RADIOPHARMACY Research Papers - Academia.edu (original) (raw)

Introduction: Rhenium-188-HEDP (188 Re-HEDP) is a therapeutic radiopharmaceutical for treatment of osteoblastic bone metastases. No standard procedure for the preparation of this radiopharmaceutical is available. Preparation conditions may influence the quality and in vivo behaviour of this product. In this study we investigate the effect of critical process parameters on product quality and stability of 188 Re-HEDP. Methods: A stepwise approach was used, based on the quality by design (QbD) concept of the ICH Q8 (Pharmaceutical Development) guideline. Potential critical process conditions were identified. Variables tested were the elution volume, the freshness of the eluate, the reaction temperature and time, and the stability of the product upon dilution and storage. The impact of each variable on radiochemical purity was investigated. The acceptable ranges were established by boundary testing. Results: With 2 ml eluate, adequate radiochemical purity and stability were found. Nine ml eluate yielded a product that was less stable. Using eluate stored for 24 h resulted in acceptable radiochemical purity. Complexation for 30 min at room temperature, at 60 °C and at 100 °C generated appropriate and stable products. A complexation time of 10 min at 90 °C was too short, whereas heating 60 min resulted in products that passed quality control and were stable. Diluting the end product and storage at 32.5 °C resulted in notable decomposition. Conclusion: Two boundary tests, an elution volume of 9 ml and a heating time of 10 min, yielded products of inadequate quality or stability. The product was found to be instable after dilution or when stored above room temperature. Our findings show that our previously developed preparation method falls well within the proven acceptable ranges. Applying QbD principles is feasible and worthwhile for the small-scale preparation of radiopharmaceuticals.

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- Cancer Research, Quality Control, RADIOPHARMACY, Radiopharmaceutical Chemistry

Tesis de Licenciatura Obtención de 188 Re-HEDP para el tratamiento del dolor asociado a la metástasis ósea Autor: Luis Ramón Velázquez Maldonado Tutor: MSc. Abmel Xiques Castillo 2004 Ciudad Habana

- by Luis Ramón Velázquez Maldonado
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- RADIOPHARMACY

Radiopharmaceuticals are active molecules which containing radionuclides in the structure
and used for diagnosis or treatment. Today, there are nearly 100 radiopharmaceuticals. They were
prepared by using reactors, generators, or cyclotron-derived radioisotopes and used in the treatment
of certain diseases, including cancer, and in the diagnosis of many diseases. The radiopharmaceuticals
consist of two parts, a radionuclide and a pharmaceutical part. During the preparation of the radiopharmaceutical,
a drug (pharmaceutical part) localized in the organ desired to be imaged or participating
in the physiological function of the organ is identified. The selected pharmaceutical part is
labeled to a suitable radionuclide to prepare the radiopharmaceutical. After the radiopharmaceutical
is given to the patient, radiation emitted from the radionuclide is detected with detectors and converted
into an image with the aid of a computer. Anatomical and physiological information are obtained
by visualizing the distribution of the radionuclide in the organism and by determining the
changes of this distribution with respect to time. Radiopharmaceuticals are used to diagnose 95% of
and 5% to treat in Nuclear Medicine. While radiopharmaceuticals used for diagnostic purposes emit
gamma rays, the radiopharmaceuticals used in the treatment emit beta radiation. More than 2700 radionuclides
are artificially produced by using cyclotron, reactors and generators. Scintigraphic imaging
techniques used to static-dynamic imaging, whole body imaging, and hybrid imaging. These
methods, which are used in Nuclear Medicine, are based on the physiological changes that occur in
the tissues, allowing early diagnosis of diseases such as cancer in particular. Diagnosis of the tumor in
the early stage, ie, at the beginning of the anatomical changes, at the physiological level, can lead to
a significant increase in the success of the treatment, without the possibility of cancer spreading. These
tests are safe and painless. For this reason, it is widely used all over the world.

- by Emre Özgenç
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- Nuclear medicine, Positron Emission Tomography, RADIOPHARMACY, Diagnosis

Radyofarmasötikler tanı veya tedavi amacıyla kullanılan, yapısında radyonüklid içeren aktif moleküllerdir. Günümüzde reaktör, jeneratör veya siklotron kaynaklı radyoizotoplar kullanılarak üretilen, kanser dâhil olmak üzere bazı hastalıkların tedavisinde ve birçok hastalığın teşhisinde kullanılan 100'e yakın radyofarmasötik bulunmaktadır. Bir radyofarmasötik, radyonüklid ve farmasötik kısım olmak üzere iki kısımdan oluşmaktadır. Radyofarmasötiğin hazırlanması sırasında, görüntülenmesi istenen organ içinde lokalize olan veya organın fizyolojik fonksiyonuna katılan bir ilaç (farmasötik kısım) belirlenmektedir. Seçilen farmasötik kısım uygun bir radyonüklid ile bağlanarak işaretleme işlemi ile radyofarmasötik hazırlanmaktadır. Hazırlanan radyofarmasötiğin hastaya verilmesinden sonra radyonüklidten yayılan radyasyon dedektörlerle belirlenerek bilgisayar yardımı ile görüntüye dönüştürülmektedir. Radyonüklidin organizmadaki dağılımının görüntülenmesi ile anatomik, bu dağılımın zamana göre değişikliklerinin saptanması ile de fizyolojik bilgiler elde edilmektedir. Nükleer tıpta radyofarmasötiklerin %95'i tanı, %5'i tedavi amacıyla kullanılmaktadır. Tanı amaçlı kullanılan radyofarmasötikler gama ışını yayar iken, tedavide kullanılan radyofarmasötikler beta ışını yaymaktadırlar. Nükleer tıpta kullanılan radyonüklidlerin hepsi yapay olarak üretilmektedir. Günümüzde 2.700'den fazla radyonüklid, siklotron, reaktör ve jeneratörlerde üretilmektedir. Nükleer tıpta kullanılan sintigrafik görüntüleme teknikleri; statik görüntüleme, dinamik görüntüleme, tüm vücut görüntüleme ve hibrid görüntülemedir. Nükleer tıpta kullanılan bu yöntemler dokularda meydana gelen fizyolojik değişikliklere dayandığından erken evrede özellikle kanser gibi hastalıkların teşhisine imkân vermektedir. Tümörün erken evrede, yani anatomik değişiklikler başlamadan fizyolojik düzeyde değişiklikler oluştuğu anda teşhis edilebilmesi kanserin yayılmasına fırsat kalmadan tedaviye başlanabilmesini, dolayısıyla tedavi başarısının önemli ölçüde artmasını sağlayabilmektedir. Bu tetkikler güvenli ve ağrısızdır. Bu nedenle tüm dünyada yaygın olarak kullanılmaktadır.

