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ISSN: 2155-6148
Journal of Anesthesia & Clinical Research
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Radio-Synthesis, and In-vivo Skeletal Localization of 177Lu- zoledronic Acid as Novel Bone Seeking Therapeutic Radiopharmaceutical

Rashid Rasheed*, Nadeem Ahmad Lodhi, Muhammad Khalid, Muhammad Mushtaq and Muhammad Mansoor

Ginum Cancer Hospital, Nizampur, Sialkot Road, Gujranwala, Pakistan

*Corresponding Author:
Rashid Rasheed
Ginum Cancer Hospital, Nizampur
Sialkot Road, Gujranwala, Pakistan
Tel: +92 55 3493370
Fax: +92 55 3493379
E-mail: [email protected]

Received date: January 23, 2015, Accepted date: March 03, 2015, Published date: March 09, 2015

Citation: Rasheed R, Lodhi NA, Khalid M, Mushtaq M, Mansoor M (2015) Radio-Synthesis, and In-vivo Skeletal Localization of 177 Lu- zoledronic Acid as Novel Bone Seeking Therapeutic Radiopharmaceutical. J Anesth Clin Res 6:516. doi: 10.4172/2155-6148.1000516

Copyright: © 2015 Rasheed R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Objectives: The aim of this work is to study the effects, adverse effects and recovery time of IV mixed propofol and ketamine (ketofol) in 3:1 ratio as a sedative analgesic in children with acute lymphoblastic leukemia undergoing bone marrow aspiration.
Methods: This was a prospective, observational pilot study of twenty patients; 3-12 years with ALL requiring sedation for BMA were included. Mixture of ketofol (3:1) was administered intravenously in a dose of 0.5 mg⁄ kg at 30-second to 1-minute intervals aiming to achieve a sedation level of 3 or 4 on Ramsay scale to start the procedure. Patient satisfaction was the primary outcome in our study. Faces pain scale - revised (FPS-R) was used to assess the degree of analgesia. Secondary outcomes included sedation time, recovery time, adverse events and safety.

Results: 20 patients were enrolled for the study. The median dose of ketofol is 3 mg/kg of propofol and 1 mg/kg of ketamine with no patients required extra doses, The median score on the pain faces scale was (comfortable) (1-3; 95%CI 1.08-2.92). Median recovery time was 22 minutes (16-30; 95%CI 14.08-29.32). The cardiorespiratory adverse events were transient, tolerable and easily corrected.

Conclusion: Combination of ketamine and propofol in the same syringe in this pilot study produced effective sedation, which is illustrated by the degree of satisfaction shown by patients. Moreover, rapid recovery and absence of clinically significant adverse events were noticed among children requiring procedural sedation and analgesia for bone marrow aspiration. A high recommendation of using large sample size should be considered for further assessment and verification of our results.

Keywords

Propofol ketamine sedation; Analgesia; Acute lymphoblastic leukemia; Bone marrow aspiration

Introduction

A larger percentage of patients suffering from primary breast, lungs and prostate cancer developed metastasis in bones in the advance stage of their diseases. Bone metastases occur frequently in 70% of patients with breast or prostate cancer and in 40% of patients with lung cancer [1,2], while the bone pain is the most prominent symptom associated with bone metastases. The pain becomes progressively severe as the disease advances. Targeted radiotherapy is considered a standard treatment in the management of bone metastasis using suitable radionuclides linked to bone seeking ligands [3-9]. Targeted radionuclide therapy, involves the specific deposition of ionizing radiation at the skeletal with the minimum radiation induced bone marrow suppression, and found to be an effective treatment for the palliation of pain [10,11]. A great deal of effort has been made in identifying a potential therapeutic radionuclide used for palliation of bone metastasis with more favorable decay characteristic [12-14]. In order to develop effective radiopharmaceuticals for bone pain palliation, it is essential to carefully consider the choice of appropriate radionuclides as well as the carrier moiety with suitable pharmacokinetic properties that could result in good in- vivo localization in bone and concentrate in skeletal lesions, with minimum exposure to red bone marrow.

