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99mTc-Doxycycline Hyclate: A New Radiolabeled Antibiotic for Bacterial Infection Imaging 

Derya Ilem-Ozdemira*, Makbule Asikoglua, Hayal Ozkilicb, Ferda Yilmazc, Mine Hosgor-Limoncuc, Semin Ayhand

a. Faculty of Pharmacy, Department of Radiopharmacy, Ege University, Bornova, Izmir, Turkey.
b. Faculty of Medicine, Department of Nuclear Medicine, Ege University, Bornova, Izmir, Turkey.
c. Faculty of Pharmacy, Department of Pharmaceutical Microbiology, Ege University, Bornova, Izmir, Turkey.
d. Faculty of Medicine, Department of Pathology, Celel Bayar University, Manisa, Turkey



*Corresponding author: Derya Ilem-Ozdemir, Faculty of Pharmacy, Department of Radiopharmacy, Ege University, Bornova, Izmir, Turkey, Tel: +90 533 446 40 26, Fax: +90 232 388 52 58, e-mail: deryailem@gmail.com
















Abstract

Doxycycline hyclate (DOX) is a broad spectrum antibacterial tetracycline derivative with a wide range of activity against gram-positive and gram-negative bacteria, chlamydiae, rickettsiae and mycoplasmas. In this study, we prepared DOX cold kit for radiolabeling with Technetium-99m (99mTc). The stability of 99mTc-DOX in human serum was identified, sterility and pyrogenicity of the radiopharmaceutic were estimated, gamma scintigraphy and in vivo biodistribution with infected rats were investigated. The results were revealed that DOX was successfully labeled with 99mTc from the instant cold kit. Radiochemical purity was found greater than 90 % and the labeled compound was stable in human serum during incubation period up to 24 hours. According to the sterility and pyrogenicity tests; the improved instant cold kit was found to be sterile and pyrogen free.  According to gamma scintigraphy studies, 99mTc-DOX showed a high uptake in infected thigh muscle. In vitro and In vivo characteristics of the 99mTc-DOX, is making promising for infection imaging.

Key Words: 99m-Technetium, Doxycycline hyclate, Radiolabeled antibiotic, Imaging of Infection.

Introduction
Many bacterial infections are caused by pathogen microorganisms, which are capable of adhering to host cells, invading host cells and tissues, secreting toxins, and evade the host�s immune defenses [1,2]. In many cases it is very important for clinical decision-making and treatment planning not only to determine whether or not there is an inflammatory response [3]. Timely identification and localization of infectious foci is a critical step in appropriate treatment of patients with or suspected of having infectious processes [4]. 
The radiological imaging techniques including computed tomography (CT), nuclear magnetic resonance (NMR) and ultrasonography (US) cannot detect infection foci in the early phase of development. Furthermore, these techniques provide information on only a part of the body. In contrast, nuclear medicine scintigraphic imaging is an excellent non-invasive method of whole-body scanning, allow to determinate infectious foci in all parts of the body, based on pathophysilogical and pathobiological changes which occur earlier in the infection process [4,5]. During the past years several radiopharmaceuticals have been developed for infection imaging [2]. Today 67Ga-citrate scintigraphy, 99mTc-nanocolloid, radiolabeled monoclonal antigranulocyte antibodies are available for this purpose. Also radiolabeled leukocytes are still used in the diagnosis of focal bacterial infection. But the potential drawback in radiolabeling white cells is that patient blood is labeled ex vivo, the procedure carries the risk of needle-stick injury and possible infection [6-8]. Therefore it is an acute need to develop new diagnostic agents for infection imaging [9,10]. A novel approach using bacterially binding radiolabeled antibiotics was evaluated with different researchers. 99mTc labeled ciprofloxacin [7,11], alafosfalin [8,12], enrofloxacin [13], gatifloxacin, cefepime [14], ceftriaxone [15],levofloxacin [16] and cefotaxime [17] were evaluated as an infection imaging agent. Also �r�ml� has described a different radiolabeling procedure for DOX which include different proportions of stannous chloride   but the researcher did not evaluate the in vivo biodistribution studies [18].
DOX is a broad spectrum antibacterial tetracycline derivative with a wide range of activity against gram-positive and gram-negative bacteria, chlamydiae, rickettsiae and mycoplasmas. The slight chemical variation from tetracycline does not significantly alter the bacteriostatic properties of DOX but does increase its lipophilicity, resulting in a large volume of distribution, increased binding to plasma proteins, and a longer elimination half-life. Bacteriostatic effect of DOX is occur by inhibiting the bacterial protein synthesis due to the disruption of messenger and transfer RNA at the ribosomal sites [19-21].
In this study, we prepared DOX cold kit for radiolabeling with Technetium-99m (99mTc). The stability of 99mTc-DOX in human serum was identified, sterility and pyrogenicity of the radiopharmaceutic were estimated, gamma scintigraphy and in vivo biodistribution with infected rats were investigated. 