- by Meliha Ekinci
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- Nuclear medicine, Cancer Therapy, RADIOPHARMACY, Diagnosis
- by Meliha Ekinci
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- RADIOPHARMACY

The aim of the present study is to develop drug delivery systems with methotrexate (MTX) loaded chitosan nanoparticles for breast cancer diagnosis. For this purpose, chitosan/tripolyphosphate (TPP) nanoparticles were prepared by ionotropic gelation process at different concentrations and these nanoparticles were storaged at stability cabins at 25 ± 2 °C temperature / 60 ± 5 % relative humidity and 40 ± 2 °C temperature / 75 ± 5 % relative humidity during 6 months and they were evaluated in terms of particle size, PdI value and zeta potential during storage period. MTX loading studies were performed to optimum nanoparticle formulations (F1: 0.250 % low viscous chitosan, 0.125 % TPP; F4: 0.500 % low viscous chitosan, 0.125 % TPP). Prepared MTX loaded chitosan nanoparticles were evaluated in terms of yield, encapsulation efficiency and accelerated stability studies. After that, MTX loaded chitosan nanoparticles (1 mg MTX) were radiolabeled with 99mTc (1 mCi) using stannous tartrate (1 mg) and ascorbic acid (0.1 mg) which are used as reducing agent and antioxidant agent, respectively. Radiolabeling yields were observed over 90%, with the performed quality control studies. In vitro quality control and cell culture studies were performed on the labeled MTX loaded chitosan nanoparticles. Cancerous/Healty cell incorporation ratios of 99mTc-MTX-Chitosan nanoparticles were determined on MCF-7 (breast cancer) and HaCaT (human keratinocyte) cell lines. According to the studies; newly developed formulations have 2 times higher uptake than cancerous than healty cell line. After all these experience depending on good properties of developed formulations (F1m ve F4m) such as: apropriate mean particle size (F1m: 169,000 ± 10,316 nm; F4m: 427,633 ± 61,312 nm), PdI value (F1m: 0,499 ± 0,020; F4m: 0,594 ± 0,076) and zeta potential (F1m: 20,133 ± 1,144 mV; F4m: 29,067 ± 2,201 mV), encapsulation efficiency (F1m: 35,209 ± 1,333 %; F4m: 63,539 ± 3,931 %), high labeling yield (˃90%) and stability, high Canserous/Healty cell uptake ratio (F1m: 6,646; F4m: 2,215) it was considered that 99mTc-MTX-Chitosan nanoparticles might be used in human breast cancer diagnosis in nucleer medicine patients. Keywords: Technetium-99m; Methotrexate; Chitosan; Nanoparticle; Radiolabeling; Cell culture; Breast cancer e-mail: meliha.ekinci@ege.edu.tr

- by Meliha Ekinci
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- Breast Cancer, Chitosan, Nanoparticles, Drug Delivery System

This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like 211 At, 223 Ra, 225 Ac/ 213 Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.

- by Ján Kozempel and +1
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- RADIOPHARMACY, Radiopharmaceutical Chemistry, Targeted Therapy, Radionuclide Therapy

ÖZET “Therapy” ve “diagnostics” kelimelerinin birleştirilmesiyle oluşan “teranostik” terimi, genel anlamıyla hastalık yönetim sürecindeki
tanı ve tedavi yönteminin birleştirilmesidir. Uzayan yaşam süresi ve
kronik hastalıkların artması ile yeni ilaç teknolojilerinin geliştirmesinin
önemi gün geçtikçe artmaktadır. Bu yeni ilaç sistemlerinden biri olan
ve başta kanser olmak üzere birçok hastalığın tanı ve tedavisinde umut
veren kullanımı ile yenilikçi bir yaklaşım sunan teranostikler ile tanıdan elde edilen sonuçlarla hedefe özgü tedavi birleştirilebilmekte; kişiselleştirilmiş tıp alanında uygulamalar yapılabilmektedir.
Teranostiklerin kullanımı ile hastalığın tanısı ve tedavisinin yanı sıra
hasta tarafından tedaviye verilen cevabın izlenmesi, ilaç etkinliğinin ve
güvenliğinin artırılması da amaçlamaktadır. Bu derlemede, teranostiklerin manyetik rezonans görüntüleme, optik görüntüleme, bilgisayarlı
tomografi, ultrasonografi ve nükleer tıp yöntemleri gibi görüntüleme
yöntemlerinde kullanılmasıyla ilgili çalışmalar incelenerek örneklendirilmiştir. Ayrıca teranostiklerin kullanılabileceği nükleer onkoloji,
enfeksiyon hastalıkları, nörodejeneratif hastalıklar ve nöroinflamasyon,
kardiyovasküler hastalıklar ve inflamasyon hastalıkları gibi hastalıklara göre sınıflandırılması yapılarak, teranostiklere genel bir bakış sağlanmıştır.