Bisphosphonate (BPs) ligands are known to form stable chelates with many metals including lanthanides and act as carrier ligands

owing to their high bone affinity and selective localization in skeletal lesions. Ethylenediaminetetramethylene phosphonic acid (EDTMP) is one of the most commonly used bispohphonate ligands which form stable complexes with different radio metals, particularly with 177Lu (177Lu-EDTMP), has been utilized to palliate metastatic bone pain as a new bone seeking radiopharmaceutical [15]. BPs with an imidazole ring shows higher affinity for bone mineral and zoledronic acid (ZOL) [2-(imidazole-1-yl)-hydroxy-ehtylidene-1,1-bisphosphonic acid), Figure 1 is a bisphosphonate containing imidazole ring and the most potent of the clinically tested compound, could be chosen as another carrier ligand in developing bone pain palliation agent using radio lanthanides. ZOL can reduce the incidence and delay the onset of skeletal complication in patients with breast cancer, multiple myeloma, prostate cancer and other solid tumors. The complex of ZOL and its derivatives with 99mTc have been extensively studied as potential bone imaging agents [2,16-18].

anesthesia-clinical-research-Structure-ZOL

Figure 1: Structure of ZOL.

177Lu is presently being considered as one of the most promising radionuclide for targeted palliative care in painful bone metastasis owing to its suitable decay characteristics [T1/2=6.73 d, Eβ (max)=497 keV, Eγ=113 keV (6.4%), 208 keV (11%)]. 177Lu decay to stable 177Hf, and its long half-life provides logistic advantage for facilitating supply to places far away from the reactor. The high cross section of the target radionuclide [176Lu (n,γ)177Lu =2100barns] allows large scale production using moderate flux reactors. Additionally, its 208-keV γ-emission (11% abundance) allows for imaging of its distribution to facilitate dose calculation [19-21].

Keeping in view the specific advantages of using 177Lu in palliative radiotherapy of bone pain, the aim of this study was to develop new 177Lu-ZOL bone seeking radiopharmaceutical used in the bone pain palliation. The present work describes the preparation of 177Lu-ZOL complex, and imaging studies to evaluate its efficacy as novel bone pain palliation bone seeking radiopharmaceutical.

Experimental

Materials and methods

Enriched 176Lu2O3 (purity > 99.99%, 176Lu~52.10%) used as target for the production of 177LuCl3 was obtained from Trace Science International Canada. ZOL (99.6% pure) used was purchase form Molekula Limited, UK. All other chemicals are of analytical grade and used without further purification. What man 3MM chromatographic paper (UK) and ITLC-SC (Gelman Sciences Institute USA), were used for radio chromatography. Radio-chromatography were performed by thin layer chromatography scanner Bio scan Inc., USA connected with NaI(Tl) detector. High performance liquid chromatography (HPLC) studies were conducted using Hitachi L6200 HPLC system with NaI(Tl) detector integrated with Bio scan Chrom Lite.

The radionuclide purity of 177LuCl3was determined by γ-ray spectrometer, which consisted of p-type coaxial high purity germanium (HPGe) detector having 60% relative efficiency and 1.95 FWHM at 1,332 KeV γ-ray of 60Co. The detector was connected to Ortech-570 amplifier Trump PCI 8K ADC/MCA card with Gamma Vision-32 ver. 6 software. Full peak energy calibration of the detector was performed using point calibration source 152Eu covering the energy range 59-1, 480KeV. All other activity measurement were made with NaI(Tl) scintillation detector (Capintech, Inc) calibrated with 3.7 MBq 137Cs standard source.

Scintigraphic images of whole body were recorded using dual-head-digital single photon emission computed tomography (SPECT) gamma camera (Siemens Ecam, USA) integrated with Esoft Syngo software at Gujranwala Institute of Nuclear Medicine (GINUM) Gujranwala, Pakistan. The rabbit was placed on a flat hard surface with both hind legs spread out and all legs fixed with surgical tape, then an aliquot of 0.2 ml containing 15 MBq of 177Lu-ZOL was injected intravenously into the marginal ear vein of rabbit. Diazepam (5 mg) was used for anesthazing rabbits before recording the scintigrapahic images.

