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Radiolabeling of cidofovir with technetium-99m and biodistribution studies

Abstract

Radiolabeling cidofovir with technetium-99m (99mTc-CDV) is an innovative procedure that enables real-time monitoring of the drug. Essays were performed in vitro, showing high radiolabel stability within 24 h. Blood clearance, biodistribution studies, and scintigraphic images were performed in healthy mice in order to evaluate the profile of the drug in vivo. 99mTc-CDV showed biphasic blood circulation time and significant kidney uptake, indicating that 99mTc-CDV is preferentially eliminated by the renal route. Bones also showed important uptake throughout the experiment. In summary, cidofovir was successfully labeled with technetium-99m and might be used in further studies to track the drug.

Keywords:
Cidofovir; Radiotracer; Technetium-99m; Biodistribution; Scintigraphic imaging


INTRODUCTION

Cidofovir (CDV) is a cytosine nucleotide analogue with broad-spectrum anti-DNA virus activity, including human cytomegalovirus (HCMV), which was first reported in 1986 and approved by the US Food and Drug Administration (FDA), under the trade name of Vistide®, for the systemic treatment of HCMV retinitis in people with acquired immunodeficiency syndrome (Jackowska, 2018Jackowska J, Klimza H, Piersiala K, Wierzbicka M. Outcomes of bevacizumab and cidofovir treatment in HPV-associated and recurent respiratory papillomatosis - review of the literature. Otolaryngol Pol. 2018;72(4):1-8.; Broekema, Dikkers, 2008Broekema FI, Dikkers FG. Side-effects of cidofovir in the treatment of recurrent respiratory papillomatosis. Eur Arch Oto-Rhino-Laryngology. 2008;265(8):871-9. ; Andrei, Snoeck, 2010Andrei G, Snoeck R. Cidofovir activity against poxvirus infections. Viruses. 2010;2(12):2803-30. ). Currently, CDV has been used to treat some viral infections, but mainly recurrent respiratory papillomatosis (RRP), which is a chronic disease caused by Human Papilloma Virus (HPV) and affects mainly children and teenagers. The use of antivirals as adjuvants on the treatment of RRP has been shown to be more effective in the control of laryngeal lesions, with cidofovir (CDV) being the most used off-label drug currently used (Tran, Galt, Bashirzadeh, 2018Tran MN, Galt L, Bashirzadeh F. Recurrent respiratory papillomatosis: the role of cidofovir. Respirol Case Reports. 2018;6(8):1-3.; Rasmussen et al., 2017Rasmussen ER, Schnack DT, Jorkov AS, Raja AA, Oslen CH, Homoe P. Long-term follow-up and outcome in patients with recurrent respiratory laryngeal papillomatosis. Dan Med J. 2017;64(12):A5424.; Carifi et al., 2015Carifi M, Napolitano D, Morandi M, Dall’olio D. Recurrent respiratory papillomatosis: current and future perspectives. Ther Clin Risk Manag. 2015;11:731-738.). Its mechanism of action is based on the inhibition of the viral DNA polymerase, followed by incorporation into the growing DNA chain, resulting in low efficiency of DNA transcription (Fusconi et al., 2014Fusconi M, Grasso M, Greco A, Gallo A, Campo F, Remacle M, et al. Recurrent respiratory papillomatosis by HPV: review of the literature and update on the use of cidofovir. Acta Otorhinolaryngol Ital. 2014;34(6):375-81. ). Although few side effects of CDV have been reported, some of them are described as rash, headache, local inflammation, and potential nephrotoxicity; in animal studies, concerns have been raised about carcinogenicity (Coomes, 2018Coomes EA, Wolfe AI, Michelis FV, Kim DDH, Thyagu S, Viswabandya A, et al. Efficacy of cidofovir in treatment of BK virus induced hemorrhagic cystitis in post allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2018;24(9):1901-5. ; Sahota et al., 2011Sahota RS, Uddin FJ, Al-Shukri J, Moir AA. Novel method of intralesional cidofovir injection into laryngotracheal papillomata. J Laryngol Otol. 2011;125(4):402-4. ).