- by Meliha Ekinci
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- Nuclear medicine, Cancer Therapy, RADIOPHARMACY, Cancer Diagnosis

Radiopharmacy in PET and Therapy

- by Pillai M.R.A.
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- Nuclear medicine, RADIOPHARMACY

This study aimed to developed radiolabeled methotrexate (MTX) loaded nanoparticulate systems for breast cancer imaging. For this aim, two formulations (F1 and F2) of MTX loaded chitosan nanoparticles (CSNPs) were prepared via ionic gelation process by using CS and tripolyphosphate (TPP). The obtained results showed that by using F1 and F2 formulations with mean diameter of 169.000 nm and 427.633 nm, zeta potential of 20.133 mV and 29.067 mV were successfully developed with ionotropic gelation process and the encapsulation efficiency (EE) of F1 and F2 was found nearly 35% and 64% respectively. In addition, MTX-CSNPs were radiolabeled by Technetium-99m (99m Tc) and radiochemical purity and stability of labeled compound were performed using a gamma counter up to 6 h. Results indicated that MTX-CSNPs were radiolabeled by 99m Tc with high labeling efficiency (>90%) and stability. For in vitro incorporation studies the uptake differences between 99m Tc labeled MTX loaded and unloaded CSNPs, reduced/hydrolyzed (R/H) 99m Tc were evaluated in human breast cancer (MCF-7) and human keratinocyte (HaCaT) cell lines. According to cell culture studies, the incorporation percentages of 99m Tc-MTX-CSNPs were highly uptake in cancer cell line. The results demonstrated that radiolabeled MTX-CSNPs may be a promising agent for breast cancer diagnosis.

- by Derya İlem-Özdemir and +1
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- Pharmaceutical Technology, RADIOPHARMACY, Nanoparticulate Drug Delivery System
- by Pillai M.R.A.
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- Nuclear medicine, RADIOPHARMACY

Cancer is a leading cause of death, the second most common
cause, exceeded only by heart disease. Still, the current clinical
imaging methods and treatments are in many situations unable
to provide timely detection and curative therapy. The field of drug
delivery stands to be significant advances in nanotechnology and
benefits of novel nanotechnology in oncology already starts. New
strategies are being designed to deliver chemotherapeutic drugs
or imaging agents to the tumor at higher concentrations with
minimal damage to normal tissues. This review will focus on how
nanoparticles are able to function as carriers for chemotherapeutic
drugs to increase their therapeutic index; how can be used as
imaging agents to detect and monitor cancer progression.

- by Meliha Ekinci
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- Nanoparticles, Cancer Therapy, RADIOPHARMACY, Diagnosis

The object of the current study was to prepare novel microemulsion formulations of aprotinin for parenteral delivery and to compare in vitro characteristics and release behaviour of different Technetium-99m (99m Tc)-Aprotinin loaded microemulsion formulations. In addition, cytotoxicity of microemulsion formulation was evaluated with cell culture studies on human immortalized pancreatic duct epithelial-like cells. For this aim, firstly, pseudo-ternary phase diagrams were plotted to detect the formulation region and optimal microemulsions were characterized for their thermodynamic stability, conductivity, particle size, zeta potential, viscosity, pH and in vitro release properties. For in vitro release studies aprotinin was labelled with 99m Tc and labelling efficiency, radiochemical purity and stability of the radiolabeled complex were determined by several chromatography techniques. Radiolabeling efficiency of 99m Tc-Aprotinin was found over than 90% without any significant changes up to 6 hours after labelling at room temperature. After that, in vitro release studies of 99m Tc-Aprotinin loaded microemulsions were performed with two different methods; dissolution from diffusion cells and dialysis bags. Both methods showed that release rate of 99m Tc-Aprotinin from microemulsion could be controlled by microemulsion formulations. Drug release from the optimized mi-croemulsion formulations was found lower compared to drug solution at the end of six hours. According to stability studies , the optimized formulation was found to be stable over a period of 12 months. Also, human immortalized pancreatic duct epithelial-like cells were used to evaluate the cytotoxicity of optimum formulation. Developed microemulsion did not reveal cytotoxicity. In conclusion the present study indicated that the M1-APT microemulsion is appropriate for intravenous application of aprotinin.

- by Derya İlem-Özdemir
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- Pharmaceutical Technology, RADIOPHARMACY

Advances in nanotechnology have increased the use of polymers with modifiable properties in the development of drug delivery systems. In the development of more effective radiopharmaceuticals which can be used especially in imaging and treatment, the application of nanoparticles that composed of polymeric systems has gained importance today. Synthetic polymers such as poly ethylene oxide (PEO), poly glutamic acid (PGA) and poly lacticoglycolic acid (PLGA) are examples of polymers suitable for clinical use and used in the development of nanocarriers. Liposomes, micelles, polymerosomes and nanoemulsions are referred to as nanoparticle systems composed of polymeric systems. These systems are more localized in the desired tissue due to the increased permeation and retention effect (EPR), and increase the effectiveness in treatment and diagnosis. In this review, the studies on the use of polymers used in imaging and treatment and the applications of nuclear medicine in the nanoparticle systems prepared with these polymers will be evaluated.

- by Meliha Ekinci
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- Nuclear medicine, Nanoparticles, Drug Delivery System, RADIOPHARMACY

Objective: In recent years, thanks to advances in targeted radionuclide therapy, significant advances have been made in the early diagnosis and treatment of diseases. With the emergence of the concept of theranostic",
which combines diagnosis and treatment methods, Lutetium-177 (Lu-177) has gained an important place in targeted therapy and has become a leading compound in this field. In this review, it is aimed to explain the basic information about radiopharmaceuticals, targeted therapy, theranostics and Lu-177, to present 177Lu-labeled molecular carriers and 177Lu-labeled radiopharmaceuticals and to review the studies on these subjects.
Result and Discussion: 177Lu is a theranostic agent with a half-life of 6.7 days, which can be used in diagnosis and treatment in nuclear medicine thanks to its γ and β rays. Its high specific activity and easy access
to these activity levels as well as its relatively long half-life can be considered as the main factors of interest in the clinical use of this radionuclide. The clinical utility of 177Lu, a preferred radioisotope for targeted radionuclide therapy, in the treatment of neuroendocrine tumors, prostate cancer, non-Hodgkin lymphoma, adenocarcinoma, and liver cancer, and in alleviating bone pain, was investigated, and as a result, 177Lu was found to show great potential in cancer and pain therapy. With these areas of use, we believe that Lu-177 will have an important place in the field of nuclear medicine in the future.
Keywords: Lutetium-177, radionuclide, radiopharmaceutical, theranostic

- by Meliha Ekinci
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- RADIOPHARMACY, Radionuclides, Theranostics, Radiopharmaceuticals

Bacterial infection is one of the major causes of morbidity and mortality especially in developing countries. The aim of this study was to develop a new radiophar-maceutical for imaging infection. The labeling conditions were optimized, and lyophilized kits were developed for instant preparing. The stability of 99m Tc-AMOX in human serum was identified, sterility and pyrogenicity of the radiopharmaceutical were estimated, gamma scintigraphy and in vivo biodistribution with infected rats were investigated. The promising properties of 99m Tc-AMOX combined with the development of reliable and instant lyophilized kit afford the opportunity of inflammatory process imaging.