Production of 177LuCl3

177LuCl3 was produced by irradiation of 1 mg of enriched 176Lu2O3 in thermal neutron flux of ~1.2×1014 ncm-2s-1 at (PARR-I). First, 176Lu2O3 was transfer into quartz ampoule, and sealing of ampoule was done with oxyacetylene. Sealed quartz ampoule containing 176Lu2O3 was shifted into aluminum capsule, which was cold welded using carver press at 1400 psi pressure. The target was subjected to irradiation at PARR-I for 12 hr. After cooling of 8 hr, the irradiated target dissolved in 5ml of 1.0 mol L-1 HCl with few minutes of heating at 80Ë?C in a hot cell. The 177LuCl3 diluted to 10ml with double distilled water for preparation of stock solution. The mixture was filtered through 0.22 μm Millipore filter for sterilization. Total activity produced was measured with dose calibrator.

The radiolabeling of 177Lu-ZOL complex

In order to attain maximum radiochemical purity (%RCP), many factors were investigated such as the amount of ligand (ZOL), amount of 177LuCl3, pH value and the incubation time. The radiolabeling of ZOL with 177LuCl3 was carried out in 10 ml vial.

Effect of amount of the ZOL

A stock solution of ZOL was prepared by dissolving 100 mg of ZOL in double distilled water by adding few drop of 1.0 molL-1 sodium hydroxide in order to obtain a concentration of 4 mg mL-1. An aliquot of ZOL solution containing various concentrations (2.0-14 mg), with addition of 2 mg, was placed in a reaction vials respectively, 185MBq of activity of 177LuCl3 was also added and pH of the solution was adjusted to 7-8 with phosphate buffer.

Effect of amount of 177LuCl3

The fixed amount (12 mg) of ZOL was labeled with 177LuCl3, which varied from 18.5 MBq to 222 MBq. The pH of the solution adjusted to 8 with phosphate buffer and %RCP was measured after 30 min. A high RCP (>99%) was obtained when 55MBq 177LuCl3 was used. As the amount of 177LuCl3 was increased, no significant difference was observed.

Effect of pH value

Fixed amount of ZOL (12 mg) and 185MBq activity of 177LuCl3 was added into 10 reaction vials. The pH value were adjusted from 2-12 with phosphate buffer. After incubation time of 30 minute the %RCP were checked using ITLC.

Effect of incubation time

After fully overtaxing the mixture containing 12mg ZOL, 185MBq activity and pH 8 the %RCP was checked for different time starting from 10 minute up to 7 hours.

Quality control of177Lu-ZOL

Instant thin layer chromatography (ITLC)

Radionuclide purity as well as radiochemical purity was determined by Instant thin layer chromatography (ITLC) and paper chromatography (PC). An aliquot of 177Lu-ZOL were spotted with a syringe at 2 cm from the bottom on 2 × 14 cm strips. Strips were developed into mobile phase chamber containing ammonium hydroxide:methanol:water (1:2:2) as eluting solvent. The chromatogram were eluted up to 10cm, dried and subjected to 2π scanner to get actigram which show the radiochemical purity.

High performance liquid chromatography (HPLC)

To verify the complex formation of single species, one of the reaction mixture was analyzed by HPLC using reversed phase C18 column waters (3.9 × 300 mm) attached to NaI(Tl) detector. HPLC was performed using a mixture of water:methanol (2:3) as eluent. Initially, 20 μl of 177LuCl3 at pH 7 [1 ml LuCl3=5 mCi] was injected into the column and elution was monitored by activity profile. Similarly, 20 μl of test solution [1 ml 177Lu-ZL=5mCi] was injected into the column and elution was monitored. Chromatogram was obtained using Bioscan Chrom Lite software attached to Hitachi L6200 HPLC system.

Images study in rabbit:

Dual-headed single photon emission computed tomography (SPECT) gamma camera was used to obtain the images of rabbit. 177Lu-ZOL (~15MBq) was injected intravenously into the rabbit through the ear vein. Next day, before imaging procedure the rabbit was anesthetized. After 30 minute the rabbit was fixed on a board covering with piece of cloth for immobilization during the entire scanning procedure and whole body images were obtained at 24 h, 2.5 d and 7 d post injection using SPECT gamma camera.