Labeling molecules with radioisotopes, such as technetium-99m (99mTc), enables us to determine, in real-time, the radiometal complex biodistribution (Snehalatha et al., 2008Snehalatha M, Venugopal K, Saha RN, Babbar AK, Sharma RK. Etoposide loaded PLGA and PCL nanoparticles II: Biodistribution and pharmacokinetics after radiolabeling with Tc-99m. Drug Deliv. 2008;15(5):277-87. ). This method is an important tool in studying pharmacokinetics, once it permits direct visualization and quantification of the drug. 99mTc is the commonly used radioisotope due to its physical and chemical characteristics, such as low energy (140 KeV), large availability in nuclear medicine laboratories and inexpensive isotope cost (Fernandes et al., 2015Fernandes RS, Silva J de O, Lopes SCA, Chondrogiannis S, Rubello D, Cardoso VN, et al. Technetium-99m-labeled doxorubicin as an imaging probe for murine breast tumor (4T1 cell line) identification. Nucl Med Commun. 2016;37(3):307-12. ; De Barros et al., 2013De Barros ALB, Das Graças Mota L, De Aguiar Ferreira C, Corrêa NCR, De Góes AM, Oliveira MC, et al. 99mTc-labeled bombesin analog for breast cancer identification. J Radioanal Nucl Chem. 2013;295(3):2083-90. ; Yang et al., 2003Yang DJ, Kim C-G, Schechter NR, Azhdarinia A, Yu D-F, Oh C-S, et al. Imaging with 99mTc ECDG targeted at the multifunctional glucose transport system: feasibility study with rodents. Radiology. 2003;226(15):465-73.).

Technetium-99m is obtained from the Molybdenum generator as sodium pertechnetate (99mTc-NaTcO4), and the ion 99mTcO4- is chemically nonreactive. Therefore, prior reduction of 99mTc from the 7+ state to a lower oxidation state, most commonly to 4+, is required, and among various reducing agents, stannous chloride (SnCl2.H2O) is often the chosen one in preparations of 99mTc-labeled compounds. The reactive species usually combine with chelating agents, so that the chelating agent donates lone pairs of electrons to form coordinate covalent bonds (Papagiannopoulou, 2017Papagiannopoulou D. Technetium-99m radiochemistry for pharmaceutical applications. J Label Compd Radiopharm. 2017;60(11):502-20. ). CDV has several functional groups, such as -NH2, -O-, -POOH (Figure 1), which are able to donate pairs of electrons and form complexes with 99mTc. Unlike in nucleoside phosphates, in acyclic nucleoside phosphonates, such as CDV, the phosphonate group is already attached to the nucleoside analog, resulting in the formation of a phosphonomethyl ether (-P-C-O-), which confers resistance to esterases (Andrei & Snoeck, 2010Andrei G, Snoeck R. Cidofovir activity against poxvirus infections. Viruses. 2010;2(12):2803-30. ). This fact is especially important to keep the drug molecule integrity since phosphonates are very common chelator to 99mTc (Saeed et al., 2017Saeed S, Haq S ul, Sohaib M, Nawaz Khan A. Utility of Tc-99m MDP bone SPECT in evaluation of osseous involvement in craniofacial malignancies. J Cranio-Maxillofacial Surg. 2017;45(11):1815-9. ). Thus, CDV might be a potential target to electron-deficient radiometals, such as 99mTc, producing a stable complex that will allow tracking the in vivo behavior of CDV.

FIGURE 1
Chemical structure of cidofovir.

Even though there are some pharmacokinetics studies of CDV already published in the literature, radiolabeling CDV with 99mTc provides a new tool for understanding this drug’s behavior in the body, as well as obtaining a general overview of its biodistribution in real time by scintigraphy. Developing a bioanalytical HPLC method to quantify CDV in vivo can be quite challenging, especially when the purpose of the study is to screen the drug after intravenous administration, and not only in a specific organ or tissue, which justifies the development of a radiotracer capable of monitoring CDV to better understand its pharmacokinetic profile.

Therefore, the aim of this study was to label CDV with 99mTc and evaluate its in vitro stability. In addition, biodistribution studies and scintigraphic imaging were carried out in healthy mice in order to determine in vivo 99mTc-CDV’s fate.

MATERIAL AND METHODS

Material

Cidofovir hydrate (CDV), >98.0%, was purchased from Sigma-Aldrich (São Paulo, Brazil). 99mTc was obtained from an alumina-based 99Mo/99mTc generator. All reagents (analytical grade), including SnCl2.2H2O 98.0%, were purchased from Sigma-Aldrich (São Paulo, Brazil). Healthy 4-6-week-old female Swiss mice, 20g, were acquired from CEBIO-UFMG (Belo Horizonte, Brazil). All animal studies were approved by the local Ethics Committee for Animal Experiments (CEUA/UFMG), under protocol number 184/2017.

