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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 3  |  Page : 387-393

Pretargeting articulation for improving the deliverance of injected dose to the tumor: An evaluation of In vivo study for enhanced tumor uptake


Department of Chemistry, GLA University, Mathura, Uttar Pradesh, India

Date of Submission09-Jun-2022
Date of Decision24-Jul-2022
Date of Acceptance28-Aug-2022
Date of Web Publication17-Sep-2022

Correspondence Address:
Pankaj Garg
Department of Chemistry, GLA University, Mathura - 281 406, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_149_22

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  Abstract 


Background: Radiobioconjugate targeting using monoclonal antibodies linked to a high-energy radionuclide is a promising approach for treating metastatic cancer. The central problem of radiobioconjugate targeting is the small fraction of radiobioconjugate localized in the tumor. Pretargeting based on avidin–biotin approach has been recommended to maximize tumor targeting. The current study was conceded with an aim to assess a selective targeting strategy for the site-specific deliverance of an injected radioactive dose to the tumor cells. Methods: Two labeling protocols were tested and evaluated, both for the direct and indirect radiolabeling of antibodies with radionuclide technetium. A comparative evaluation of biodistribution studies relating to the deposition of injected dose in different organs was carried out in tumor-bearing nude mice both for a direct single-step and indirect multistep pretargeting approach. Results: High concentration of the injected dose was accounted in the nontarget organs and blood for a direct targeting mode, as compared to indirect multistep pretargeting with high tumor uptake. Better tumor visibility and high tumor/nontumor ratio were observed at 24 h and 48 h. However, a considerable deposition of radioactivity in the organs such as liver, spleen, kidney, and lungs as a nonspecific, reticuloendothelial system uptake was observed as a cause of concern and the use of certain blocking agents were explored, effective for reducing the same. Conclusions: The study demonstrates a successful targeting efficiency of the radiolabeled bioconjugate for technetium (Tc-99m), through a multistep pretargeting approach, and the same can be applied for other related therapy radionuclides also.

Keywords: Avidin–biotin, monoclonal antibody, pretargeting strategies, radiobioconjugate therapy, reticuloendothelial system uptake


How to cite this article:
Garg P. Pretargeting articulation for improving the deliverance of injected dose to the tumor: An evaluation of In vivo study for enhanced tumor uptake. Biomed Biotechnol Res J 2022;6:387-93

How to cite this URL:
Garg P. Pretargeting articulation for improving the deliverance of injected dose to the tumor: An evaluation of In vivo study for enhanced tumor uptake. Biomed Biotechnol Res J [serial online] 2022 [cited 2022 Oct 5];6:387-93. Available from: https://www.bmbtrj.org/text.asp?2022/6/3/387/356146




  Introduction Top


The conventional antibody targeting approach for cancer cells, involving a direct deliverance of radiolabeled antibodies to tumor cells, is characterized by slow pharmacokinetics. The circulating half-life of a monoclonal antibody (MoAb) in the blood is usually between 2 to 4 days. This long residence time of a MoAb in the blood facilitates the optimal accretion of antibodies in the tumor, but it also causes relatively a higher residence time of the radiolabeled conjugate in the nontarget tissues.[1],[2],[3],[4] To enhance the therapeutic efficacy of targeting cancer cells (i.e., high selective tumor uptake with simultaneous minimization of nontarget tissue background activity), several multistep pretargeting approaches have been recommended for the site-specific delivery of the injected dose. These multistep pretargeting methodologies have gained considerable attention for cancer imaging and targeting, as these represent a highly selective alternative to other targeting systems using direct radiolabeled antibodies[5],[6],[7] [Table 1].
Table 1: Tabular representation of different pretargeting approaches based on avidin-biotin approach

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Unlike direct targeting systems, where an effector molecule, i.e., a radionuclide or a drug, is directly linked to the targeting agent (antibody), in pretargeting systems, the effector molecule is given some time after the administration of the targeting moiety initially. This allows sufficient time for the targeting agent to localize in the tumor tissue and more importantly to get excreted and cleared from the nontarget tissues in the body and circulation.[8],[9],[10] Later in the second phase, the radionuclide is administered coupled to a small ligand molecule that has an affinity to bind with the prelocalized MoAbs in the tumor tissues and also acts as a drug clearing agent from the blood, in an attempt to maximize accumulation in the tumor while minimizing exposure to the nontarget tissue.[11],[12],[13],[14] The radiolabeled ligand distributes rapidly throughout the body and binds selectively to the prelocalized antibodies in the tumor tissues, whereas the unbound radiolabeled molecules cleared rapidly from the body.[15],[16],[17],[18] Biochemically, pretargeting involves the administration of a circulating targeting molecule (antibody), having a high noncovalent binding affinity for a small rapidly excreted effector (radioactive) molecule, which is delivered slightly delayed after the antibody has once concentrated in the target tumor (T).[19],[20]