- by Derya İlem-Özdemir and +1
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- RADIOPHARMACY, Radiopharmaceutical Chemistry

Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to describe trends in the field. Results This commentary of highlights has resulted in 19 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

- by Renata Mikołajczak
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- Radiochemistry, Medicine, RADIOPHARMACY, Springer
- by Meliha Ekinci
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- Nanotechnology, RADIOPHARMACY

Lung cancer is the leading cause of death (male and female) globally, responsible for over 1.8 million deaths. Although there have been some advances in the treatment of lung cancer, the early detection remains an issue globally. The necessity of new drugs able to efficiently accumulate and image lung cancer is quite required. In this study was developed PLGA nanoparticles loaded with Lamivudine (PLGA-NPs-LAM). The PLGA-NPs-LAM was characterized, radiolabeled with radioactive technetium (99m Tc), and in vitro evaluated. The results showed a medium size of 203.667 ± 1.436 nm, with a PDI value of 0.063 ± 0.052, and a superficial charge of − 4.597 ± 0.368 mV. The entrapment efficacy demonstrated was 48.346 ± 1.742% of LAM. Radiolabeling of PLGA-NPs-LAM with Technetium-99 m (99m Tc) showed high efficiency (>93%). The in vitro assay human lung cancer (A-549) and human fibroblast (L-929) cell lines showed that the NPs were higher uptake in A-549 line than L-929. The data demonstrated that [ 99m Tc]Tc-PLGA-NPs-LAM may be a promising agent for lung cancer diagnosis.

- by Meliha Ekinci
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- Cell Culture, Lung Cancer, RADIOPHARMACY, Cancer Diagnosis
- by Meliha Ekinci
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- Radiation, Cancer, Nanoparticle, Nuclear medicine

- by Makbule Asikoglu
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- Pharmaceutical Technology, RADIOPHARMACY

The aim of current study is to develop new nanostructured lipid carrier systems (NLCSs) containing imatinib mesylate (IMT) and evaluate their targeting efficiency on NIH-3T3 as fibroblast cells and CRL-1739 as gastric adenocarcinoma cells with radiolabeled formulations. Three formulations (F1-IMT, F2-IMT and F3-IMT) were prepared and radiolabeled with 1 mCi/0.1 mL of [ 99m Tc]Tc. The effect of reducing and antioxidant agents on radiolabeling process was evaluated and radiochemical purity of formulations was performed by radio thin-layer radiochromatography (RTLC). The results demonstrated that the radiochemical purity was found to be above 90% for [ 99m Tc]Tc-F1-IMT and [ 99m Tc]Tc-F2-IMT, while radiochemical purity of [ 99m Tc]Tc-F3-IMT was found to be 85.61 ± 2.24%. Also, [ 99m Tc]Tc-F1-IMT and [ 99m Tc]Tc-F2-IMT have better stability in cell medium and saline than [ 99m Tc]Tc-F3-IMT. Targeting efficiency of [ 99m Tc]Tc-F1-IMT and [ 99m Tc]Tc-F2-IMT comparatively evaluated by cell binding studies with [ 99m Tc]NaTcO4 on NIH-3T3 and CRL-1739 cells. The cell binding capacity and targeting/non-targeting cell uptake ratio of these two formulations was found to be higher than [ 99m Tc]NaTcO4 in CRL-1739. It is thought that the knowledge achieved in this study would contribute to using [ 99m Tc]Tc-F1-IMT and [ 99m Tc]Tc F2-IMT as an diagnosis and treatment agents. ARTICLE HISTORY

- by Meliha Ekinci
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- RADIOPHARMACY, Radiopharmaceuticals, Radiolabeling NPs, Technetium-99m

Background The cancer is serious health problem and leading cause of death in the world. Area covered There have intensively studied for diagnosis and therapy of this disease and these studies provided important insights into their mechanism of action and therapeutic/diagnostic effects. The accurence rates of cancer has dramatic increase, particularly in the developed countries. Although there are many different strategies about diagnosis and treatment for cancer, more effective new approaches are needed. Expert opinion In this review, we summarize recent developments on cancer diagnosis, radiopharmaceuticals in cancer diagnosis, nanoparticulate systems in cancer diagnosis, T cells in cancer diagnosis, cancer therapy and pharmacokinetic of anticancer drugs. We thought that while there are some current limitations such as clinical studies, ranging from diagnosis to theraphy, future improvements in cancer diagnosis and treatment will meet the most relevant issues required for the eventual approval of nano-drugs, radiopharmaceuticals, T cells in clinical practice.

- by Meliha Ekinci
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- Cancer, Cancer Therapy, RADIOPHARMACY, Cancer Diagnosis

Radiopharmaceuticals have applications in biologic research, drug
discovery, diagnosis of human disease and molecular therapeutics
for a wide variety of medical conditions. With the increasingly central
role of radiotracers for non-invasive imaging of animal models
and human research, small animal imaging centers are likely to
have a growing interest in development of radiopharmaceutical
science. Although animal experiments are giving the most valuable
information about the drug behavior in the biological system. Also
every year, millions of experimental animals are used all over the
world. The pain, distress and death experienced by the animals
during scientific experiments have been a debating issue for a long
time.
Use of cell culture techniques play a key role in new drug
development studies by giving information about receptor
interaction, drug uptake/efflux or interaction with other cellular
receptors and cellular metabolism.
This review will focus on how cell culture techniques are able to
use to estimate the uptake of developed radiopharmaceutical by
targeted receptor-bearing cells.

