Local and systemic biodistribution of a small molecule radiopharmaceutical probe after transcatheter embolization and intra-arterial delivery in a porcine orthotopic renal tumor model

Local and systemic biodistribution of a small molecule radiopharmaceutical probe after transcatheter embolization and intra-arterial delivery in a porcine orthotopic renal tumor model | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Local and systemic biodistribution of a small molecule radiopharmaceutical probe after transcatheter embolization and intra-arterial delivery in a porcine orthotopic renal tumor model Samuel L. Rice, Fernando Gómez Muñoz, Jamaal L. Benjamin, Mhd Wisam Alnablsi, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3918869/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Small molecule biomacromolecules target tumor specific antigens. They are employed as theranostic agents for imaging and treatment. Intravenous small molecule radioligands exhibit rapid tumor uptake and excretion. However, systemically administration for peptide receptor radionuclide therapy brachytherapy lacks the therapeutic index to completely treat solid tumors beyond palliation. We study intra-arterial delivery with tumor embolization of a small molecule as a means to deliver local intertumoral brachytherapy for curative internal ablation. Results ¹⁸F-Fluorodeoxyglucose (FDG) was used as a surrogate for a small molecule theranostic agent in a porcine renal tumor model, this tumor model is not known to specifically express human tumor antigens, but the model demonstrates similar vascularity. Angiography and micron particle embolization of the tumor arterioles was performed in a renal tumor model. Significantly more, 2x to 4x more tumor uptake, for study intra-arterial. administration compared to i.v (%ID/g = 44.41 ± 2.48 vs 23.19 ± 4.65 p= 0.0342* at 1 min and 40.8 ± 2.43 vs 10.94 ± 0.42 p=0.018* 10 min). At later time points, up to 120 mins after injection, washout of the tracer from the tumor was observed, but percent injected dose per gram remained elevated, with 3x higher concentration of FDG with intra-arterial administration compared to intravenous, but the difference was not statistically significant. Trend towards diminished systemic percent injected dose per gram measured in the blood, liver, kidney, spleen, muscle, and urine for study intra-arterial compared to intravenous administration. Conclusion Combining intra-arterial administration of a small molecule radioprobe surrogate with embolization of the tumor's arterioles extending the time for interaction of the drug within the tumor by diminishing flow out of the tumor via the efferent capillaries significantly increases the first pass uptake of the SM drug within a tumor and decreased the radiation to normal non-tumor tissues when compared to intravenous injection of the same drug. The minimally invasive drug delivery allows tumor specific theranostic treatment of renal tumors with a brachytherapy absorbed dose of radiation that is potentially curative. Figures Figure 1 Figure 2 Figure 3 Introduction Until only recently, we have possessed a narrow understanding of cancer and thus could only implement systemic medicines that indiscriminately targeted cells undergoing threshold growth. A priority in oncology has always been to tailor specific drugs to different tumor types with the goal of a “magic bullet” which targets only cancer cells. As our knowledge and understanding of the variations in the molecular and genetic changes displayed within individual tumor populations has grown, the field of oncology has begun to apply the use of a personalized medicine approach, exploiting custom-made drug therapies based on precise variations expressed by tumor cells. The overall objective of this novel approach to cancer therapy is to render greater safety and more efficient pharmacotherapy ( 1 – 3 ). Renal cell carcinoma (RCC) is an excellent example of this paradigm shift. RCC proved to be resistant to chemotherapy and radiation, with treatment focused on early surgical resection ( 4 , 5 ). Improved understanding of the molecular divers of RCC have resulted in the development and utilization of therapies for RCC that target vascular endothelial growth factor receptor (VEGFR), mammalian target of rapamycin (mTOR), or immune checkpoint inhibitors inducing a tumoricidal immune response, improving the overall survival ( 6 – 8 ). Many of these drugs are small molecule (SM) peptides that are tumor specific and site-directed to target certain cancers. Theranostics have adapted these drugs for functional molecular imaging and to directly treat tumors via Peptide Receptor Radionuclide Therapy (PRRT). These SM drugs typically have suitable biopharmaceutical half-lives which result in rapid accumulation at the tumor and excretion usually via the kidneys. Systemic brachytherapy therapy with PRRT has been successfully used to palliatively treat various tumors with either alpha or beta emitting radionuclides ( 9 – 12 ). However, obtaining a therapeutic index to provide curative radiation doses has not been feasible due to radiation dose limits required to prevent systemic toxicity