WO2019207594A1

WO2019207594A1 - Microsphere cold kit for the application in trans-arterial cancer therapy

Info

Publication number: WO2019207594A1
Application number: PCT/IN2019/050304
Authority: WO
Inventors: Jaya Shukla; B.R Mittal
Original assignee: Jaya Shukla
Priority date: 2018-04-26
Filing date: 2019-04-15
Publication date: 2019-10-31

Abstract

The present disclosure relates to development of ready to use microspheres (cold kit) for labeling with radionuclide. The present disclosure particularly relates to the development of radiolabeled microspheres and its application in pre and post therapy dosimetry and selective intra-arterial radionuclide therapy (SIRT). It relates to the use of radiolabeled microspheres formulated with cold kit for the treatment of liver, breast, kidney, ovarian, bladder, colorectal and other solid tumors. Disclosed microspheres selectively delivered to tumor site without harming to other organs such as thyroid, kidney and bladder.

Description

TECHNICAL FIELD

The present invention relates to the field of radionuclide therapy, and more particularly to a selective intraarterial radionuclide therapy (SIRT) which involves microsphere cold kit comprising of non-radioactive freeze-dried microspheres. The said microspheres are ready to use and are radiolabeled with diagnostic and therapeutic radionuclide in the hospital radio-pharmacy on the day therapy for the application in lung shunt study and SIRT.

BACKGROUND ART

Hepatocellular carcinoma (HCC) is a primary liver cancer and one of the world’s most lethal malignancies. The liver is also a common site of metastasis for variety of tumors like neuroendocrine tumor (NET), colorectal carcinoma, bladder carcinoma etc. However, lack of symptoms makes the diagnosis of liver cancer very difficult. Ultrasound (US), Computed tomography (CT) and hepatic angiography are the methods to diagnose the disease. The liver resection provides the only chance for a cure and could be performed with less than 5% mortality and acceptable morbidity. Never the less, the primary or metastatic liver cancers are often unresectable even if it is not spread to lymph nodes or other distant sites. The reasons include a) large sized, b) location close to a large blood vessel, c) multiple small or big lesions spread throughout the liver and d) small tumor but the patient is not healthy enough for surgery.

Selective intra-arterial radionuclide therapy (SIRT) is a reasonable and an effective therapeutic alternative, a) for the treatment of large inoperable HCC, with or without portal vein thrombosis, b) for the treatment of small inoperable tumor not suitable for percutaneous therapy for any reason, c) as a neoadjuvant therapy before hepatic transplantation to reduce the risk of recurrence in the graft or before hepatic resection to shrink the tumor size, and d) as an adjuvant therapy, after surgery or percutaneous ablative therapy to reduce the risk of recurrence. SIRT offers reduced toxicity profiles, highly effective tumor responses, prolonged survival and improved quality of life. Various radioisotopes (1-131, Y-90, Re-l88, P-32 etc.) either labeled with lipiodol or microspheres have been used for SIRT to target the tumor by making use of the dual blood supply of the liver. The radioactive substance through the hepatic artery is delivered to the tumor, giving a favorable uptake ratio of tumor to normal tissue (TNR). Currently available options, for such therapy, are either not up to the mark (Re- 188 lipiodol) or are very expensive (Y- 90 Thera/S irSpheres) and therefore remain unaffordable for most of the patients.

Further, in HCC several disease related collaterals are often formed that communicate with adjacent organs. Therefore, pretherapy dosimetry is mandatory to study the fraction of delivered dose, from the tumor, reaching to adjacent organs before deciding the dose for SIRT. For this reason, a“Scout dose” is delivered to tumor and image is acquired under gamma camera. The region of interests is drawn around liver, tumor, lungs and other organs where ever the localization of radioactivity is visualized. Based on shunt fraction and maximum tolerated dose (MTD) to normal liver (30 Gy) and lung (12 Gy), the therapy dose is calculated. Y-90 emits therapeutic pure beta particles (EPmax-2.2 MeV) that are non- imageable radiations. Therefore, the pretherapy dosimetry or the shunt study for Y - 90 microspheres (TheraSpheres and SirSpheres) is done by using Tc-99m (Eg-140 keV) macro-aggregated albumin (MAA) particles, one to two weeks prior to therapy, for dose calculation. However, the aforesaid procedure involves separate catheterization (invasive procedure), use of Tc-99m MAA and catheter that poses extra financial burden on patients. Also, the use of human serum albumin (HSA) during labelling may cause hypersensitive reactions in some patients. Moreover, Tc-99m MAA particles do not behave exactly similar toY-90 microspheres The commercially available Y-90 microspheres are highly expensive and therefore unaffordable by majority of patients, especially in India. The cases of gastroduodenal reflux are also reported using Y-90 microspheres for SIRT. Thus, there is a need for providing a cost-effective option for SIRT. The cold microsphere kit described in the invention provides one such option that covers all drawbacks of existing available options. The present invention comprising ready to use microspheres that can easily and quickly be radiolabeled with radionuclides (Tc- 99m, Re- 188, Lu-l77 etc.) in hospital radio-pharmacy for shunt study and SIRT. Beside therapeutic beta particles, both Re- 188 and Lu-l77 emits imageable gamma (g) photons that are exploited for pre-therapy dosimetry.