- by Meliha Ekinci
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- Cell Culture, RADIOPHARMACY, Radiopharmaceuticals

Cationic nanoparticles of CS were developed according to ionotropic gelation process as potential cancer
cell targeting agent. CS nanoparticles (CSNP) (F1 and F2) diameters varied between ranges of 100
e800 nm. Particle size, polydispersity index and zeta potential values of formulations were measured by
photon correlation spectroscopy. The morphological analysis for CSNPs was provided with scanning
electron microscopy. For cell incorporation study, F1 and F2 were directly labeled by Technetium-99m
(99mTc), radiochemical purity and stability of the complex were analyzed by radioactive thin layer
chromatography and radioactive high performance liquid chromatography studies. After that, incorporation
of 99mTc labeled F1 and F2 were evaluated in U2OS and NCIeH209 cell lines. The six well plates
were used for all experiments and the integrity of each cell monolayer was checked by measuring its
TEER values with an epithelial voltammeter. Results confirmed that F1 and F2 formulations were successfully
radiolabeled with 99mTc. The incorporation percentages of 99mTc labeled F1 and F2 in NCIeH209
and U2OS cell lines were found different when they compared to 99mTc solution. Since 99mTc labeled F1
and F2 highly uptake in cancer cell line. The results demonstrated that radiolabeled CSNPs may be a
promising agent for cancer diagnosis.

- by Derya İlem-Özdemir and +1
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- Pharmaceutical Technology, Nanoparticles, RADIOPHARMACY

Background: Aprotinin is a monomeric globular polypeptide, which derived from bovine lung
tissue and theoretically attractive molecule in ameliorating the effects of acute pancreatitis.
Acute pancreatitis is an inflammatory condition of the pancreas that is painful and at times
deadly. Over the following two decades Aprotinin therapeutic potential on pancreatitis is
proven experimentally, its clinical therapeutic success is limited due to low targeting to
pancreas.
Objective: The aim of this study was to evaluate the biodistribution of Technetium-99m (99mTc)-
Aprotinin solution (99mTc-Aprotinin-S) and 99mTc-Aprotinin loaded microemulsion, which was
prepared for the aim of treatment for acute pancreatitis.
Method: Aprotinin was radiolabeled with 99mTc. Radiochemical purity was determined with
radioactive thin layer chromatography studies. 99mTc-Aprotinin-S and 99mTc-Aprotinin loaded
microemulsion (99mTc-Aprotinin-M) was administered to acute edematous, severe necrotizing
pancreatitis and air pouch model induced rats. Tissue distribution of Aprotinin was investigated
with gamma scintigraphy and biodistribution studies.
Results: Aprotinin was radiolabeled by 99mTc with high radiochemical purity (95.430 ± 0.946%).
The complex was found to be stable at room temperature up to 6 h. Animal studies have shown
that similar to that of other small proteins Aprotinin is accumulated primarily in the kidney.
The scintigraphy and biodistribution studies showed that, while i.v. administration of 99mTc-
Aprotinin-S distributed mostly in kidneys and bladder, 99mTc-Aprotinin-M, with droplet size of
64.550 ± 3.217 nm, has high uptake in liver, spleen and pancreas.
Conclusion: This might be concluding that microemulsions may be suggested as promising
formulations for selectively targeting Aprotinin to pancreas inflammation.

- by Derya İlem-Özdemir and +2
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- RADIOPHARMACY, Pharmaceutical Formulation Technology

Bisphosphonates can be labeled with Technetium-99m ( 99m Tc) and are used for bone imaging because of their good localization in the skeleton and rapid clearance from soft tissues. Over the last decades bone scintigraphy has been used extensively in the evaluation of oncological patients to provide information about the sites of bone lesions, their prognosis and the effectiveness of therapy by showing the sequential changes in tracer uptake. Since the lesion visualization and lesion/bone ratio are important utilities for a bone scanning radiopharmaceutic; in this study incorporation of 99m Tc labeled alendronate sodium ( 99m Tc-ALD) was evaluated in U 2 OS (human bone osteosarcoma) and NCI-H209 (human bone carcinoma) cell lines. ALD was directly labeled by 99m Tc, radiochemical purity and stability of the complex were analyzed by radioactive thin layer chromatography and radioactive high performance liquid chromatography studies. For cell incorporation study, NCI-H209 and U 2 OS cell lines were used with standard cell culture methods. The six well plates were used for all experiments and the integrity of each cell monolayer was checked by measuring its transepithelial electrical resistance (TEER) with an epithelial voltammeter. Results confirmed that ALD was successfully radiolabeled with 99m Tc. 99m Tc-ALD incorporated with NCI-H209 and U 2 OS cells. The uptake percentages of 99m Tc-ALD in NCI-H209 and U 2 OS cell lines were found significantly different. Since 99m Tc-ALD highly uptake in cancer cell line, the results demonstrated that radiolabeled ALD may be a promising agent for bone cancer diagnosis.

- by Derya İlem-Özdemir
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- Orthopaedics, RADIOPHARMACY, Radiopharmaceutical Chemistry

The author discusses the feasibility of PET measurements of rHct using 68Ga-labelled plasma albumin and 15O- or 11C-labelled red blood cells, administered either simultaneously or sequentially. The effects of regional cerebral haematocrit, amount of administered radioactivity and the timing and duration of PET scans on measurement error are examined. The radiation dose to various organs resulting from several protocols estimated and compared. The consideration of both absorbed radiation dose and effects of protocol on measurement errors are generally applicable to any physiological measurements requiring determination of more than one parameter.