In vitro studies

Radiolabeling procedure

CDV (1.0 mg) was dissolved in 300 µL of NaCl 0.9% (w/v). An aliquot of 100 µL of a SnCl2.2H2O 98.0% solution in HCl 0.25 M was added and the pH was adjusted to 7.0 with a 1M NaOH solution. The vacuum was applied in the vials and an aliquot of 0.1 mL of Na99mTcO4 (37 MBq) was added. The final solution was kept at room temperature for 15 minutes to complete the radiolabeling procedure.

Radiochemical purity evaluation

The radiolabeled efficiencies were analyzed by ascending thin layer chromatography (TLC) on silica gel strips (TLC-SG; Merck, Darmstadt, Germany) as the stationary phase and acetone as the mobile phase. In this system, free 99mTcO4- showed Rf = 1, while 99mTcO2 99mTc-CDV showed Rf = 0. The amount of free 99mTcO4- was determined by measuring the radioactivity of the strips in a gamma counter (Wallac Wizard 1470-020 Gamma Counter; PerkinElmer Inc., Waltham, Massachusetts, USA). The solution was purified from 99mTcO2 using a 0.22 µm syringe filter (6). The analysis was performed in triplicate. The HPLC analysis was conducted using a previously validated method for specificity, linearity, precision, and accuracy, adapted from Santoyo et al. (2002)Santoyo S, De Jalón EG, Ygartua P, Renedo MJ, Blanco-Príeto MJ. Optimization of topical cidofovir penetration using microparticles. Int J Pharm. 2002;242(1-2):107-13. , using an Agilent® with a DAD detector at a wavelength of 274 nm. HPLC mobile phase consisted of a mixture of a 1,5mM tetrabutylammonium phosphate and a 3,5 mM monobasic sodium phosphate buffer solution with acetonitrile 99.9% (97:3 v/v), pH=6.0. A Purospher® C-18 column (5.0 µm, 4.6 mm x 250 mm) was used at a rate of 1.0 mL/min, under isocratic elution, with an injection volume of 10 µL. Samples were collected every 10 seconds, in different tubes, for 25 min, and radiation was measured in a gamma counter.

In vitro stability

TLC-SG was used to estimate the stability 99mTc-CDV in the presence of saline 0.9% (w/v) and mouse plasma. To determine the saline stability, the labeled solution was kept at room temperature and the radiochemical stability was determined from samples taken at 1, 2, 4, 6 and 24 h after incubation. Plasma stability was assessed by incubating a volume of 90 µL of the 99mTc-CDV solution, under agitation, at 37°C with 1.0 mL of fresh mouse plasma. EDTA was used as an anticoagulant. Radiochemical stability was determined from samples taken at 1, 2, 4, 6 and 24 h after incubation. Both stability analyzes were performed in triplicate.

Partition coefficient

Aliquots of 0.1 mL of the 99mTc-CDV (0.37 MBq) were added to tubes containing 2.0 mL of n-octanol/water (1:1). The tubes were submitted to vigorous stir for 5 min. After phase separation, aliquots of 0.5 mL from each phase were collected and radioactivity was measured in a gamma counter. The analysis was performed in triplicate. Partition coefficient was determined according to the equation:

Partition coefficient = log organic phase cpm x 100 aquous phase cpm

Plasma protein binding

Plasma protein binding profile was estimated by the protein precipitation method. An aliquot of 45 µL of 99mTc-CDV was added to 3 different vials containing 500 µL of fresh mouse plasma and incubated at 37 °C, under agitation. EDTA 99.9% was used as an anticoagulant. At 30 min, 1 and 4h after incubation, an aliquot of 1.5 mL of acetonitrile was added to each vial for plasma protein precipitation. Samples were centrifuged at 5000xg for 3 min, and the radioactivity of supernatant and pellet was measured in a gamma counter. The analysis was performed in triplicate. Percent of protein binding was calculated according to the equation:

% Plasma protein binding = precipitate x 100 sup erna tan t + precipitate

Animal studies

Blood clearance

99mTc-CDV was administrated to each mouse (n=7), previously anesthetized with a mixture of xylazine (15 mg/kg) and ketamine (80 mg/kg), through the tail vein, and a small incision was made in the distal tail to facilitate rapid and reliable blood collection. Blood samples (~20 µL each) were collected at 1, 5, 10, 15, 30, 45, 60, 90, 120 and 240 min after administration. Each sample was weighed and the radioactivity was measured with an automatic scintillation counter. The percentage of injected activity per gram (%ID/g) and its mean ± SD in each sample were determined, and the data were plotted as a function of time. Blood clearance analysis was performed using GraphPad PRISM, version 5.00 software (GraphPad Softwar Inc., La Jolla, California, USA).

Ex vivo biodistribution

Aliquots of 3.7 MBq of 99mTc-CDV were injected intravenously into the tail vein of Swiss mice (n=7). At 1 and 4 h after injection, mice were anesthetized with a mixture of xylazine (15 mg/kg) and ketamine (80 mg/kg). Blood, spleen, kidneys, stomach, lungs, heart, intestines, muscle, bone, thyroid, brain and liver were removed and placed in pre-weighed plastic test tubes. The radioactivity was measured by an automatic scintillation counter. A standard dose containing the same injected amount was counted simultaneously in a separated tube, which was defined as 100% radioactivity. The results were expressed as the percentage of injected dose per gram of tissue (%ID/g).

Scintigraphic images

Aliquots of 3.7 MBq of 99mTc-CDV were injected intravenously into the tail vein of Swiss mice (n=7). Mice were anesthetized and then horizontally placed under the collimator of a gamma camera (Mediso, Budapest, Hungary) coupled with a low-energy high-resolution collimator. Images were acquired at 1 and 4 h after injection using a 256x256x16 matrix size, with a 20% energy window set at 140 Kev for a period of 300s each.

Statistical analysis

All data are expressed as mean ± SD and they were analyzed by GraphPad PRISM, version 5.0 software (GraphPad Software Inc.).

RESULTS

Radiochemical purity and in vitro stability

99mTc-CDV was efficiently labeled with technetium-99m, showing, after filtration in a 0.22 µm sterile filter, radiochemical yields of 99.3 ± 0.2% (n=3). Results obtained by HPLC analysis corroborate with TLC data, as demonstrated in Figure 2. The radiation peak (Figure 2A) occurs at almost the same retention time of 99mTc-CDV obtained in the chromatogram (Figure 2B), which indicates a single 99mTc-labeled species, indicating similar radiochemical yields than those obtained by TLC. Radiochemical stability was also performed at 1, 2, 4, 6 and 24 h post-incubation in saline, at room temperature, or in mouse plasma, at 37 °C. The complex 99mTc-CDV remains stable, in both media, even after long periods, as shown in Figure 3.

FIGURE 2
Reverse phase HPLC chromatogram (a) and radiochromatogram (b) of 99mTc-CDV.

FIGURE 3
In-vitro stability of 99mTc-CDV as a function of time in the presence of saline, at room temperature, and in the presence of mouse plasma, at 37 °C (n=3).

Partition coefficient

The partition coefficient of 99mTc-CDV was determined by the ratio between n-octanol and water, and the log P found for 99mTc-CDV was in the hydrophilic range (log P = -1.39 ± 1.9) (n=3).

Plasma protein binding

High plasma protein binding was observed for 99mTc-CDV. At 30 min post-incubation, 45.7 ± 1.5% of 99mTc-CDV was bound to plasma protein. After 1 h, 90.1 ± 0.8% of binding was reached, and the level of protein binding was kept at 91.1 ± 1.0% after 4 h (n=3).

Animal studies

Blood clearance

The injection of 99mTc-CDV through the tail vein of the mice showed a long blood clearance of the complex, with a biphasic half-life profile. Figure 4 exhibits the distribution half-life of 2.3 min and the elimination half-life of 227.1 min and an area under the curve of 2850% ID/min (n=7).

FIGURE 4
Blood clearance of 99mTc-CDV in healthy female SWISS mice. All data are the mean percentage (n=7) of the injected dose of 99mTc-CDV per gram of blood, ±SD of the mean.

