Aptamer-based therapeutics and their potential in radiopharmaceutical design

Aptamers, short, single stranded oligonucleotide entities, have been developed in the past 15 years against a plethora of targets and for a variety of applications. These range from inhibition of receptors and enzymes to the identification of small molecules in sensor applications, and from the development of targeted therapeutic to the design of novel diagnostic and imaging agents. Furthermore, aptamers have been designed for targets that cover a wide range of diseases, from HIV to tropical diseases, cancer and inflammation. Their easy development and flexibility of use and manipulation, offers further potential. In this paper we review their selection and consider some of the recent applications of aptamers in the design of radiopharmaceuticals for the targeted radiotherapy and medical imaging of disease

Development of anti-MUC1 DNA aptamers for the imaging and radiotherapy of breast cancer

Background Aptamers have shown great potential as novel targeted radiopharmaceutical entities for the diagnosis and imaging of disease. They offer reduced immunogenicity, good tumour penetration, rapid uptake and clearance compared with their monoclonal antibody counterparts. In previous work we have reported the labelling of such aptamers against breast-cancer-related biomarkers with radionuclide ligands. Methods We have now conjugated previously selected aptamers against the protein core of the MUC1 glycoprotein tumour marker with chelating agents and labelled them with 99mTc, for the diagnostic imaging of breast cancer. The conjugation is achieved using standard peptide coupling reactions between an amino modification on the aptamer and the carboxylic group on the ligands. Labelling with 99mTc used tin chloride as the reducing agent, and analysis was by HPLC where both the UV and the gamma emission was monitored. Radiolabelled aptamer conjugates were separated from free, unconjugated 99mTc using microcon filters. For the analysis of the pharmacokinetic properties of the aptamer–radionucleotide conjugate we used gamma-camera imaging in MCF-7 breast cancer tumour model systems. Results We coupled the aptamer with the highest affinity for the MUC1 glycoprotein to different ligands (MAG2 or meso-2,3-dimercaptosuccinic acid) and labelled it with active 99mTc to obtain stable complexes that were used in pharmacokinetic studies. This allows us to compare the properties of a single conjugate with a biaptamer conjugate, as two of the DMSA–aptamer conjugates can coordinate the metal core. An efficient and convenient labelling of the aptamer with short half-life radioisotopes was achieved as the last step of the synthesis (postconjugation labelling). The labelled aptamers were separated from free 99mTc using microcon filter separation and were monitored by HPLC at all stages, to ensure that only radiolabelled aptamers were injected and imaged for their pharmacokinetic properties. Conclusion The aptamer–chelator conjugates have strong 99mTc binding properties and the resulting complexes are highly stable in vivo both in terms of nuclease degradation and leaching of the metal. The presence of more than one molecule of aptamer per complex alters the binding and pharmacokinetic properties of the radiolabelled products, allowing the complex to remain longer in circulation and thus offering improved tumour imaging properties, without affecting the tumour penetration of the aptamer. Furthermore, different ligands affect accumulation of the aptamer in different organs, as they alter the lipophilic properties of the conjugate. These results aim to open new possibilities for the diagnostic imaging of, and potentially the targeted radiotherapy of, breast cancer. </br

Development of anti-MUC1 DNA aptamers for the imaging and radiotherapy of breast cancer

Aptamers are novel oligonucleotide-based recognition molecules which can bind to almost any target, including extracellular proteins, antibodies, peptides and small molecules. Aptamers can be rapidly generated, and offer reduced immunogenicity, good tumour penetration, rapid uptake and clearance, and can thus be used as alternatives to monoclonal antibodies in molecular targeted radiotherapy and diagnostic imaging

Capacitor Voltage Estimation Scheme with Reduced Number of Sensors for Modular Multilevel Converters

This paper presents a new method to measure the voltage across the submodule (SM) capacitors in a modular multilevel converter (MMC). The proposed technique requires only one voltage sensor per arm. This reduces the number of sensors required compared to conventional sensor-based methods. Therefore, the cost and complexity of the system are reduced, which in turn improves the converter’s overall reliability. The proposed method employs an exponentially weighted recursive least square (ERLS) algorithm to estimate the SM capacitor voltages through the measured total arm voltage and the switching patterns of each SM. There is thus no need for extra sensors to measure these control signals as they are directly provided from the controller. The robustness of the proposed method is confirmed via introducing deviations for the capacitance values, dynamic load changes, DC voltage change and start-up transient condition. Simulation and experimentally validated results based on a single-phase MMC show the effectiveness of the proposed method in both, steady-state and dynamic operations

Radiotherapy, cancer and some anatomical structures related with the pelvic floor: an evaluation of the scientific literature

Radiotherapy is a cancer treatment that uses high-energy X-rays or other types of ionizing radiation to try to kill the cancer cells in various organs/tissues. PubMed is a database used as a tool in various publications. The aim of this work was to evaluate, in the PubMed, the number of publications (NP) in radiotherapy and cancer in various organs related to the pelvic floor as well as brachytherapy. The searches were performed (August 2008) in the PubMed (http://www.pubmed.com) using the words: (i) radiotherapy (RT) or cancer (CA), (ii) RT and CA, (iii) RT and CA and prostate, RT and CA and testis, RT and CA and breast, RT and CA and kidneys, RT and CA and vulva, RT and CA and vagina, RT and CA and penis, RT and CA and uterus, RT and CA and ovary, RT and CA and bladder, and RT and CA and urethra. A search using brachytherapy was also performed. The NP in each subject was determined and was 2178635 to CA and about 9% of them are related with RT. The NP in RT and CA and breast or prostate is bigger than for the other organs, whereas brachytherapy is mainly cited in the studies about CA of prostate, bladder and breast. In conclusion, our findings demonstrate the importance of radiation therapy studies in the cancer of several organs. This information is crucial in understanding the field and demonstrates areas of significant progress or existing gaps of research in radiotherapy treatment of various cancers of the pelvis. Furthermore, it could significantly aid the interprofessional team in the determination of actions related to the treatment of patients that are undertaking radiotherapy, due to the possible complications of this modality of treatment