Results and Discussion

Production of 177LuCl3:

Irradiation of 176Lu2O3 at thermal flux of ~1.2×1014 ncm-2s-1 for 12 hr has resulted 177LuCl3 with specific activity of 11.1 GBq/mg (300 mCi/mg) at 8 hour after the end of bombardment (EOB). Radionuclide purity was checked using HPGe detector using γ-ray spectrum. Analysis of γ-ray spectrum revealed different peaks at 72, 113, 208 and 250 keV, which correspond to photo peaks of 177Lu. The radionuclide purity was found to be >99%.

Radiolabelling of 177Lu-ZOL

After drying the developed Whatman 3MM and ITLC strips, it was subjected to 2π scanner to get actigram which depicted the %RCP of the 177Lu-ZOL. The labeling yield was found to be 99.10 ± 0.40. 177Lu-ZOL move with solvent front with Rf=0.7 ± 0.03, while free 177LuCl3 remained at the point of spotting (Rf=0.0-0.1) shown in the Figure 2a,2b.

anesthesia-clinical-research-mixture-ammonium

Figure 2: ITLC Radiochromatogram of (a) LuCl3 (b) 177Lu-ZOL; eluted using mixture ammonium hydroxide:methanol:water (1:2:2).

Elution was repeated thrice for calculating %RCP and Rf values. Optimization of radiolabeling condition of 177Lu-ZOL was performed by varying several reaction parameter, such as the amount of ZL, amount of 177LuCl3, pH value and incubation time.

Effect of amount of ligand ZOL

A aliquot of ZL solution at various concentrations, 2, 4, 6, 8, 10,12 and 14 mg were taken in a reaction vial and 185MBq of activity was added, pH of the solution were adjusted to 7-8. %RCP of these formulations were determined to be 88.01 ± 0.9, 91.6 ± 0.76, 94.2 ± 1.0, 95.1 ± 0.16, 98.1 ± 0.3, 99.1 ± 0.5, 99.1 ± 0.6 respectively. The results are shown in Figure 3a, which signify that when amount of the ligand ZL was 12 mg or more, the overall labeling yield was >99%.

anesthesia-clinical-research-Effect-reaction

Figure 3a: Effect of reaction factor on the labeling yield of 177Lu- ZOL: (a) the amount of ZOL ligand.

Effect of amount of 177LuCl3:

Reaction vials containing fixed amount of ZOL (250 μl, 12 mg) and various amounts of 177LuCl3, 18.5 MBq, 37 MBq, 55 MBq, 111 MBq, 148 MBq, 185 MBq, 222 MBq, and pH of the solutions were adjusted to 7-8. The %RCP of each reaction vial were checked after 30 min and found to be 89.5 ± 0.5, 93.0 ± 0.2, 96.5 ± 0.4, 98.4 ± 0.9, 98.9 ± 0.1, 99.3 ± 0.35, 99.2 ± 0.8 respectively shown in Figure 3b. The results suggested that activity of 111MBq above has no significant effect on radiolabeling yield of complex.

anesthesia-clinical-research-labeling-yield

Figure 3b: Effect of reaction factor on the labeling yield of 177Lu- ZOL: (b) the amount of 177LuCl3.

Effect of the pH value

Fixed amount of ZOL (250 μl, 12 mg) and 185 MBq activity of 177LuCl3 were added into cylindrical vials. The pH values of vials were adjusted 2-12 respectively with Phosphate buffer. The mixture was reacted at room temperature for 30 min. The results shown in Figure 3c indicate that when the pH value is the range of 7-8, an RCP>99% can be obtained.

anesthesia-clinical-research-pH-value

Figure 3c: Effect of reaction factor on the labeling yield of 177Lu- ZOL: (c) The pH value.

Effect of incubation time

One of the reaction mixture at 8 pH value, containing (250 μl, 12 mg) ZOL and 185 MBq of 177LuCl3 activity at room temperature, the %RCP was checked after regular time interval ranging from 10 min to 7 hours. The results shown in Figure 3d, the high RCP>99% was obtained at 30 min after which no significant change was observed.

anesthesia-clinical-research-incubation-time

Figure 3d: Effect of reaction factor on the labeling yield of 177Lu- ZOL: (d) The incubation time.