Two most prominent pretargeting methodologies have been suggested for the successful delivery of the injected drug: (i) pretargeting strategy based on strong interaction between streptavidin/avidin and biotin (Vitamin H) (here, the antibody is labeled with avidin/streptavidin and the radiolabeled isotope is linked to the biotin as the therapy agent) and (ii) pretargeting strategy, based on the use of bispecific antibodies (one directed against the tumor antigen and the other directed against a metal chelate; here, the radioactive isotope is linked to the chelate).[21],[22],[23],[24] The ultimate aim of both approaches is to maximize the accumulation of radiolabeled MoAbs in the tumor tissues and to minimize their deliverance to nontumor tissue. Pretargeting using the avidin–biotin approach not only enhances the target/nontarget ratio by multiplication of 4:1 at each avidin–biotin interaction but also confers the possibility of using a universal radiolabeled effector molecule, which can be utilized with a variety of primary antibodies [Figure 1]. An avidin–biotin approach has the advantage of exceptionally high binding affinity, i.e., 1015 per mole between the pretargeted antibody conjugate and the radiolabeled ligand.[25],[26],[27],[28] Attempts have been made by us to utilize this for pretargeting strategies for improving the targeting efficacy of the injected dose, where a primary avidin-linked anticancer antibody is first injected followed by a labeled biotin molecule carrying the isotope, capable of conferring either an image localization (radioimmunoscintigraphy) or cancer cell elimination (radioimmunotherapy).[29],[30],[31],[32],[33]
Figure 1: Radiolabeled antibody-conjugate, targeting tumor cell surface using avidin–biotin approach. Enhancement of tumor/nontumor ratio in multiplication of 4:1 for each avidin–biotin interaction, thus creating a force multiplier effect on tumor tissues

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  Methods Top


Chemicals

Radioisotopes

Radionuclides like technetium-99m (Tc-99m) were readily available from the Board of Radiation and Isotope Technology (BRIT), Mumbai, India. Tc-99m, in fact, the daughter product of molybdenum-99 because of having a low half-life (T1/2 = 6.007h), was obtained by milking the parent, using molybdenum-99-Tc-99m generator (solvent extraction type) supplied by BRIT, Mumbai, India.

Antibodies

The antibodies whose labeling was studied include the following:

  1. Human immunoglobulin: Polyclonal nonspecific mixture marketed as Bharglob (Bharat Serums and Vaccines Limited, Thane, Mumbai). The composition of Bharglob is as follows:
  2. M3 monoclonal antibody: Directed against the tissue polypeptide-specific antigen, which is a pancarcinoma proliferation antigen of cytokeratin 8–18 family of IgG1 class. The antibodies were used both for assessing a single-step direct radiolabeling technique as well as indirect multistep pretargeting techniques that can be accomplished either by the use of metal chelates or by the avidin–biotin method.


Biotin, avidin, and other reagents used

Biotin (commonly known as Vitamin H), used to label with different radioisotopes, was obtained from “M/s Sigma Chemicals” either in pure form or in the form of biotin derivatives. Biotin in its native pure form was used during the experimental trials. Avidin was procured from Abcam PLC (Shanghai), in the form of an avidin conjugation kit (ab102862) used for the conjugation of primary antibodies. The other laboratory chemicals and reagents used for radiolabeling studies were obtained from the central research laboratory of the chemical sciences department of the institute.

Experimental animal model and equipment used

Albino mice used for the experimental animal study were procured from the central animal house of the institute. Fifteen animals in the experimental study were used, divided into three groups of five each for evaluating the direct single-step, indirect two-step and three-step pretargeting approaches. The related studies were carried out following the principles and guidelines outlined in the guide for the care and use of laboratory animals, approved under the institutional ethical committee under CPCSEA (1260/PO/ERC/S/09/CPCSEA/IAEC/2018/). The use of instruments such as ZLC-7500 Single-Photon Emission Computed Tomography (SPECT) Gamma Camera (Siemens, Germany) for imaging experimental animal models, Auto Gamma Counter (Packard, Germany) for counting in animal organs after sacrifice, and “Deluxe Isotope Calibrator” (Victoreen, USA) for measuring radioactivity was facilitated from the Department of Nuclear Medicine, Medical College Agra, India.