- by Kimberlee Kearfott
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- Pharmacology, Physiology, Radiochemistry, Radiation Health Physics

Nonivasive diagnosis of cancer can be provided by molecular imaging using hybrid modality to obtain better sensitivity, specificity and depiction localization of the disease. In this study, we developed a new molecular imaging agent, radiogadolinium(III)-DOTA-PAMAM G3.0-trastuzumab in the form of 147Gd-DOTA-PAMAM G3.0-trastuzumab, that can be both target-specific radiopharmaceutical in SPECT as well as targeted contrast agent in MRI for the purpose of diagnosis of HER-2 positive breast cancer. 147Gd radionuclide emits γ-rays that can be used in SPECT modality, but because of technical constraint, 147Gd radionuclide was simulated by its radioisotope, 153Gd. Gd-DOTA complex has also been known as good MRI contrast agent. PAMAM G3.0 is useful to concentrate Gd-DOTA compelexes in large quantities, thus minimizing the number of trastuzumab molecules used. Trastuzumab is human monoclonal antibody that can spesifically interact with HER-2. Synthesis of radiogadolinium(III)-DOTA-PAMAM G3.0-trastuzumab was initiated by conjugating DOTA NHS ester ligand with PAMAM G3.0 dendrimer. The DOTA-PAMAM G3.0 produced was conjugated to trastuzumab molecule and labeled with 153Gd. Characterization DOTA-PAMAM G3.0-trastuzumab immunoconjugate was performed using HPLC system equipped with SEC. The formation of immunoconjugate was indicated by the shorter retention time (6.82 min) compared to that of trastuzumab (7.06 min). Radiochemical purity of radiogadolinium(III)-DOTA-PAMAM G3.0-trastuzumab was >99% after purification process by PD-10 desalting column. Radiogadolinium(III)-DOTA-PAMAM G3.0-trastuzumab compound was stable at room temperature and at 2–8 0C as indicated by its radiochemical purity 97.6 ± 0.5%–99.1 ± 0.5% after 144 h storage.

- by Renata Mikolajczak
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- Radiochemistry, Medicine, RADIOPHARMACY, Springer

The aim of this thesis is to develop a nanoparticular bioradiopharmaceutical containing atezolizumab that can be used for the diagnosis of early stage non-small cell lung cancer in nuclear oncology patients with high involvement in the target tissue with good scintigraphic separation and low radiation damage in non-target tissue. For this purpose, PLA/PVA nanoparticles were prepared by evaluating the effect of various parameters and the formulations were optimized after physicochemical characterization and surface and morphological property analysis. These nanoparticles were kept in stability cabinets containing 25±2 °C temperature, 60±5% relative humidity and 40±2 °C temperature, 75±5% relative humidity for 6 months and evaluated in terms of particle size and distributions and zeta potentials. Then, the formulation with ideal properties was studied and PLA/ PVA/Atezolizumab nanoparticles were prepared to actively target the PD-L1 ligand in non-small cell lung cancer cells using three different preparation methods (solvent evaporation, adsorption and covalent binding). The prepared PLA/PVA/Atezolizumab nanoparticles were evaluated in terms of loading efficiency, encapsulation efficiency and accelerated stability studies and the most suitable preparation method was determined to be solvent evaporation method, and in subsequent studies, PLA/PVA/Atezolizumab nanoparticles prepared by this method were used. The nanoparticles were then labeled with 99mTc radionuclide using stannous chloride as the reducing agent. As a result of the quality control studies, it was determined that the labeling efficiency was over 99%. In vitro quality control, cytotoxicity and cell culture studies were performed with 99mTc labeled PLA/PVA/Atezolizumab nanoparticles. 99mTc-PLA/PVA/Atezolizumab nanoparticles Tumor/Normal cell binding rates were compared with studies using A-549 (non-small cell lung cancer cell) and L-929 (healthy fibroblast cell) cell lines. As a result of the studies, it was found that the formulations developed in the cancerous cell showed more than the uptake of the healthy cell. It was seen from the flow cytometry and MTT analysis results that they were effectively retained in cell lines and did not show cytotoxicity. As a result of biodistribution studies performed in nude male mice carrying lung cancer tumors, it was observed that active targeted nanoparticle formulation was more retained in tumor tissue than non-active targeted nanoparticle formulation (> 14 times). The formulation developed as a result of all these studies has; suitable particle size (230.6±1.768 nm) and distribution (0.163±0.036) and zeta potential (-2.23±0.55 mV), high antibody binding (80.58%), high radiolabeling efficiency (99%) and stability, high Tumor/Normal tissue uptake ratio (>14 times) it was considered that 99mTc-PLA/PVA/Atezolizumab nanoparticles might be used in the diagnosis of non-small cell lung cancer and in evaluating the response to treatment in lung cancer patients was found to be promising.

- by Meliha Ekinci
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- Nanoparticles, Drug Delivery System, Lung Cancer, RADIOPHARMACY

Radiopharmaceuticals contain radionuclides and pharmaceuticals. Research on radiopharmaceuticals has been increasing in recent years by increasing the
importance of early diagnosis in diseases. It is generally accepted that the investigation and development of new radiopharmaceuticals are time and resource-consuming.
Computational methods have provided exciting contributions to pharmaceutical research and development. The need for designing new radiopharmaceutical drugs enhances the importance of computational programs. At this point, the structure,
chemical, physical and physicochemical properties of molecules should be predicted/ evaluated by using computational methods. While these methods obtain
useful estimates, they make it easier for researchers and clinicians to make the right choices. Also, by providing accurate and effective results, they contribute to reducing
the cost of research and can be used to simulate complex biochemical situations before research helping us to avoid harmful effects of drugs. In this study, the authors
emphasis about radiopharmaceuticals and the computational tools related to the development of new radiopharmaceuticals.

- by Emre Özgenç
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- Drug development, Drug Delivery System, RADIOPHARMACY, Factorial Design

Introducción: El objetivo del presente trabajo fue desarrollar una formulación liofilizada que permitiera obtener el 188 Re-HEDP con elevada eficiencia. Materiales y Métodos: La formulación fue liofilizada en dos viales: A. HEDP, floruro de estaño (II), ácido gentísico y ácido clorhídrico 0,1 mol/L; B. perrenato de sodio, acetato de sodio 0,054 g/mL en solución de cloruro de sodio 0,9 %. En la eficiencia de marcaje del HEDP con 188Re se estimó la influencia de 5 factores a partir de un diseño experimental del tipo 2 5 (pH, tiempo de incubación a 80 °C, relación molar Sn 2+ :ReO 4 -, relación molar HEDP: ReO 4 -, masa de perrenato de sodio). Se estudió la biodistribución del compuesto en ratas Sprague Dawly, tras la administración i.v. de 0.75 mg de HEDP marcado con 188 Re. Resultados y Discusión: A partir de los resultados del diseño, se determinó que los factores que influían en el marcaje eran el pH ácido, la adición de portador y una relación alta de HEDP: ReO 4 -.