Aptamer-based radiopharmaceuticals for diagnostic imaging and targeted radiotherapy of epithelial tumors

In the continuous search for earlier diagnosis and improved therapeutic modalities against cancer, based on our constantly increasing knowledge of cancer biology, aptamers hold the promise to expand on current antibody success, but overcoming some of the problems faced with antibodies as therapeutic or delivery agents in cancer. However, as the first aptamer reached the market as an inhibitor against angiogenesis for the treatment of macular degeneration, aptamers have found only limited applications or interest in oncology, and even less as radiopharmaceuticals for diagnostic imaging and targeted radiotherapy of tumours. Yet, the chemistry for the labelling of aptamers and the options to alter their pharmacokinetic properties, to make them suitable for use as radiopharmaceuticals is now available and recent advances in their development can demonstrate that these molecules would make them ideal delivery vehicles for the development of targeted radiopharmaceuticals that could deliver their radiation load with accuracy to the tumour site, offering improved therapeutic properties and reduced side effects

Nano-Aptamer for Breast Cancer Imaging: Initial Considerations.

The application of aptamers especially in the use of drug delivery systems (DDSs) has the potential to develop in vivo nanoparticles for theranosis (therapy+diagnosis). With the advent of medical imaging and radiotherapeutics, this area of research developing the next era of radiopharmaceuticals is both attractive and promising. Overall, nano-radiopharmaceuticals have the potential to solve several problems regarding the in vivo stability of aptamers. This paper discusses a study in the development and proof-of-concept of nano-aptamers and supporting its use as a nano-radiopharmaceutical for the treatment of breast cancer and other potentially related disease states

Effect of an extract of Centella asiatica on the biodistribution of sodium pertechnetate (Na^99mTcO₄) and on the fixation of radioactivity on blood constituents

This study evaluates the effects of an acute treatment with a Centella asiatica (CA) extract on the biodistribution of the radiopharmaceutical Na99mTcO4 and on the fixation of technetium-99m on blood constituents. Wistar rats were treated with CA extract and, 1 hour after, Na99mTcO4 was administered; organs/tissues were withdrawn and weighted. The radioactivity was counted to calculate the percentage of activity per gram (%ATI/g). Also, blood samples were withdrawn, plasma (P), blood cells (BC), insoluble fraction (IF) and soluble fractions of P and BC were isolated and the radioactivity was counted to calculate the percentage of activity (%ATI). Data indicated that the acute treatment with CA extract changed significantly (p99mTcO4 and the fixation of the technetium-99m on blood constituents in an acute treatment

Nuclear medicine procedures and the evaluation of male sexual organs: a short review

Sexuality consists of three aspects that are interrelated and inseparable, biological, physiological and social. The biological aspect considers the individual's capability to give and to receive pleasure. In consequence, it covers the functionality of the sexual organs and the physiology of human sexual response cycle. Diagnostic imaging modalities, such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) have been used to evaluate clinical disorders of the male reproductive system. PET and SPECT procedures basically involve the administration of a radiopharmaceutical that has a higher uptake in a specific tumor or tissue. The aim of this brief review is to present some radiopharmaceuticals that have been used in the clinical evaluation of the male sexual organs (testes, prostate, seminal vesicles, penis) related with male sexuality. This information could be useful in better understanding the male sexual response cycle, as well as the sexual disorders, when considering the male sexual organs and the pelvic floor. Moreover, the findings obtained with PET and SPECT imaging could help to evaluate the efficacy of clinical results of therapeutic procedures. In conclusion, the knowledge from these images could aid in better understanding the physiology of the different organs related with sexuality. Furthermore, they could be important tools to evaluate the physiological integrity of the involved organs, to improve clinical strategies and to accompany the patients under treatment

Continuous positive airway pressure and body position alter lung clearance of the radiopharmaceutical 99mtechnetium-diethylenetriaminepentaacetic acid (99mTc-DTPA)

The purpose of this investigation was to evaluate the pulmonary clearance rate of 99mtechnetium-diethylenetriaminepentaacetic acid (99mTc-DTPA) through the use of continuous positive airway pressure (CPAP) in different postures. It was a quasi-experimental study involving 36 healthy individuals with normal spirometry. 99mTc-DTPA, as aerosol, was nebulized for 3 min with the individual in a sitting position. The pulmonary clearance rate was assessed through pulmonary scintigraphy under spontaneous breathing and under 20 and 10 cmH2O CPAP in the sitting and supine positions. The clearance rate was expressed as the half-time (T1/2), that is, the time for the activity to decrease to 50% of the peak value. 20 cmH2O CPAP produced significant reduction of the T1/2 of 99mTc-DTPA in the supine position (P = 0.009) and in the sitting position (P = 0.005). However, 10 cmH2O CPAP did not alter the T1/2 of DTPA in both positions. The postural variation from supine to the sitting position with 10 cmH2O CPAP (P = 0.01) and 20 cmH2O (P = 0.02) also reduced the T1/2 of 99mTc-DTPA. High levels of positive pressure in normal lungs resulted in faster 99mTc-DTPA clearance. Moreover, the sitting position further increased the clearance rate of the 99mTc radioaerosol imaging in the two pressure levels studied.Key words: Continuous positive airway pressure, 99mTc-DTPA, scintigraphy, posture