from circulating non-target radiation. Interventional radiology (IR) provides an opportunity to identify the arterial vascularity that supplies a renal tumor via a transcatheter procedure. This has the potential to locally deliver and concentrate a SM drug directly into a tumors extracellular matrix which can hypothetically improve the first pass uptake. A clinical trial has evaluated i.a. infusion of PRRT for neuroendocrine liver metastasis and found no difference in the tumor-to-non-tumor (T/N) uptake ratio in liver masses directly treated by i.a. infusion and those that were exposed to secondary systemic circulation, thus direct arterial infusion alone appears similar to intravenous (i.v.) injection ( 13 ). We report on the intra-arterial (i.a) infusion of a surrogate of a SM drug (¹⁸F-Fluorodeoxyglucose [FDG]) along with pseudovascular isolation (PVI) of a renal tumor in an oncopig model of a human tumor. We hypothesize PVI with embolization of a tumors arterioles can constrain the efferent blood flow from the capillaries of a tumor into the systemic venous system, prolonging the time a SM drug has to interact with a tumors antigens, improve the diffusion of the SM into the tumor and its extracellular matrix, increase the uptake of drug within the tumor, and thus decreasing the radiation exposure to systemic tissues when compared to i.v. injection. Methods and Materials The Institutional Animal Care and Use Committee (IACUC) approved all research procedures. The animals’ housing facility was accredited by the AAALAC International and was in compliance with the United States Department of Agriculture Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals. Procedures were performed by a board-certified interventional radiologist. Five, nine-week-old Oncopigs (transgenic pigs with Cre-inducible TP53R167H and KRASG12D mutations) with a mean body weight of 20–25 kg were obtained from Sus clinicals Inc (Chicago, IL). The animals were allowed to acclimate to our animal facility for 5 days. Prior to any procedures the animals were fasted for 12 hours. Each pig was sedated with an intramuscular injection of solution containing ketamine hydrochloride, acepromazine, and atropine sulfate. Anesthesia was induced with isoflurane administered via mask. Once the pig was anesthetized, an endotracheal tube was inserted, and anesthesia was maintained with isoflurane, nitrous oxide, and oxygen. Tumor inoculation Using real-time ultrasound (US) guidance, an 18-gauge coaxial core biopsy of the right and left kidneys were obtained (Bard Mission, BD, Franklin Lakes, NJ). The tissue sample was allowed to incubate at room temperature for 20 mins with an adenoviral vector (10 9 pfu Ad5CMVCre, University of Iowa Viral Vector Core) in phosphate-buffered saline that contained 15 mM calcium chloride. Calcium chloride added to adenovirus in phosphate-buffered saline results in co-precipitation of adenovirus and calcium phosphate, which improves viral transduction. The virus carries the Cre recombinase gene and activates TP53R167H and KRASG12D expression. A slurry was fashioned from the 1 ml mixture and Gelatin sponge (Gelfoam, Pfizer) using a 3-way stopcock, and the mixture, containing virus, core biopsy, and gelatin was injected percutaneously back into the upper and lower poles of the kidney, through the coaxial needle which was kept in place after the initial tissue biopsy. Two sites were inoculated in each kidney, upper and lower poles were selected to be as far apart as possible, easy and safe to access, and deep enough to avoid leakage of injected material into the peritoneum. Angiography with pseudovascular isolation Employing real-time US image guidance, a 21-gauge needle was advanced into the femoral artery, using Seldinger technique this was exchanged for a 5 French (Fr) vascular sheath. Selective angiograms of the left and right renal artery were performed, using a 5 Fr glide cobra catheter and a coaxially inserted 2.4 Fr Prograt (Terumo Medical, Somerset NJ) microcatheter selected segmental artery images were obtained. 40 µm calibrated Embozene particles (Varian Medical Systems, Palto Alto, CA) were mixed with Omnipaque™ (iohexol) (GE, Healthcare, Chicago, Il). The embolic mixture was injected slowly and intermittently under fluoroscopic monitoring, the injection was continued until near complete filling of the capillary bed was achieved. Small Molecule Theronostics Surrogate Radiotracer Infusion Control animals underwent i.v. administering of the SM radiotracer suspended in 2 mL of normal saline (n = 2). After embolization, experimental animals (n = 3) received i.a. infusion, the radiotracer was mixed with 2 mL Omnipaque contrast and slowly injected through the microcatheter into the renal artery supplying the renal tumor under real-time fluoroscopic guidance to ensure continued forward flow into the tumor without non-target reflux. Each injection occurred intermittently for 60 seconds. Approximately 266 Mbq (7.2 mCi) of ¹⁸F-Fluorodeoxyglucose (FDG) was given to each animal. Ex vivo Biodistribution Before infusion of the radiotracer, real-time US was used to place an 18-gauge coaxial needle into the renal tumor; additional