- by Luis Ramón Velázquez Maldonado
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- RADIOPHARMACY

The aim of the present study is to evaluate doxycycline hyclate biodistribution by gamma scintigraphy in inflamed rats. The Technetium-99m (99m Tc) eluted was used for labeling of doxycycline hyclate. 99m Tc-doxycycline hyclate was prepared with a radiochemical yield greater than 90%, adding 99m Tc to doxycycline hyclate in the presence of stannous tartarate and ascorbic acid. Scintigraphic studies in rats were carried out using experimentally induced inflammation in the left thigh muscle using turpentine oil. Static images were acquired by a gamma camera in different time intervals for 6 hours. For quantitative evaluation of 99m Tc-doxycycline hyclate uptake, the regions of interest were drawn around and uptakes were calculated as counts per pixel. According to in vivo studies, the accumulation of 99m Tc-doxycycline hyclate in the inflamed muscle was found higher than the control muscle. Teknesyum-99m Doksisiklin Hiklat'ın Biyodağılımı Özet Çalışmamızın amacı, inflamasyon oluşturulmuş ratlarda doksisiklin hiklatın tutulumunu gama sintigrafi ile incelemektir. Doksisiklin hiklatın Teknesyum-99m eluatı ile işaretlendi. 99m Tc-doksisiklin hiklat, kalay tartarat ve askorbik asit varlığında %90'ın üzerinde bir radyoişaretleme verimi ile işaretlendi. Sol uyluk kaslarında turpentin yağı ile inflamasyon oluşturulmuş ratlarda görüntüleme çalışmaları yapıldı. Gama kamera ile 6 saat boyunca farklı zamanlarda statik görüntüler alındı. 99m Tc-doksisiklin hiklat tutulumunun kantitatif değerlendirmesi için, ilgi alanları çizildi ve piksel başına düşen sayım miktarı hesaplandı. İn vivo çalışmalara göre, 99m Tc-doksisiklin hiklat'ın inflame kasdaki tutulumu normal kasdan daha yüksek bulundu.

- by Derya İlem-Özdemir
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- Pharmaceutical Technology, RADIOPHARMACY

Radiolabeled antibiotics are promising radiopharmaceuticals for the precise diagnosis and detection of infectious lesions. Doxycycline Hyclate (DOX) was chosen to investigate new 99m Tc-labeled antibacterial agent. Ready to use freeze dry kits were formulated with optimum labeling conditions. Human serum stability, sterility, and pyrogenicity of kits were estimated, and gamma scintigraphy, in vivo biodistribution, and histopathological studies with bacterial infected rats were performed. DOX were successfully labeled by 99m Tc with high radiochemical purity, and the labeled compound was stable in human serum. Kits were sterile, pyrogen-free, and stable up to 6 months. Static images depicted rapid distribution throughout the body and high uptake in bacterial infected thigh muscle. The uptake ratios of radiopharmaceuticals in infected thigh muscle were found above 2 up to 5 h. Five hours after injection, the rats were sacrificed, and biodistribution was determined. Samples of bacterial infected muscle, healthy muscle, blood, liver, spleen, lung, kidney, stomach, intestine, urine and heart were weighed, and the radioactivity was measured by using a gamma counter. The %ID/g of 99m Tc-DOX was found 0.23 ± 0.06 for infected thigh muscle. According to the imaging, biodistribution, and histopathological studies, the promising characteristics of 99m Tc-DOX make the new radiopharmaceutical valuable to examine for future studies.

- by Derya İlem-Özdemir and +1
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- Pharmacy, RADIOPHARMACY

The aim of this study was to develop aprotinin-loaded microemulsion (MA) for intravenous
administration and evaluate the biodistribution and therapeutic potential of developed
formulation in acute pancreatitis models in rats. Phase diagrams were constructed to identify
microemulsion region and the optimal microemulsion was evaluated for physicochemical
properties and treatment effect in rats, and comparisons made with the solution of aprotinin
(SA). To evaluate the biodistribution of the drug by gamma scintigraphy aprotinin was
radiolabeled with 99mTc radionuclide. Mild and severe acute pancreatitis was induced in rats by
subcutaneous injections of cerulein and introductal infusion of 3% sodium taurocholate into
the bile-pancreatic duct, respectively. In addition, serum amylase and pancreatic tissue
myeloperoxidase activities were measured to evaluate the pancreatic damage. According to
gamma scintigraphy and biodistribution studies, accumulation times and distribution of
99mTc-MA and SA were different. While MA was highly uptake by reticuloendothelial system,
SA was mostly excreted by kidneys and bladder. Compared with the mild acute pancreatitis
group, treatment with MA significantly decreased the serum amylase activity and pancreas
myeloperoxidase activity. Furthermore, the protease inhibitor molecule aprotinin has
therapeutic potential in acute pancreatitis. Finally, MA may be suggested as a promising
alternative for treatment of acute pancreatitis.

- by Derya İlem-Özdemir and +1
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- Pharmaceutical Technology, RADIOPHARMACY

The purpose of this work is to prepare a self-microemulsifying drug delivery system (SMEDDS) for risedronate sodium (RSD) and to compare the permeability with RSD solution. The solubility of RSD was determined in different vehicles. Phase diagrams were constructed to determine the optimum concentration of oil, surfactant, and cosurfactant. RSD SMEDDS was prepared by using a mixture of soybean oil, cremophor EL, span 80, and transcutol (2.02:7.72:23.27:61.74, w/w, respectively). The prepared RSD SMEDDS was characterized by droplet size value. In vitro Caco-2 cell permeability studies were performed for SMEDDS and solution of radioactive (99 m Tc-labeled RSD) and nonradioactive RSD. The experimental results indicated that RSD SMEDDS has good stability and its droplet size is between 216.68 ± 3.79 and 225.26 ± 7.65 during stability time. In addition, RSD SMEDDS has higher permeability value than the RSD solution for both radioactive and nonradioactive experiments. The results illustrated the potential use of SMEDDS for delivery of poorly absorbed RSD.