Cell lines used

The commonly used cell line was Ehrlich Ascitic Tumor cell line, obtained from the Institute of Nuclear Medicine and Allied Sciences (New Delhi). A concentration of 2 × 107 cells/ml was injected subcutaneously in an immunosuppressed mouse for generating a tumor.

Methodology

Radiolabeling of an antibody (Bharglob) with the radionuclide Tc-99m was attempted both by direct and indirect methods based on the avidin–biotin approach and was carried out in the following steps:

Direct labeling of a nonspecific antibody (Bharglob) with technetium (Tc-99m)

Purification and reduction of nonspecific gamma globulin (Bharglob)

To concentrate the gamma globulin and render it free of preservatives, the commercial Bharglob (nonspecific antibody) preparation was first dialyzed. Antibody was then concentrated to a required concentration (1 mg/ml) by putting the dialyzing membrane bag in a polyethylene glycol (Mw = 6000) solution. Further reduction of nonspecific antibody was carried out using a 2-mercaptoethanol solution, where the –S–S– bond present in the gamma globulin (nonspecific antibody) was reduced to the thiol (–SH–) group, which opens its further binding options with the radioisotope. The reduced gamma globulin (Bharglob) was finally collected in a vial, marked as (vial-1).

Methodology for direct radiolabeling of antibody (Bharglob) with technetium (Tc-99m)

A mixture of 0.12 mg of SnCl2.2H2O, 0.2 ml NaCl, and 2.7 mg of Na4PTP. 2H2O (protein tyrosine phosphatase [PPT), as a chelating agent in metal ion buffer, was reconstituted with 3.5 ml of distilled water and 1 ml of this solution was added to the above (vial-1.) containing the reduced Bharglob. After this, 1.5 mCi of TcO4 eluate activity from a solvent extraction generator in a volume of 0.7 ml was added to each of these vials. The reaction was allowed to proceed for 10 min at room temperature. The function of PTP is to act as an intermediate chelate preventing weak nonspecific globulin labeling and allowing high-affinity labeling through the –SH– groups.

Indirect labeling of a nonspecific antibody (Bharglob) with Tc-99m (through avidin–biotin approach)

Methodology for radiolabeling of biotin with technetium-99m (biotinylated technetium)

900 μg of biotin in the pure form was dissolved in per ml aqueous solution of C2H5OH/H2O (1:1) and collected in a test tube. 500 μl of potassium sodium tartrate solution prepared in distilled water (molar concentration; 0.05 M) was added to the above hydroalcoholic biotin solution. 10 μl of stannous chloride solution (SnCl2.2H2O; molar concentration: 0.005 M) was added to the same biotinylated solution and finally 1 ml of technetium generator eluate pertechnetate (TcO4-) with an activity of the order of 5 mCi was added to the above solution mixture and allowed to incubate at room temperature for 20 min in a boiling water bath.

Avidin linked antibody and its conjugation with biotinylated technetium

Avidinylation of antibodies was carried out using the avidin conjugation kit obtained from Abcam PLC (ab102862). The technical protocol was followed to conjugate avidin with an antibody. The technical protocol of “Abcam” recommends using 10 ml, 100 ml, and 1 ml of antibody solution with 10 mg, 100 mg, and 1 mg concentration kit formats, respectively, for obtaining optimal results.[34] To enhance the efficacy of targeting cancer cells with a high tumor/nontumor ratio, indirect multistep (two-step, three-step) pretargeting approaches based on avidin–biotin interaction were tested and evaluated. In pretargeting, a primary avidin-linked anticancer antibody is first injected initially, followed by a labeled biotin molecule carrying the isotope injected 2–3 days later.[35],[36],[37]

In vivo experimental observations

Assessment of targeting for both direct and indirect multistep pretargeting approaches