DISCLOSURE OF INVENTION

1) The primary objective of the present invention is to provide ready to use microspheres for radiolabelling.

2) Another objective of the present invention is to provide cost-effective microspheres for application in selective intra-arterial radiation therapy (SIRT).

3) Another objective of the present invention is to provide a system having an option for radiolabeling microspheres with Tc-99m for shunt studies and with Re- 186/Re- 188 for SIRT.

4) Yet another objective of the present invention is to provide non-radioactive microspheres, wherein radiolabeling is performed at any hospital radio pharmacy by heating microspheres with Tc-99m or Re-l88.

5) Yet another objective of the present invention is to provide microspheres for the treatment of liver tumor, but not limited to tumors like breast, ovarian, bladder, kidney, colorectal and other solid tumors.

6) Yet another objective of the present invention is to provide kit for single patient therapy comprising two vial kit or single vial kit for multiple patients use, including shunt study and SIRT dose.

7) These and other features and advantages of the present invention may be incorporated into certain embodiments of the invention and will become more fully apparent from the following description or may be learned by the practice of the invention as set forth hereinafter. The present invention does not require that all the advantageous features and all the advantages described herein be incorporated into every embodiment of the invention. BRIEF DESCRIPTION OF DRAWING

The present invention will become more understandable from the description given herein and the accompanying drawings below. These are given by way of illustration only and therefore not limited to present invention and wherein:

Figure- 1. Microspheres size distribution of ready to use microspheres cold kit. Figure-2. Scanning electron micrograph of ready to use microspheres (cold kit). Figure-3. The powder X-ray diffraction pattern of microspheres of cold kit.

Figure-4. Radiolabelling Yield (%) of Re- 188 microspheres from various batches of ready to use microsphere cold kit.

Figure-5. Radio-chromatogram showing radiochemical purity of Tc-99m microspheres prepared with ready to use cold kit a) at lh and b) 6h.

Figure-6.Radio-chromatogram demonstrating the radiochemical stability of Re- 188 microspheres prepared from ready to use microsphere cold kit.

Figure-7. Re-l88 microspheres prepared with ready to use microsphere cold kit stored at -20 °C.

Figure-8. Pre-therapy dosimetry-Lung shunt study with Tc-99m and Re-l88 microspheres prepared with ready to use microsphere cold kit.

Figure-9. Post-therapy images of Re- 188 microsphere prepared with ready to use microsphere cold kit.

BEST MODE(S) FOR CARRYING OUT THE INVENTION

Example-1

Preparation of Mierospheres: The micro spheres were formulated by adding hydrochloric acid (HC!) to stannous salt (10-250 g) in a vial and puting in a boiling water bath. The vial was removed, cooled at room temperature and added with filter sterile ascorbic acid (5-20 mg) as antioxidant. The vial was freeze dried and stored at -20 °C.

Example-2

Particle size analysis; The prepared particles were washed thrice with milli-Q water and a suspension was prepared. A portion of suspension was stored for particle size analysis (zeia analyzer) and rest was lyophilized. A continuous flow was maintained, and a light beam was passed to analyze particle size. The distribution of particles was shown in figure- 1. The average and maximum size of particles was 5 pm and 20 pm respectively.

