone marrow transplant preparation.

The I-131 based antibody targeting CD45+ cells for bone marrow ablation before transplantation. It is still undergoing the phase of testing and planned clinical trials. Early studies showed the potential to image the radioiodinated antibodies using SPECT [22, 23].

The radiolabelled antibodies were used for total body irradiation in preparation for bone marrow transplantation (BMT). report results of a study on patients with acute myelogenous leukemia in a phase I clinical trial where results showed that it is possible while appending I-131 to M195 antibody to deliver beta emitter particles to the targeted cells in the bone marrow, it was also possible to image the disease in the bone marrow.

The tumor-homing property of mesenchyme stem cells (MSCs) allows targeted delivery of therapeutic genes into the tumor microenvironment. The application of sodium iodide symporter.

(NIS) as a theranostic gene allows noninvasive imaging of MSC biodistribution and transgene expression before therapeutic radioiodine application. Linking therapeutic transgene expression to induction of the chemokine CCL5/RANTES allows a more focused expression within primary tumors, as the adoptively transferred MSC develop carcinoma-associated fibroblast-like characteristics. Although RANTES/CCL5-NIS targeting has shown efficacy in the treatment of primary tumors, it was not clear if it would also be effective in controlling the growth of metastatic disease. To expand the potential range of tumor targets, we investigated the biodistribution and tumor recruitment of MSCs transfected with NIS under control of the RANTES/CCL5 promoter (RANTES-NIS-MSC) in a colon cancer liver metastasis mouse model established by intrasplenic injection of the human colon cancer cell line LS174t. Results show robust MSC recruitment with RANTES/ CCL5-promoter activation within the stroma of liver metastases as evidenced by tumor-selective iodide accumulation, immunohistochemistry, and real-time polymerase chain reaction. Therapeutic application of 131I in RANTES-NIS-MSC– treated mice resulted in a significant delay in tumor growth and improved overall survival. Conclusion: This novel gene therapy approach opens the prospect of NIS-mediated radionuclide therapy of metastatic cancer after MSC-mediated gene delivery [24].

*Recent Advances in Biodistribution, Preclinical and Clinical Applications of Radiolabelled Iodine DOI: http://dx.doi.org/10.5772/intechopen.99113*

#### **4.4 Newly introduced radioiodine labeled nanoparticles and microspheres**

in the area of preclinical development regarding tumor targeted therapy using radioiodine labeled molecules an active research work is undergoing using Nano and microsphere technologies. The good example of such radiopharmaceutical is tositumomab (131I-labeled anti-CD20 antibody), which received Food and Drug Administration (FDA) approval for the treatment of Non-Hodgkin's lymphoma in 2003.

Initial clinical trials of 131I- labeled iodized oil (131I- labeled Lipiodol) were completed in the late 1980s/early 1990s (285–288), and clinical investigations of this treatment modality continued until 2013 (NCT00116454, NCT00870558 and NCT00027768).

Administration of 131I- labeled Lipiodol in the adjuvant setting, after resection or radiofrequency ablation for hepatocellular carcinoma, yielded a 6- month increase in recurrence free survival and a 24- month increase in median overall survival [25].

RPT has proven to be an effective cancer treatment when other standard therapeutic approaches have failed. However, despite more than 40 years of clinical investigation, RPT has not become a part of the cancer treatment armamentarium in the same way as other therapies. 'Targeted' cancer therapies are associated with clinical trial failure rates of 97% (ref. 1), partly because the agents targeted a pathway that was not involved in promoting the cancer phenotype2. By contrast, RPT has been unsuccessful owing to a failure to adopt and rigorously evaluate this treatment modality, which may be explained in part by the multidisciplinary nature of the treatment.

Additional challenges facing the development and application of RPT include public perception and fear of radioactivity as well as the perceived complexity of the treatment.

The need for a new specialty or subspecialty to provide the multidisciplinary training needed to safely and effectively administer RPT agents to patients and subsequently manage them. Such a specialty or subspecialty would require training in nuclear medicine, radiation oncology and also general oncology as delivery of radiation is involved, the participation of medical physicists familiar with both imaging and radionuclide dosimetry is important.

The article by Jongho Jeon [25], reviews recent progress in cancer therapy using radiolabeled nanomaterials including inorganic, polymeric, and carbon-based materials and liposomes. The article first provides an overview of radiolabeling methods for preparing anticancer agents that have been investigated recently in preclinical studies. Next, they discuss the therapeutic applications and effectiveness of beta or alpha emitter-incorporated nanomaterials in animal models and the emerging possibilities of these nanomaterials in cancer therapy [26].

In contrast to biologics or chemotherapeutics, both radiation delivery and the biological response to radiation may be mathematically modeled and used to understand the parameters of a treatment that are most important in influencing efficacy and toxicity. The capability to use multiple agents in one carrier is very unique about nanomaterials [27].

#### **5. Conclusion**

Unlike chemotherapy and external beam radiation therapy RPT has not yet been established as a treatment modality in oncology. Mainly because lots of suggested

RPT agents are still undergoing clinical trials and some are still in the preclinical stage. The known fact is that, the tumor response to RPT can be mathematically modeled and also the radiation dosimetry is well established [24, 25]. There are research projects underway that focus on the use of combination therapy using targeted RPT along with chemotherapy for example in the treatment of resistant tumors that cannot be treated uniquely by traditional therapy like chemotherapy, this area of research is also quit active at the present time [28].

One challenge is the validation studies and the regulatory approval of clinical software packages that need to be established prior to routine clinical use is still underway. Certainly this area of research and development is very dynamic and requires multidisciplinary team work including oncology, nuclear medicine, imaging sciences and medical physics; and clinically also it will probably require some kind of new medical subspecialty. The medical physicist should be trained in both imaging based and radionuclide dosimetry methods. As medical physicists we see this as an opportunity for future medical physicist starting his or her career to specialize in this new evolving area of clinical medical physics.