Fifteen nude mice (age: 6–7 weeks; wt. 22–25 g approximately), bearing human carcinoma cells, were divided into three groups (five in each group; direct labeled group; indirect two-step and three-step groups). In a two-step pretargeting approach, the mice were injected with 100 μg of an avidin–antibody conjugate, followed by an intravenous injection of 50 μg Tc-99m -biotin solution (activity; 5 mCi) delivered 24 h later. The three-step pretargeting approach is a modified form of a two-step process, with the only difference including a rapid blood clearance reagent delivered intermediately, after the administration of the main targeting moiety (antibody–avidin conjugate). In a three-step pretargeting method, mice were subjected to a tail vein injection with 100 μg of an avidin linked antibody conjugate, followed by an excess of 1 mg–2 mg of galactosylated albumin–biotin delivered 48 h later through intraperitoneal (i.p) injection. Finally, 50 μg of Tc-99m-biotin solution with an activity of 5mCi was delivered intravenously (i.v) after 1 day. However, in a direct single-step targeting group, an antibody was delivered directly in conjugation with the radionuclide Tc-99m as a single step via i.v. the route, 24 h after the initiation of the experiment. Systematic imaging for mice of each group at 4, 24, and 48 h was carried out by the Siemens Orbitor ZLC-7500 SPECT Gamma Camera. After imaging the mice was sacrificed, their organs were isolated and weight and radioactive counts in different organs were determined through the Auto-Gamma Counter. Finally, the percentage of injected dose delivered per g of tissue (percentage injected dose per gram [%ID/g]) and tumor/nontumor ratio were calculated.


  Results Top


Analysis of results obtained from in vivo biodistribution studies of the radiolabeled product in tumor-bearing mice

The Tc-99m-labeled biotin conjugate studies were evaluated for 48 h. Besides tumor, a substantial amount of injected radioactivity was observed in organs such as the liver, spleen, kidneys, and lungs indicative of reticuloendothelial uptake. However, this has been reduced substantially for indirect multistep approaches as compared to a direct single-step targeting approach where a separate blood clearing agent was delivered as an intermediate step. The biodistribution of the %ID/g in different organs is reported in [Table 2]. It has been observed that for a direct single-step targeting approach, a high concentration of the injected dose was reported in the blood pool even up to 48 h. The clearance of radiolabeled conjugate from the blood was observed slow, and therefore, the tumor/nontumor ratio was not highly obtained, as desired. The percentage tumor uptake (%ID/g) was reported as 0.49% and 0.89%, respectively, at 4 and 24 h after injection in a direct labeled approach, whereas the tumor uptake (%ID/g) in a two-step labeling approach was substantially increased and reported as 1.21% and 1.89% at 4 and 24 h, respectively. Finally, in a three-step pretargeting approach, the tumor uptake action was observed significantly higher than in the previous two approaches and was observed at 1.60%, 4 h after injection. Better tumor visibility and high tumor/nontumor ratio were reported even at 24 and 48 h, and this was due to a substantial reduction in the blood background activity due to the presence of galactosylated albumin–biotin, delivered separately as a blood cleaning agent intermediately. However, high radioactivity in the organs such as the liver, spleen, kidney, and lungs as a nonspecific uptake was still reported and was an important area of concern for us to resolve [Table 3].
Table 2: Biodistribution of the radiolabeled product in different organs of tumor-bearing nude mice (percentage injected dose per gram, mean±standard deviation; n=3)

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Table 3: Tumor/nontumor ratio for various organs at different time intervals using different approaches (mean±SD; n=3)

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Reduction in the reticuloendothelial system uptake

It is evident from the experimental data in [Table 3] that a considerable fraction of the injected radiolabeled dose was delivered to the nonspecific, nontumor organs such as the liver, kidney, and spleen, i.e., reticuloendothelial system (RES) uptake. To reduce the RES uptake, we explore the use of selective blocking agents and tested them in our subsequent experimental trials.[38] These blocking agents were administered in a concentration of 1 mg/ml (dissolved in phosphate-buffered saline, pH = 7.4, through tail vein injection in the experimental animal at least 4 h before the actual delivery of the radiolabeled product, for both single-step direct and multistep indirect targeting modes. From the experimental results of the study, it has been confirmed that among all the possible blocking agents evaluated, prior administration of unlabeled nonspecific gamma globulin was reported to be most effective in reducing the RES localization of the injected dose [Table 4].
Table 4: Mean percentage reduction in reticuloendothelial system uptake with different blocking agents injected 4-24 h prior to the actual radiolabeled product (avidinylated antibody-conjugated biotinylated technetium) (n=3 mice in each group)

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Statistical analyses

All the experimental tests were performed in triplicate and the data were expressed as mean of ± standard deviation.