Ex vivo biodistribution

Figure 5 shows the biodistribution of 99mTc-CDV at 1 and 4h after intravenous administration in healthy mice. At both times, maximum uptake was observed in the kidneys, followed by the bones. Moreover, important uptake was also observed in the small intestine and the liver, indicating that intestinal route contributes to the excretion of 99mTc-CDV. No significant uptake was observed in other organs (n=7).

FIGURE 5
Biodistribution profile of 99mTc-CDV following intravenous tail-vein administration in healthy female SWISS mice. All data are the mean percentage (n=7) of the injected dose of 99mTc-CDV per gram of tissue ± SD of the mean.

Scintigraphic images

Scintigraphic imaging exhibited a similar profile to the one presented by the biodistribution studies, as shown in Figure 6. The image of 1h shows a strong signal in the abdominal area, most likely as a result of the high uptake by the kidneys, small intestine, and liver. At the time of 4 h, signal strength decreases, due to drug clearance. In addition, in both images, it is noticeable the signal emitted by bone uptake (arrows) (n=7).

FIGURE 6
Scintigraphic images obtained at 1 (a) and 4 (b) h after intravenous injection of 99mTc-CDV into healthy mice (n=7). The arrows indicate bone uptake.

DISCUSSION

Cidofovir is a cytidine analog that suppresses viral replication by the selective inhibition of DNA synthesis, being active against all kinds of herpesvirus, cytomegalovirus, adenovirus, polyomavirus and human papillomavirus (Sala, Suriol, Montero, 2017Sala NP, Suriol AF, Montero ER. Intralesional cidofovir in human papilomavirus infection in interdigital spaces. Farm Hosp. 2017;41(1):132-3. ). Even though CDV is not licensed for this indication, it is currently the mainstay of antiviral therapy for adenovirus (Vora, Brothers, Englund, 2017Vora SB, Brothers AW, Englund JA. Renal toxicity in pediatric patients receiving cidofovir for the treatment of adenovirus infection. J Pediatric Infect Dis Soc. 2017;6(4):399-402. ). Indeed, there are several case series showing the efficacy of CDV in adenovirus pneumonia (Lee et al., 2017Lee M, Kim S, Kwon OJ, Kim JH, Jeong I, Son JW, et al. Treatment of Adenoviral Acute Respiratory Distress Syndrome Using Cidofovir With Extracorporeal Membrane Oxygenation. J Intensive Care Med. 2017;32(3):231-8.). It is known that intralesional CDV may help control papilloma regrowth and reduce disease severity in children with recurrent respiratory papillomatosis, as well (Goon et al., 2008Goon P, Sonnex C, Jani P, Stanley M, Sudhoff H. Recurrent respiratory papillomatosis: An overview of current thinking and treatment. Eur Arch Oto-Rhino-Laryngology. 2008;265(2):147-51. ).

The diverse chemistry of 99mTc has led to the development of numerous 99mTc radiopharmaceuticals suitable for various diagnostic procedures, since they will distribute, after being systemically administrated, and accumulate in the organ or tissue of interest according to their design (Papagiannopoulou, 2017Papagiannopoulou D. Technetium-99m radiochemistry for pharmaceutical applications. J Label Compd Radiopharm. 2017;60(11):502-20. ). In this regard, considering there is still no published study on the radiolabeling of CDV, the aim of this study was to develop a radiotracer with 99mTc in order to further evaluate the in vivo biodistribution of CDV.

After being purified from 99mTcO2, the stability of the complex 99mTc-CDV was evaluated and it showed stability over 90% in both saline and plasma, at all evaluated times. These results guarantee that, during all time of analysis, monitoring the behavior of 99mTc reflects the behavior of CDV itself.

Blood clearance data show that blood levels of 99mTc-CDV decays in a biphasic manner, showing a slow half-life of 227.1 min. These results are in agreement with a previously published study, in which CDV showed a slow half-life of 5.8 h (Brown et al., 2015Brown AEC, Cohen MN, Tong S, Braverman RS, Rooney JF, Giller R, et al. Pharmacokinetics and safety of intravenous cidofovir for life-threatening viral infections in pediatric hematopoietic stem cell transplant recipients. Antimicrob Agents Chemother. 2015;59(7):3718-25.). The relatively long half-life of the 99mTc-CDV, a small and hydrophilic complex, might explain the high plasma protein binding for 99mTc-CDV, with a maximum of 88.9±0.0% at 1 h post-incubation. log P of -1.39 ± 1.9 found for 99mTc-CDV also reflects the high hydrophilicity of the complex due to its polar character. It is worth mentioning, that, to the best of knowledge, this is the first report of radiolabeled CDV. The use of radiolabeled molecules is an exquisite strategy to track in vivo, at real time, the desired compound providing quantitative information about tissue distribution.