Further the morphology of microparticles was analyzed by scanning electron microscope ( SEM). The lyophilized particles were mounted on a stub using semi- conductive double -sided adhesive tape, coated with gold and was placed on the SEM chamber for analysis. The vacuum is maintained, and sample was excited by secondary electrons. The applied voltage and current were 10 V and 2 A respectively The particles were spherical in shape (figure-2).

The crystallite size was analyzed by powder X-ray diffraction method. The angle for diffraction scattering is proportional to the crystallite size during the movement of particles through the light beam (figure 3). The XRD pattern for the sample matched well with standard pattern corresponding to S11O2 with pdf no. of 00-001- 0657. The peaks observed at 2Q position of 26.6°, 33.9° and 52.2° corresponds to the following lattice planes: (1 1 0), (1 1 1) and (2 1 1) of tetragonal structure with P42/ncm space group.

The values of lattice parameters obtained using le-bail refinement method were observed to be:

a=4.9859 A c=3.1295 A

Example-3

Radiolabeling with Tc-99m pertechnetate or Re-188 perrhenate: The freeze dried mierospheres stored at -20 °C were thawed to room temperature (RT). Freshly eluted Tc-99m pertechnetate or Re- 188 perrhenate in 0.9% saline was added in the microsphere containing vial and heated at 90-100 °C for 30 minutes. The vial was cooled to RT, sterile buffer (phosphate/acetate pH-8) was added to make the formulation pH 6.5-7.0 and centrifuged at 3000 rpm for 10 minutes. The supernatant was removed. The radioactivity in pellet and supernatant was measured with pre-calibrated dose calibrator. The percent labelling (labelling efficiency) was calculated as below:

% labelling=——— :— ^{ai tlvlty m pellet} - * 100 — Equation -1

activity in pellet+activity in supernatent

The pellet was washed with saline and suspended in I ml water for injection or saline. The quality control of radiolabeled mierospheres was performed on following parameters:

Labelling efficiency: The freeze-dried mierospheres were labelled with Tc-99m pertechnetate and Re- 188 perrhenate. The labeling efficiency of various batches of freeze-dried formulations with Tc-99m and Re- 188 was noted and found to be more than 90% (figure 4)

Radiochemical purity and Stability: The paper chromatography (PC) of radiolabeled microsphere pellet suspended in water/saline was performed by putting 4m1 of suspension as spot on a Whatman strip (l2cm*lcm) at lem above the base. The strip was developed, up to 11 cm, in a tube having 0.9% saline as mobile phase. The strip was removed and scanned in a radio-TLC scanner. Also, the strip was cut in to two parts, 2 cm above the spot, and counted in the well counter (Nal(Tl)) with the energy window set for Re-l88 (155 ±20%) or Tc-99m (140+20%).

Re- 188 or Tc-99m mierospheres remained at the point of spot, being particulate, (R_f=0) and Re-l88 perrhenate moves with the solvent front (R_f=l). Similarly, the counts were concentrated on the part containing spot. However, the solvent front showed only minimal, background, counts. The radiochemical purity (RCP) was calculated as :

counts at the bsae

RCP= * 100 Equation -2 counts at the base+counts on the solvent front

The calculated radiochemical purity was always more than 99%.

The PC as mentioned above was done up to 6 h for Tc-99m microspheres and up to 96 h for Re- 188 microspheres. The radio-peaks on Radio-TLC scans were observed. The single radio-peak was observed up to 6 h for Tc-99m microspheres and up to 96 h for Re- 188 Microspheres, demonstrated that the radiolabeled microspheres (Tc-99m and Re- 188) are stable (figure 5 and 6)

Sterility: The unlabeled microspheres (cold-kit) and the radiolabeled microspheres were tested for sterility. The test was carried out using sterile fluid thioglycolate medium (FTM) and soybean casein digest medium (SCD), in a laminar flow hood. The content of the kit vial reconstituted with sterile saline and radiolabeled (Tc- 99m/Re-l88) microspheres were aseptically transferred and inoculated in both fluid nutrient medium (FTM, SCD), incubated at 30-35°C and 20-25°C respectively. The observations were made daily up to 7 days for any microbial growth by visual examination in form of turbidity. The radiolabeled and unlabeled microsphere samples were found sterile.