Materials and Methods
All chemicals and solvents were used without further purification. DOX was obtained from AppliChem (Germany). Stannous tartrate was purchased from Sigma-Aldrich (USA) and ascorbic acid was purchased from Sigma-Aldrich (United Kingdom). 99mTc was eluted from the Molybdenum-99 (99Mo)/99mTc-generator (Nuclear Medicine Department of Ege University). Thioglycollate Broth (TB) and Tryptic Soy Broth (TSB) mediums and all solvents were obtained from Merck (Germany). Dose Calibrator (Atomlab 100, Biodex Medical Systems) was used for counting radioactive samples.  Escherichia Coli bacteria were obtained from Pharmaceutical Microbiology Department of Ege University. The Animal Ethics Committee of the Ege University gave approval for the animal experiments (Number: 2010-37, 2010). Results are reported as mean �standard error.

Preparation of 99mTc-DOX
99mTc-DOX was prepared from lyophilized cold kit, which is included; 1 mg DOX, 30 �g stannous tartarate and 0.1mg ascorbic acid. 1mL of 0.9 % sodium chloride was injected in to the kit to dissolve the dried powder. Then the content was radiolabeled with (370 MBq) 99m-Technetium sodium pertechnetate (99mTcO4-).  The vial was shaken and incubated at room temperature for 15 min. After incubation the reaction product was filtered through a 0.22�m pore size filter for sterilization.  

Radiochemical Analysis of 99mTc-DOX
The radiochemical purity was determined by instant thin layer chromatography (ITLC) and radio high performance liquid chromatography (R-HPLC) studies. 

ITLC Analysis 
One drop of reaction product was spotted on two ITLC-SG chromatographic paper strips (each of 1x8 cm). First strip was developed in acetone while the other one is developed in Acetonitrile/Water/Trifluoroacetic acid (ACN/W/TFA; 50/25/1.5) solvent system. After complete the development both strips were dried and scanned in a TLC scanner (Bioscan AR 2000), and percentages of Reduced/Hydrolyzed (R/H) 99mTc, free 99mTc and 99mTc-DOX was calculated. 

R-HPLC Analysis
The compounds were further analyzed by an Ultra-HPLC system equipped with a C18 column connected to a photodiode array detector (PDA) and additional NaI gamma detector for the 99mTc compounds. Chromatographic analysis was performed by injected the 10 �L reaction mixture in to the column. The flow rate was 0.5 mL/min for analytical runs. In all runs the eluent was 0.1% TFA in ACN.

Stability of 99mTc-DOX in Human Serum
To test the serum stability of 99mTc-DOX, 100 �L reaction medium was added to 1 mL of freshly prepared human serum. The mixture was incubated at 37 �C for 24 h. Two drops of sample was spotted on chromatographic strips at different time intervals up to 24 h and TLC studies were performed to determine the stability of 99mTc-DOX in human serum. 