In this sense, we also performed biodistribution studies in healthy mice to predict the behavior of CDV after being administrated systemically. At 1 and 4 h post-administration, maximum uptake was observed in the kidneys, as expected, due to the high hydrophilicity of CDV, as demonstrated by its partition coefficient. In addition, this profile indicates a main renal excretion and might be related to the high nephrotoxicity of CDV, as previously described in the literature (Mareri et al., 2016Mareri A, Lasorella S, Iapadre G, Maresca M, Tambucci R, Nigro G. Anti-viral therapy for congenital cytomegalovirus infection: pharmacokinetics, efficacy and side effects. J Matern Neonatal Med. 2016;29(10):1657-64.). Furthermore, a high uptake was found in the bones. Bones are composed of various inorganic ions, mainly calcium and phosphate and, therefore, they show an affinity for compounds that present these ions. Even though CDV presents a phosphonate group instead of a phosphate one, both are very similar, which explains the bone uptake, as demonstrated before with MDP (methoxy diphosphonate), a radiopharmaceutical used to diagnose bone metastasis (Saeed et al., 2017Saeed S, Haq S ul, Sohaib M, Nawaz Khan A. Utility of Tc-99m MDP bone SPECT in evaluation of osseous involvement in craniofacial malignancies. J Cranio-Maxillofacial Surg. 2017;45(11):1815-9. ). It is important to mention that small intestine and liver showed moderate uptake indicating the contribution of the intestinal route. Scintigraphic imaging of the mice corroborates with the biodistribution data found.

These results pose new perspectives to monitor CDV in vivo in real time in different experimental models to better understand drug behavior. Moreover, CDV has gained great attention in the pharmaceutical field since its applications, already mentioned, in several virus infections. As a result, many researchers have studied different formulations, nano- and micro-particles to improve CDV efficiency (Santoyo et al., 2002Santoyo S, De Jalón EG, Ygartua P, Renedo MJ, Blanco-Príeto MJ. Optimization of topical cidofovir penetration using microparticles. Int J Pharm. 2002;242(1-2):107-13. ). By using the novel radiotracer (99mTc-CDV) it might be possible to evaluate the release profile of CDV in different formulations and compare innovative release systems with conventional ones. Thus, this work shows a promising tool for assessing CDV in both in vitro and in vivo assays.

CONCLUSION

Our feasibility study demonstrated that CDV can be successfully labeled with 99mTc, showing high and prolonged stability. In addition, in vitro assays showed a high plasma protein binding. In vivo assays confirmed a relatively slow half-life of CDV and its main renal excretion. In addition, scintigraphic imaging confirmed the results presented by the biodistribution studies. In summary, these results infer that 99mTc-CDV can be reliably used as a radiotracer to perform in vitro and in vivo studies.

ACKNOWLEDGMENTS

We wish to thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil) for its financial support and fellowships.