Apyrogenicity: The Limulus Amebocyte Lysate ( LAL ) test for bacterial endotoxins was performed with freeze dried microspheres and radiolabeled microspheres (after decaying the product). LAL test is based on the formation of gel clot in the presence of endotoxin. This test was performed in randomly selected samples (cold-kits and radiolabeled microspheres) in a thermally regulated and vibration-free environment and the gel formed was inspected manually.

The permissible limit of endotoxin in injectable formulation is 175 EU per injected volume according to USP and per mL according to Ph. Eur. The sensitivity of LAL test is 0.125 EU of endotoxin concentration. The positive water control (PWC) was prepared by adding endotoxin (0.25 and 0.5 EU/mL) in water. 100 pL (0.1 mL) sample or positive (endotoxin) control was mixed with 100 pL of LAL reagent, under aseptic conditions and incubated for one hour undisturbed at 37±1°C. Formation of an opaque gel that remained firm when the assay tubes were inverted, indicated presence of endotoxins. While formation of a viscous gel that did not maintain its integrity or absence of a firm gel confirmed negative reaction. In all the samples tested gel formation was not observed and therefore, passed the apyrogenicity test.

Shelf-life of !yopMMzed mkrospheres: The freeze-dried microspheres were radiolabeled with Tc-99m and Re- 188 and showed good radiolabeling yield up to 1 year (Figure 7). Therefore, the estimated shelf-life at -20°C storage is 1 year.

Clinical study; The clinical studies were performed in the Department of Nuclear Medicine and Department of Radio-diagnosis as per the protocol approved by the Institutional Ethics Committee (No. INT/IEC/20l8/000979),The clinical studies of Re- l88/Tc-99m- Microspheres prepared, with ready to use microsphere kit, were performed after obtaining informed written consent from the patients and their relatives. A trans-arterial catheter was placed into the hepatic artery by an experienced interventional radiologist.

Pretherapy dosimetry: A‘scout dose’ of 3-5 mCi (111-185 MBq) of radiolabeled (Tc-99m/Re-l88) microspheres was delivered to tumor via hepatic artery and a whole-body image was acquired under gamma camera equipped with low energy all-purpose collimator when Tc-99m microspheres were delivered and with medium or high energy collimator when Re- 188 microspheres were delivered. The ROIs were drawn around lung and liver. The anterior and posterior counts were noted, and geometric mean was calculated. The lung shunt percent (%)was calculated as a percent (%) fraction of lung and liver (Figure 8). The fraction of dose to normal liver was also calculated as tumor to normal liver ratio (TNR) to calculate the therapeutic dose for tumor with minimal radiation dose to lung and normal liver.

Delivery of therapeutic dose: After calculation of therapeutic dose Re- 188 microspheres, as described above, the therapeutic dose was delivered to tumour using same catheter used for pretherapy dosimetry on the same day. The post therapy whole body and SPECT/CT images were obtained at 24 h and/or 48 h to observe the retention of Re- 188 microspheres and to calculate dose delivered to tumor. Corrections for scatter was done by acquiring images in triple window, the photopeak, lower and upper scatter windows. The attenuation correction was performed by patients CT Images. (Figure-9).

INDUSTRIAL APPLICABILITY

The method of preparation of microspheres is simple and includes mixing stannous salt in hydrochloric acid followed by heating of mixture at 90-l00°C for 90 mins. The microsphere formulation is freeze dried and stored as ready to use microspheres for radiolabeling with Tc-99m and Re- 188 for its further use in planning (pre therapy dosimetry) and selective intra-arterial radionuclide therapy (SIRT).

The advantage of using these microspheres is it’s a low-cost production. The preparation procedure is very simple. The freeze-dried formulation is used for radiolabeling with Tc-99m and Re- 188 for its use in pre-therapy planning and selective intra-arterial radionuclide therapy (SIRT).

The freeze-dried formulation can be stored at -20°C for more than 12 months and is used for in-house radiolabeling i.e. at hospital radio-pharmacy using freshly eluted Tc-99m and Re-l88. Availability of cost effective transportable small sized generators of Tc-99m and Re- 188, makes the formulation equitable.

The size of microspheres is less than 20 micron (as reveled by zeta size analyzer). However, 50 percentile microspheres were of approximately 5 micron.

Radiolabeling of the freeze-dried formulation is simple heating for 30 minutes at 90-l00°C. The radiochemical purity of radioactive formulation is above 99%. The radioactivity remained bound above 99% after 6 h and 96 h incubation at 37°C to Tc-99m and Re- 188 microspheres respectively.