Microbiological Analysis of 99mTc-DOX Kit

Sterility Test 
The sterilities of the kits were tested by direct inoculation method according to the European Pharmacopeae 6.0 recommendations. The dilutions of the kits were aseptically inoculated to the sterilized TB and TSB medium vials, and incubated at 35�2 �C. At the end of the incubation, absence of clearly visible growth of microorganisms in the vials exhibited the sterility. 

Pyrogenicity Test 
Pyrogenicity test was performed by the gel clot method which based upon the reaction between bacterial endotoxin and the specific lysate. In the presence of endotoxin the gel is formed via a clotting reaction and the sample is fail. Endotoksin limit value of the kit and Maximum Valid Dilution (MVD) was estimated according to European Pharmacopeae 6.0. The LAL test is performed by Pyrotell (Associates of Cape Cod, Incorporated, Falmouth, Massachusetts) Gel-Clot formulation.


Animal Studies
Wistar albino rats (200�250 g) were used for animal studies. Experiments with rats were performed according to a protocol approved by Animal Ethics Committee of the Ege University.

Induction of Infection Model
E.coli suspension was used to create infection model. Groups of six rats were intramuscularly injected with 200 �L (4x1010cfu/1mL) E.coli suspension into the right thigh muscle. Then the infection was allowed to develop for 24 hours. 

Scintigraphic Imaging Studies of 99mTc-DOX
After the infection focus was allowed to develop for 24 hours swelling appeared and gamma scintigraphy studies were performed.  Rats were intravenously injected with 99mTc-DOX (3.7MBq) via tail vein and during the scintigraphy studies animals were under anesthetize with Ketamine/Xylazin cocktail.  The scintigraphic images were obtained with a dual head gamma camera (Infinia General Electric) equipped with a low-energy high-resolution collimator viewing the whole body of rats. After administration of radiopharmaceuticals, serial static images were acquired in a 256 � 256 matrix for 60 second each, at different time intervals (5 minutes, 1, 2, 3 and 5 hours post injection).

Biodistribution Studies
5 hours after injection, the rats were sacrificed and biodistribution was determined. Samples of infected muscle, healthy muscle, blood, liver, spleen, lung, kidney, stomach, intestine, urine and heart were weighed and the radioactivity was measured using a gamma counter (Sesa Uniscaller). The results were expressed as the percentage of injected dose per gram of tissue (%ID/g). 

Histopathology
After the time of sacrifice, the infected and healthy rat muscle specimens dissected out and were fixed with 10% neutral buffer formalin and embedded in paraffin using routine procedures. Sections 4-5 �m in thickness were stained with hematoxylin/eosin for histological examination. All biopsy specimens were interpreted in a blinded fashion by conventional light microscopy.

Statistical Analysis
The calculation of means and standard deviations were made on Microsoft Excel. Oneway Anova was used to determine statistical significance. Differences at the 95% confidence level (p<0.05) were considered significant. 

	Results
	Radiolabeling and Radiochemical Purity
An instant cold kit was prepared contained DOX, stannous tartrate and ascorbic acid. The radiochemical purity of 99mTc-DOX was greater than 90 %, acquired via both TLC and also R-HPLC studies. Over a period the resulting complex was quite stable and radiochemical purity was found �90 % up to 6 hours.

Stability of 99mTc-DOX in Human Serum 
During incubation in human serum, compound was stable as determined by ITLC. As shown in  REF _Ref334805005 \h  \* MERGEFORMAT Figure 1, percentage of 99mTc-DOX was decreased from 97.46 � 0.62 to 94.02 � 0.41 within 24 hours. 

	Microbiological Analysis of 99mTc-DOX Kit
	According to sterility test, since there was no growth in batches, kits were sterile. Also gel clot test showed that kits were pyrogen free.
	