  Discussion Top


The use of radiolabeled antibody conjugates specific for tumor-associated antigens was evaluated both for imaging and therapy of malignant tumors. Biodistribution studies relating to the deposition of injected dose in different organs were carried out in tumor-bearing nude mice both through direct single-step and indirect multistep pretargeting labeling approaches [Figure 2]. Two radiolabeling protocols for labeling Tc-99m with a nonspecific antibody Bharglob were tested and evaluated both for direct and indirect pretargeting strategies. The direct targeting of the radiolabeled bioconjugate reports a higher concentration of the radioactive dose in the blood and other nontarget organs, due to the longer retention time of the radiolabeled antibody in the body and also due to the lack of a rapid blood clearing agent. A two-step indirect pretargeting delivery mode, when tested, showed a significant enhancement in the tumor uptake, with a considerable amount of radioactive dose also deposited to the liver, spleen, kidney, lungs, etc., indicative of nonspecific RES uptake. This can be understandable because of the time gap between the pretargeted antibody and the radiolabeled biotin, which allows sufficient time for the complete accumulation of radiolabeled antibody conjugate both to the tumor and to nontumor sites. Similarly, in a three-step pretargeting approach when evaluated, high radioactive uptake in the tumor was observed immediately after 4 h of the injection, with a better tumor/nontumor ratio even up to 24 h. Low blood background activity was observed which can be assumed due to an excess amount of galactosylated albumin–biotin delivered intermediately. A considerable amount of radioactive uptake in the liver, spleen, kidney, etc., was also reported as a cause of concern. To reduce this undesirable RES uptake, separate experiments were designed and the results obtained showed that the prior administration of unlabeled nonspecific gamma globulin, reported as an effective blocking agent, reduced the nonspecific uptake and enhanced the high tumor versus non tumor ratio.
Figure 2: Three-step pretargeting scheme: Streptavidin-conjugated antibodies injected intravenously in the tumor (1st-step)*; injection of galactosylated albumin biotin after 2–4 days (2nd-step)*; followed by administration of radiolabeled biotin 48 h later (3rd-Step)

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  Conclusions Top


The experimental data obtained from the research study point out some interesting and challenging facts. The study was conducted successfully assessing the amount and selective deliverance of injected dose to the tumor versus nontumor organs through two different targeting modes, for attaining high tumor kill enhancement. The same approach can be implemented to other radionuclides of interest such as rhenium-186/188, lutetium-177, and gold-199, which on account of having their unique properties can ideally be suited both for scintigraphy and therapy purposes.[39],[40],[41]

Limitations of the study

Despite periodic analogies between different radioactive metals, the difference in their redox potential and carrier ion concentration makes this targeting approach complex and demands a much critical control and evaluation of labeling parameters such as ligand concentration, the concentration of reducing agent used, and reaction time. Similarly, the biodistribution studies relating to the accumulation of radioactive dose in the nontarget tissues were observed to be more sensitive to radionuclides other than technetium. Harsh labeling conditions, in that case, will often relate to reduced immunoreactivity or in vivo degradation of the radiolabeled complex and this can have a fair chance for nontumor accumulation of the radioactive dose (RES uptake).[42],[43] Thus, the present study demonstrates the successful targeting efficacy of the radiolabeled bioconjugate for technetium Tc-99m, through a multistep pretargeting approach, and the same can be applied to other radionuclides also, but the stability of the radiolabeled product delivered needs more critical evaluation. If successful, this can be a role model for the deliverance of other radionuclides, effective for cancer therapy and other treatment-related purposes.[44],[45],[46]

Acknowledgments

We thank Prof. D.K. Hazra (Retd. Eminent Scientist) for technical advice and also Mr. Saurya Bansal for designing and framing of original figures.

Ethical policy and institutional review board statement

The related study was carried out at GLA University, Mathura, India, in accordance with the principles and guidelines outlined in the guide for the care and use of laboratory animals, approved under the institutional ethical committee of GLA University, Mathura, India, under CPCSEA (1260/PO/ERC/S/09/CPCSEA/IAEC/2018/).

Reporting guidelines

The manuscript adheres to the STROBE reporting guidelines (for observational studies) only.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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