Targeted radiotherapeutics

The current study was undertaken to develop laboratory techniques and protocols for the preparation and evaluation of therapeutic radiopharmaceuticals and the selection of targeted radiotherapeutic compounds with potential use in cancer treatment. For the study, DOTA-[Tyr ]-octreotate (DOTATATE), a somatostatin cyclic peptide hormone analogue (TATE coupled) with a macrocyclic chelator (DOTA), was used because it has been... 

For Lu-DOTATATE, multiple dose therapy is more effective than single dose therapy, since a decrease of the tumour proliferation index was observed. The data obtained suggest that optimizing the time interval for multiple dose regimens leads to increases in the therapeutic efficacy. These data show that Lu-DOTATATE could be an effective targeted radiotherapeutic agent. 

Advances in tumor biology, recombinant antibody technology, and radio synthetic chemistry have led to a flurry of activity in the development and clinical application of endoradiotherapeutic agents. However, it is important to bear in mind that radionuclide therapy is actually not a new concept, having been used in patients for more than 60 years. A number of textbooks provide excellent chronicles of early efforts in radionuclide therapy (Spencer 1978 Harbert 1987 Spencer et al. 1987). A notable example is sodium [ ijiodide, which has been utilized for the treatment of hyperthyroidism and thyroid carcinomas and remains the most widely utilized targeted radiotherapeutic in current clinical use. Radiocolloids such as those labeled with either Au or have been used for more than 50 years for the treatment of diseases such as malignant pleural effusions and intraperitoneal tumors. 

Another feature of tumors that can have a major impact on the distribution of targeted radiotherapeutics is tumor interstitial fluid pressure. Interstitial fluid pressure results in a pressure gradient that can inhibit the delivery of molecules from the plasma to the extracellular fluid in central regions of a tumor. Tliis pressure gradient is not present in normal tissues because they have a lymphatic system however, tumors do not, creating an additional barrier that must be overcome. Experimental evidence of an elevated interstitial pressure in murine tumor models has been reported by Boucher et al. (1990). As expected, the effect was most apparent at the tumor periphery. Using a mathematical model, the magnitude of this outward convection fluid flow was predicted to be 0.1-0.2 pm/s (Jain and Baxter 1988). 

The fact that peptides are much smaller than mAbs presents different issues that must be addressed in order to develop them as a targeted radiotherapeutic. With peptides, the probability of label substitution in the binding recognition portion of the molecule is much higher... 

Stolz B, Weckbecker G, Smith-Jones PM, Albert R, Raulf F, Bruns C. The somatostatin receptor-targeted radiotherapeutic [ °Y-DOTA-DPhe Tyr ]octreo-tide ( °Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours. Eur J Nucl Med 1998 25 668-674. 

EGER targeting was also used for systemic delivery of pDNA expressing the sodium iodide symporter (NIS) gene to liver cancer cells, followed by administration of radioactive isotope iodine-131, which accumulates in the tumor by NIS-mediated uptake in radiotherapeutic doses [227]. 

Radiotherapeutics attack cancer by causing radiation damage to DNA in cells. The requirements differ from those for drug delivery because the radiotherapeutic can act at a distance and does not have to separate from the delivery particle. Radiotherapeutics can be selected to provide action over a range of distances, from tens of nanometers to hundreds of microns. Three radiotherapy modalities can be identified. Brachytherapy, most often used with beta-emitters, uses tightly enclosed radioactive material that is brought in close proximity to the tumor. A second modality is intravenous injection so that the radiopharmaceutical binds to the outside of the tumor cells or is taken up by the cell and irradiates from within. The third approach uses a carrier loaded with the radiotherapeutic that is transported to the vicinity of the target cells, and then released. 

As part of the coordinated research project (CRP) on comparative evaluation of therapeutic radiopharmaceuticals, the ior-CEAl-(scFv)2 fragment and the somatostatin peptide analogues ior-P1394 and [DOTA,Tyr ]octreotate (DOTATATE) were evaluated as targeted agents. The results obtained from in vitro and in vivo studies deomonstrate the clinical usefulness of these radiolabelled biomolecules as radiotherapeutic agents. 

M.E. Werner, S. Karve, R. Sukumar, N.D. Cummings, J.A. Copp, R.C. Chen, et ah. Folate-targeted nanoparticle delivery of chemo-and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis. Biomaterials 32 (2011) 8548—8554. 

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