Scintigraphic Imaging Studies of 99mTc-DOX
The uptake of 99mTc-DOX following i.v. administrations were assessed on static images. The images depicted rapid distribution throughout the body and uptake in the infected thigh muscle within one hour after injection. As can be seen in Figure 2 there was a higher activity infected thigh muscle as compared to healthy thigh muscle. 
	For quantitative evaluation, regions of interest were drawn around the target (infected thigh muscle) and non-target (healthy thigh muscle) regions of the rats. The 99mTc-DOX uptake was calculated by dividing the average counts per pixel within the region of target to the average counts per pixel within the region of non-target. 
According to the imaging studies, the uptake ratios of 99mTc-DOX (Target/Non-Target) were found 2.13�0.56, 2.23�0.55 and 2.24�0.84 at 5 minutes, 3 and 5 hours after injection, respectively ( REF _Ref335152600 \h  \* MERGEFORMAT Table 1).  These ratios indicated a significant uptake of 99mTc-DOX in infection foci. The data suggest that 99mTc-DOX remained at the infection foci during the whole experiments, there being no statistically significant differences in the ratios during the studied period (pe"0.05). 
Biodistribution Studies
Based on data presented in  REF _Ref335221723 \h  \* MERGEFORMAT Table 2, biodistribution of 99mTc-DOX was determined for lung, kidney, spleen, urine, intestine, heart, blood, liver stomach infected and healthy thigh muscle. Radiopharmaceutical was removed from the circulation mainly through the kidneys and urine.  99mTc-DOX was found to accumulate in the infected thigh muscle of rats to the 0.23 %ID/g.
According to the biodistribution studies, Target/Non-Target ratio of the 99mTc-DOX was found as 2.62 �0.88, 5 hours after injection. 

Histopathology
Conventional haematoxylin and eosin-stained sections (Microscopic appearances) of the infected and healthy rat muscle tissue are shown in Figure 3. Infected rat muscle exhibits acute suppurative inflammation with polymorphonuclear leucocytes infiltration which indicates the presence of bacterial infection. 
  
Discussion
In this study, DOX was successfully labeled with 99mTc from an instant cold kit. The preparation of the kit utilized a mixture of DOX (1 mg), reducing agent stannous tartrate (30 �g) and antioxidant agent (0.1 mg) that was lyophilized for a period of 24 hours. Radiochemical purity of 99mTc-DOX was � 90 %. According to in vitro stability studies, the labeled compound was stable for a period of time up to six hours. In addition, 99mTc-DOX complex was stable in human serum during incubation period up to 24 hours. 
	According to the sterility and pyrogenicity tests; the improved instant cold kit was found to be sterile and pyrogen free. 
The rat infection model resulted in a focal swelling and fewer in thigh muscles and validated by the pathological evidence. Rats with infection foci injected with 99mTc-DOX showed a Target/Non-Target ratio as 2.24�0.84 5 hours after injection. The rapid up take at the site of infection was seen on images at 1h after injection.
The higher uptake of 99mTc-DOX in kidneys and urine is demonstrating the excretion of the antibiotic. Though low soft tissue uptake, the infectious site capture easily.
	Several antibiotics were radiolabeled for infection imaging [12, 16, 17, 22 ]. 99mTc labeled ceftizoxime, ciprofloxacin, alafosfalin, levofloksasin, cefotaxime has been injected to the infected animals, the Target/Non-Target ratios were found as of 1.97 � 0.31, 3.23�0.05, 2.75�0.46, 1.93�0.09, 2.89�0.58 1 hour after injections, respectively.

Conclusion
DOX was radiolabeled with high radiochemical purity. The labeled compound was found to be stable in human serum up to 24 hours. The prepared cold kit was found sterile and pyrogen free. The bacterial infection imaging capacity of 99mTc-DOX was evaluated. Based on the in vivo studies, 99mTc-DOX has higher uptake in infected thigh muscle than non-infected muscle. In vitro and in vivo characteristics of the 99mTc-DOX, is making promising for infection imaging.

Acknowledgments 
This study was supported by The Scientific and Technological Research Council of Turkey (Tubitak-110 S 229). The authors would like to acknowledge the support of T.R. Prime Ministry State Planning Organization Foundation Grant Project Number: 09DPT001 for TLC Scanner. Also the authors thank to Ege University Nuclear Medicine Department technicians for their technical assistance for the animal experiments.

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