These microspheres are approved by the Institutional ethics committee for use in patients suffering from unresectable liver cancer. Patients are recruited as per the standard inclusion and exclusion criteria for SIRT. The written consent is obtained after informing the patient and the attendant regarding the procedure and associated risk. Catheter is placed by femoral artery puncture and 3-5 mCi Tc-99m microspheres (scout dose) are delivered. The whole-body image is acquired under gamma camera equipped with low energy all-purpose collimator for calculation of lung shunt fraction and dose to be delivered for therapy.

Re- 188 is a theranostic radionuclide. It emits therapeutic beta particles (Epmax- 2. lMeV) and imageable g photons (Eg-155 keV). Therefore, Re-l88 microspheres can also be used for pre-therapy planning. For this purpose, Re- 188 microspheres (3-5 mCi) are delivered to the lesion through trans-arterial catheter similarly as described above for Tc-99m microspheres. Imaging is done with gamma camera and high or medium energy parallel hole collimator is used.

The lung shunt is calculated from the counts in lungs and the liver after drawing ROI on liver and lungs. If the radioactivity is seen in spleen, the liver ROI is extended to include spleen. Liver and tumor volumes and tumor to normal liver ratios are calculated. The radioactivity for therapy dose is calculated to deliver 100- 150 Gy to tumor while restricting 30 Gy to normal liver, 12 Gy to lungs and 3 Gy to red marrow

The distribution pattern reveals that the microspheres are well localized in the lesions where these are delivered. However, small fraction of activity is also noted in lungs and spleen, based on the type of tumor. The major cause of extra hepatic localization is the formation of disease related collaterals and invasion of tumor in to portal vein also known as portal vein thrombosis, specifically in HCCs. However, in metastatic liver cancer (e.g.; neuroendocrine tumor, colorectal or bladder etc.) the lung and spleen shunt is minimal. Major portion of the microspheres is localized in the lesion only.

The calculated therapeutic dose is delivered to tumor, just after the shunt and dose calculation, as described above. The same catheter is used for delivery of shunt dose and therapy dose. Both procedures are completed in single day. This reduces the procedural cost to at least half of the cost involved for Y-90 microsphere therapy (glass or resin). Coiling of gastric or other artery is also not required. The microspheres are small in size and easily administered through micro catheter. No resistance or reflex is noted during delivery of microspheres.

The additional advantage of using these microspheres is that same microspheres are used for labeling with Tc-99m and Re-l88. Therefore, the pretherapy scan also simulates the behavior of Re- 188 microspheres in the patient. In contrary, in Y-90 based microsphere therapy, the pretherapy dosimetry for lung shunt is done with Tc-99m MAA (macroaggregated albumin), that neither have same material nor morphology or size. Post therapy scan is done at 24 h and/or 48 h to monitor the localization of microspheres in the tumor. Re-l88 also emits imageable gamma photons. The whole body and SPECT/CT images are acquired using gamma camera equipped with medium/high energy collimator. The post therapy scans demonstrated the good localization and retention of Re- 188 microspheres in lesion. No significant amount of Tc-99m or Re-l88 is leached from the microspheres as free Tc-99m or Re-l88. Thyroid and salivary glands are never visualized. Hence, there is no requirement to protect thyroid or salivary glands before or during SIRT.

The following presents a simplified description of the invention in order to provide a basic understanding of some aspects of the invention. This description is not an extensive overview of the present invention. It is not intended to identify the key/critical elements of the invention or to delineate the scope of the invention. Its sole purpose is to present some concept of the invention in a simplified form. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.

Features that are described and/or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and/or in combination with or instead of the features of the other embodiments. The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only and not for the purpose of limiting the invention as defined by the appended claims and their equivalents.

It is to be understood that the singular forms“a,”“an,” and“the” include plural referents unless the context clearly dictates otherwise.

By the term“substantially” it is meant that the recited characteristic, parameter, or value need not be achieved exactly, but that deviations or variations, including for example, tolerances, measurement error, measurement accuracy limitations and other factors known to those of skill in the art, may occur in amounts that do not preclude the effect the characteristic was intended to provide.