HPLC studies:

The HPLC chromatogram in Figure 4a,4b clearly showed two distinct peaks at different retention time. The first peak belongs to Free 177LuCl3, whereas second peak correspond to 177Lu-ZOL complex, depicting the formation of complex with single species. The results obtained from HPLC are in comparison with ITLC.

anesthesia-clinical-research-reverse-phase

Figure 4: HPLC radiochromatogram of (a) free 177LuCl3 (b) complex 177Lu-ZOL; on reverse phase column using ethanol:water (3:2) as mobile phase.

Imaging study in rabbit:

Whole body images of normal rabbits at 1 d, 2.5 d and 7 d after 177Lu-ZOL administration are presented in Figure 5a,5b,5c. 177Lu in rabbit skeleton was visualized after accumulation of injected labeled zoledronate. The tracer is clearly visible in skeleton at 1 d and 2.5 d post administration with slight activity in upper part of body, whereas at 7 d, due to clearance of activity from other organs, the skeleton image is dominant. Table 1 presents the activity ratio of bone to kidneys and upper part of the body. The bone uptake is quite high, and ratio increases with lapse of time.

anesthesia-clinical-research-radiopharmaceutical

Figure 5: SPECT whole body images (a), (b) and (c) of rabbit recorded at 1 d, 2.5 d, and 7 d, post injection 177Lu-ZOL, respectively showing skeletal uptake of the therapeutic radiopharmaceutical ( Activity of 177Lu-ZOL = ~15MBq) (A= anterior and B= posterior).

Ratio 1 Day 2.5 Day 7 Day
Bone/LK 10.87 10.76 12.29
Bone/RK 12.52 12.76 15.66
Bone/U&B 5.71 10.42 14.72
Bone/Lungs 5.14 8.54 15.07

Table 1: Digital data of 177Lu-ZOL distribution in rabbit. LK= Left kidney, RK = Right Kidney, U&B= Urinary Bladder.

Currently, for the examination/imaging of bones 99mTc phosphate complexes such as 99mTc-PyP (pyrophosphate), 99mTc-MDP, 99mTc-HEDP (etidronat), 99mTc-EDTMP (oksabifor) were evaluated, but the biggest interest in the radionuclear diagnosis of the skeleton is given to the bisphosphonate of the latest generation – zoledronic acid (which is successfully used for treatment of bone metastases). Zoledronic acid has maximum affinity to the areas of high metabolism and accelerated resorption in the bone tissue [17]. The 99mTc-ZOL is used for finding centers of pathologic changes of different origin and dissemination in the skeleton: primary and metastatical malignant tumors, osteomelitis, bone-joint tuberculosis, arthritis of different origin and others.

The high affinity of biphosphonates towards bone is based on their ability to become incorporated into the hydroxyapatite crystal by chemisorption on to the surface of bone. 99mTc-ZOL and 99mTc-MDP were administered intravenously to the rabbits for scintigraphic studies. Between 99mTc-ZOL and 99mTc-MDP, there were no significant differences in the ratios of femur/back ground (BG) and lumbar vertebrae/BG, whereas epiphysis/BG and the kidney/BG ratios of 99mTc-MDP were higher than 99mTc-ZOL in the statics imaging studies [2].

Lanthanides (Lu is a member) are usually most stable in solution as trivalent ions (M3+) with the exception of cerium and europium which can exist as quadrivalent and bivalent species. Lanrhanides in aquous solution bind to water molecule, and due to their large size, their coordination number are usually 7 and 10. Very few six coordinate species are known, while coordination numbers of 8 and 9 are the most common. Lanthanides form stable complexes with nitrogen or oxygen donor chelators. Figure 6 shows the predicted structure of 177Lu-ZOL. In summary, the rabbit SPECT imaging results shows that 177Lu-ZOL possess excellent characteristics for the promising application as a novel bone therapeutic radiopharmaceutical.

anesthesia-clinical-research-Proposed-structure

Figure 6: Proposed structure of 177Lu-ZOL.

Conclusion

Optimization of reaction conditions for preparation of 177Lu-ZOL having a radiochemical purity of 99% has been achieved. The complex was found stable up to 7 hours. Scintigraphic studies in rabbits show high uptake of complex in skeleton up to 7 days, the duration of studies. Due to better physical properties of 177Lu compared to 153Sm (FDA, USA approved drug 153Sm-EDTMP) and acceptable biodistribution results of 177Lu-ZOL seemed to be a potential new candidate for clinical trials for bone pain palliation therapy.

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