- by Derya İlem-Özdemir and +1
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- Pharmaceutical Technology, RADIOPHARMACY, Pharmaceutical Sciences

Abstract In the present study 99mTc-MTX was prepared
with high labeling yield by a new simple and easy formulation
method. According to cell culture studies, 99mTc-
MTX incorporated with both MCF-7 and CRL8798 cells,
with significant differences in the uptake percentages. Since
99mTc-MTX highly uptake in cancer cell line, the results
demonstrated that radiolabeled MTX may be promising for
breast cancer diagnosis of oncological patients.

- by Meliha Ekinci and +1
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- RADIOPHARMACY, Radiopharmaceutical Chemistry

The syntheses of four a-aminomethyl phosphonates and their complexation studies with 99mTc and 186/188Re are reported. Complexation
conditions were standardized to give maximum yields, which ranged from 90–97%. The yields of complexation were estimated by paper
chromatography. The 99mTc complexes were stable for more than 4 h, while the 186/188Re complexes were stable for 3–8 days when stored
at 4°C. Biodistribution of these complexes in Wistar rats were carried out, and the uptake in bone and other soft tissue are detailed. Bone
uptake of the 99mTc complexes varied from 40–60% at 30 min postinjection depending on the ligands. The uptake in soft tissue was
minimum with all the complexes. A comparison of the biodistribution studies of the 99mTc complexes with that of the well-established
radiopharmaceutical 99mTc-MDP was carried out for the purpose of evaluating the efficacy of the radiopharmaceutical preparation with the
complexes of these ligands. The bone uptake of the 186/188Re complexes varied from 19–28% corresponding to 1.6–3% per g at 3 h
postinjection. The residual activity in both 99mTc and 186/188Re complexes showed renal clearance. © 2001 Elsevier Science Inc. All rights
reserved.
Keywords: Tetraphosphonates; 99mTc complexes; 186Re complexes; 99mTc-MDP; 186Re-HEDP; Skeletal imaging

- by Pillai M.R.A.
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- RADIOPHARMACY

The aim of the current study is to develop new nanostructured lipid carrier systems (NLCS) containing imatinib mesylate (IMT) and evaluate their targeting efficiency on NIH-3T3 as fibroblast cells and CRL- 1739 as gastric adenocarcinoma cells with radiolabeled formulations. Three formulations (F1-IMT, F2- IMT, and F3-IMT) were prepared and radiolabeled with 1mCi/0.1mL of [99mTc]Tc. The effect of reducing
and antioxidant agents on the radiolabeling process was evaluated and radiochemical purity of formulations was performed by radio thin-layer radiochromatography (RTLC). The results demonstrated that the radiochemical purity was found to be above 90% for [99mTc]Tc-F1-IMT and [99mTc]Tc-F2-IMT, while radiochemical purity of [99mTc]Tc-F3-IMT was found to be 85.61 ± 2.24%. Also, [99mTc]Tc-F1-IMT and [99mTc]Tc-F2-IMT have better stability in cell medium and saline than [99mTc]Tc-F3-IMT. Targeting efficiency of [99mTc]Tc-F1-IMT and [99mTc]Tc-F2-IMT comparatively evaluated by cell-binding studies with [99mTc]NaTcO4 on NIH-3T3 and CRL-1739 cells. The cell binding capacity and targeting/non-targeting cell uptake ratio of these two formulations was found to be higher than [99mTc]NaTcO4 in CRL-1739. It is thought that the knowledge achieved in this study would contribute to using [99mTc]Tc-F1-IMT and [99mTc]Tc F2-IMT as diagnosis and treatment agents.

- by Emre Özgenç
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- Cell Culture, RADIOPHARMACY, Nanostructures, Characterization

ABSTRACT In the present study 99mTc-MTX was prepared with high labeling yield by a new simple and easy formulation method. According to cell culture studies, 99mTc-MTX incorporated with both MCF-7 and CRL8798 cells, with significant differences in the uptake percentages. Since 99mTc-MTX highly uptake in cancer cell line, the results demonstrated that radiolabeled MTX may be promising for breast cancer diagnosis of oncological patients.

Alendronate sodium (ALD) is a second generation amino bisphosphonate that use for treatment of bone diseases. Since ALD is poorly absorbed from the gastrointestinal tract and its absorption is markedly reduced by food, the aim of this study is to evaluate the bone uptake of ALD through vaginal route. To evaluate the bone uptake of ALD by gamma scintigraphy, ALD was radiolabeled with Technetium-99m (99mTc). Vaginal suppositories and injectable solution of 99mTc-ALD was prepared and gamma scintigraphy studies were performed with intravaginally and intravenously 99mTc-ALD applied rabbits. The results were revealed that ALD was successfully labeled with 99mTc. After intravaginal and intravenous application, 99mTc-ALD showed a high uptake in bone. Despite accumulation times and uptake ratios showed differences between administration routes, our preliminary observations suggest that the intravaginal route appears to be a viable alternative for ALD application and should be evaluated in future clinical studies.

Radiation absorbed dose estimates were made for K-38, Rb-81, Rb-82, and Cs-130, potential radionuclides for myocardial and brain studies with positron emission tomography (PET). Biodistribution data for K-42, Rb-86, and Cs-137 in rats were used, together with the most recent radiation absorbed dose computational techniques and data. Renal radiation absorbed doses for K-38, Rb-81, Rb-82, and Cs-130 were estimated to be 56, 120, 19, and 150 mrad, respectively, per mCi administered. Corresponding radiation absorbed doses in the heart were 42, 54, 13, and 68 mrad/mCi. Radiation absorbed doses in the brain of 1.3, 3.5, 0.25, and 3.7 mrad/mCi were estimated for these four radionuclides,

- by Kimberlee Kearfott
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- Pharmacology, Physiology, Radiochemistry, Radiation Physics