REFERENCES

  • Andrei G, Snoeck R. Cidofovir activity against poxvirus infections. Viruses. 2010;2(12):2803-30.
  • Broekema FI, Dikkers FG. Side-effects of cidofovir in the treatment of recurrent respiratory papillomatosis. Eur Arch Oto-Rhino-Laryngology. 2008;265(8):871-9.
  • Brown AEC, Cohen MN, Tong S, Braverman RS, Rooney JF, Giller R, et al. Pharmacokinetics and safety of intravenous cidofovir for life-threatening viral infections in pediatric hematopoietic stem cell transplant recipients. Antimicrob Agents Chemother. 2015;59(7):3718-25.
  • Carifi M, Napolitano D, Morandi M, Dall’olio D. Recurrent respiratory papillomatosis: current and future perspectives. Ther Clin Risk Manag. 2015;11:731-738.
  • Coomes EA, Wolfe AI, Michelis FV, Kim DDH, Thyagu S, Viswabandya A, et al. Efficacy of cidofovir in treatment of BK virus induced hemorrhagic cystitis in post allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2018;24(9):1901-5.
  • De Barros ALB, Das Graças Mota L, De Aguiar Ferreira C, Corrêa NCR, De Góes AM, Oliveira MC, et al. 99mTc-labeled bombesin analog for breast cancer identification. J Radioanal Nucl Chem. 2013;295(3):2083-90.
  • Fernandes RS, Silva J de O, Lopes SCA, Chondrogiannis S, Rubello D, Cardoso VN, et al. Technetium-99m-labeled doxorubicin as an imaging probe for murine breast tumor (4T1 cell line) identification. Nucl Med Commun. 2016;37(3):307-12.
  • Fusconi M, Grasso M, Greco A, Gallo A, Campo F, Remacle M, et al. Recurrent respiratory papillomatosis by HPV: review of the literature and update on the use of cidofovir. Acta Otorhinolaryngol Ital. 2014;34(6):375-81.
  • Goon P, Sonnex C, Jani P, Stanley M, Sudhoff H. Recurrent respiratory papillomatosis: An overview of current thinking and treatment. Eur Arch Oto-Rhino-Laryngology. 2008;265(2):147-51.
  • Jackowska J, Klimza H, Piersiala K, Wierzbicka M. Outcomes of bevacizumab and cidofovir treatment in HPV-associated and recurent respiratory papillomatosis - review of the literature. Otolaryngol Pol. 2018;72(4):1-8.
  • Lee M, Kim S, Kwon OJ, Kim JH, Jeong I, Son JW, et al. Treatment of Adenoviral Acute Respiratory Distress Syndrome Using Cidofovir With Extracorporeal Membrane Oxygenation. J Intensive Care Med. 2017;32(3):231-8.
  • Mareri A, Lasorella S, Iapadre G, Maresca M, Tambucci R, Nigro G. Anti-viral therapy for congenital cytomegalovirus infection: pharmacokinetics, efficacy and side effects. J Matern Neonatal Med. 2016;29(10):1657-64.
  • Papagiannopoulou D. Technetium-99m radiochemistry for pharmaceutical applications. J Label Compd Radiopharm. 2017;60(11):502-20.
  • Rasmussen ER, Schnack DT, Jorkov AS, Raja AA, Oslen CH, Homoe P. Long-term follow-up and outcome in patients with recurrent respiratory laryngeal papillomatosis. Dan Med J. 2017;64(12):A5424.
  • Saeed S, Haq S ul, Sohaib M, Nawaz Khan A. Utility of Tc-99m MDP bone SPECT in evaluation of osseous involvement in craniofacial malignancies. J Cranio-Maxillofacial Surg. 2017;45(11):1815-9.
  • Sahota RS, Uddin FJ, Al-Shukri J, Moir AA. Novel method of intralesional cidofovir injection into laryngotracheal papillomata. J Laryngol Otol. 2011;125(4):402-4.
  • Sala NP, Suriol AF, Montero ER. Intralesional cidofovir in human papilomavirus infection in interdigital spaces. Farm Hosp. 2017;41(1):132-3.
  • Santoyo S, De Jalón EG, Ygartua P, Renedo MJ, Blanco-Príeto MJ. Optimization of topical cidofovir penetration using microparticles. Int J Pharm. 2002;242(1-2):107-13.
  • Snehalatha M, Venugopal K, Saha RN, Babbar AK, Sharma RK. Etoposide loaded PLGA and PCL nanoparticles II: Biodistribution and pharmacokinetics after radiolabeling with Tc-99m. Drug Deliv. 2008;15(5):277-87.
  • Tran MN, Galt L, Bashirzadeh F. Recurrent respiratory papillomatosis: the role of cidofovir. Respirol Case Reports. 2018;6(8):1-3.
  • Vora SB, Brothers AW, Englund JA. Renal toxicity in pediatric patients receiving cidofovir for the treatment of adenovirus infection. J Pediatric Infect Dis Soc. 2017;6(4):399-402.
  • Yang DJ, Kim C-G, Schechter NR, Azhdarinia A, Yu D-F, Oh C-S, et al. Imaging with 99mTc ECDG targeted at the multifunctional glucose transport system: feasibility study with rodents. Radiology. 2003;226(15):465-73.

Publication Dates

  • Publication in this collection
    18 Sept 2020
  • Date of issue
    2020

History

  • Received
    12 July 2018
  • Accepted
    20 Dec 2018
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br