It should be emphasized that the term“comprises/comprising” when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

The present invention relates to non-radioactive microsphere for application in trans-arterial therapy, wherein the non-radioactive ready to use microspheres are formulated for radiolabeling with Re- 188 in hospital radio-pharmacy. These microspheres may also be labelled with other radionuclides like Re- 186, Lu-l77, and Y-90, Zr-89, Cu-64, P-32 etc.

Re-l88 has imageable g- emission of 155 Kev and is utilized to study lung shunt on the same day using same Re- 188 microspheres prepared for the therapy i.e. same batch. It reduces the cost of the overall procedure. In addition, the said microspheres can also be radiolabeled with Tc-99m for shunt studies. In this case, same microspheres will be labeled with Tc-99m for shunt calculation and with Re- 188 for SIRT.

A small dose (3-5 mCi) of labelled microspheres (Re- 188 or Tc-99m) is delivered to tumor, after the placement of trans-arterial catheter, to calculate shunt to adjacent organs (lungs and gastric reflux) and tumor to non-tumor ratio (TNR) for dosimetry purpose. After determining the dose to lung and normal liver, the therapeutic dose is calculated and delivered on the same day using same catheter, thereby making the procedure simple and cost effective. The trans-arterial catheters, used for the procedure, are costly. Use of described microspheres reduces the procedural cost to more half as compared to Y-90 microsphere treatment procedure.

Microspheres are smaller in size (1-20 pm; >50% ~5 pm). Small particles bypass the lungs and accumulate in the spleen, thereby reducing the chances of radiation induced pneumonitis and accumulation in spleen help in maintenance of hematological parameters. Small particles are easily administered, without any resistance, and gastro-duodenal reflux is not reported during administration of microspheres discussed in this invention.

Although the embodiments herein are described with various specific embodiments (examples), it will be obvious for a person skilled in the art to practice the invention with modifications. However, all such modifications are deemed to be within the scope of the invention.

Claims

CLAIMS We claim:

1. A ready to use microspheres cold kit for trans-arterial radionuclide delivery comprising; microspheres for radionuclide labeling.

2. A method of preparation of microspheres, comprising;

a) mixing of metal salt in hydrochloric acid,

b) heating at 90-l00°C temperature,

c) adding an antioxidant and

d) freeze drying.

3. The method of preparation of microspheres as claimed in claim 2, wherein metal salt is stannous salt, but not limited to salt of magnesium (Mg), copper (Cu), lead (Pb), niobium (Nb), vanadium (V), gallium (Ga), titanium (Ti), germanium (Ge), zirconium (Zr), aluminum (Al), manganese (Mn), Iron (Fe), zinc (Zn), silica (Si).

4. The method of preparation of microspheres as claimed in claim 2, comprises ascorbic acid as antioxidant but not limited to use of salts and esters of ascorbic acid, gentisic acid.

5. The method of preparation of microspheres as claimed in claim 2, wherein; the reaction is single step and single pot reaction.

6. The microspheres as claimed in claim 2, characterized by; spherical shape with diameter less than 20-micrometer (pm).

7. The microspheres as claimed in claim 1, are produced by the process as claimed in claim

2.

8. A process of radiolabelling of microspheres comprising; mixing of micropheres with radionuclide, followed by heating at 90-l00°C for 30 minutes and then separation of radiolabeled microspheres by centrifugation.

9. The radionuclide as claimed in Claim 1 and 8, selected from the group of Re- 186, Re- 188, Tc-99m, Ga,68, Lu-l77, Y-90, Zr-89.

10. The radionuclide as claimed in Claim 1, is Tc-99m for pretherapy dosimetry studies, but not limited to Re- 186, Re- 188, Ga-68, Lu-l77, Zr-89.

11. The radionuclides as claimed in Claim 1, is Re- 188 for selective intra-arterial radionuclide therapy (SIRT) and post therapy dosimetry, but not limited to Re- 186, Lu-l77, Y-90, Zr- 89.

12. The ready to use microspheres cold kit for trans-arterial radionuclide delivery as claimed in claim 1 , is used for the treatment of liver tumor, but not limited to tumors like breast, ovarian, bladder, kidney, colorectal and other solid tumors.

13. The ready to use microspheres cold kit for trans-arterial radionuclide delivery as claimed in claim 1, is used for pre therapy dosimetry studies and as therapeutic agent for SIRT and for post therapy dosimetry studies.