needles were placed with image guidance into the normal contralateral kidney, liver, spleen, and muscle tissue in the right thigh. A 5 Fr Yueh needle was inserted with image guidance into the bladder and urine was aspirated from the bladder until it was empty. After infusion of the radiotracer, coaxial biopsy tissue samples were taken at various time points: 1, 5, 15, 30, 60, 90, and 120 mins for blood; 5, 15, 30, 60, and 120 mins for urine; and 1, 10, 30, 60, and 120 mins for tissue biopsies. The tissues were subsequently rinsed in normal saline and placed into a weighed gamma counter tube. The tissue was weighed and counted in a gamma-counter for activity using a calibrated Perkin Elmer (Waltham, MA) Automatic Wizard2 Gamma Counter by using an energy window of 300–700 keV for 18 F. The mass of radiotracer injected into each animal was measured and used to determine the total number of counts (counts per minute, [c.p.m.]) by comparison to a standard syringe containing and independently measured activity and mass. Count data were background and decay-corrected to the time of injection and the percent injected dose per gram (%ID/g) for each tissue sample calculated by normalization to the total activity injected. Statistical Analysis Data were analyzed by the unpaired, two-tailed Student’s t-test. Differences at the 95% confidence level (p = 0.05) were considered to be statistically significant. Results Tumor growth Tumor inoculation within the kidney of the oncopig was successful in all animals. After 20 days tumors were measured with ultrasound, the tumor mass used in this experiment varied in size from 2.2 to 2.8 cm in the longest axis. Angiography and Pseudovascular isolation Angiography and embolization were successful in 100% of the experimental animals. Distal embolization of the tumors arterial vasculature with 40 µm calibrated particles was performed with the goal of arteriole embolization with sluggish continued forward flow of blood into the tumor with 3 beat stasis within the vasculature supplying the tumor. This was verified with real time digital subtraction angiography. The volume of particles needed to achieve this degree of embolization was variable for each tumor and depended on the size of the vascular bed. Once embolization was accomplished, i.a. infusion into the tumor vessels was performed under real-time angiographic guidance (Fig. 1 ). For control animals, the radiotracer was infused through an auricular vein and flushed with normal saline. In vivo Biodistribution of large molecule surrogate radiotracer The ability of i.a. administration of a surrogate SM radiotracer probe to be concentrated in a tumor with the assistance of vascular embolization was assessed by conducting acute biodistribution studies in a large animal orthotopic renal tumor model and later compared to the uptake after systemic i.v. injection of the same probe in our control pigs (Fig. 1 ). At the earliest time point, 1 minute after injection, i.a. injection with SM is almost two times greater in the tumor than with i.v. infusion, this is significantly significant (SS), (%ID/g = 44.41 ± 2.48 vs 23.19 ± 4.65 p = 0.0342). At 10 mins the difference in the amount of SM drug within the renal tumor after i.a. or i.v. infusion increases to four times which is also significant, 40.8 ± 2.43 vs 10.94 ± 0.42 p = 0.018 respectively. We identify washout of the tracer at later time points, but the trend towards increased uptake of the SM drug is at least three times as great for i.a., this continues but is not significant, up to 120 mins 31.06 ± 1.68 (i.a.) vs 9.49 ± 0.44 (i.v.), p = 0.0874 (Fig. 1 , Table 1 ). The difference within other normal tissues between i.a. and i.v. infusion trends towards decreased uptake for the experimental group compared to the control but is nonsignificant (Fig. 2 , Table 1 ). Differences in the amount of radiotracer in the blood pool are significantly less with i.a. at one minute, 12.11 ± 0.76 vs 24.86 ± 2.16 p = 0.0181*. Over the next 120 minutes again we see a trend towards less uptake with i.a. compared to i.v. which is not SS (Table 2 , Fig. 2 ). Discussion In our experiment we evaluated a novel transcatheter technique called PVI. Our goal was to block the efferent vascular flow from a tumor by embolizing the arterioles with micron sized particles to improve local drug delivery within the tumor of a SM radiotracer (Fig. 3 ). We used a transgenic orthotopic renal tumor model for RCC in a porcine oncopig, and compared the biodistribution of a SM theranostic radiotracer surrogate, FDG, after two distinctive delivery approaches 1) control group with i.v. administration and 2) experimental group with local i.a. administration after PVI. We observed a SS increase in the tumor uptake with i.a. compared to i.v. infusions. The oncopig is a novel transgenic large animal orthotopic tumor model. This model has been previously used to study tumors in the liver, pancreas, and lungs ( 14 – 16 ). In the evaluation of the liver tumors in this model, an assessment of the tumors vascularity, tumor perfusion, and embolization was performed, the model exhibited similarities to human hepatocellular carcinoma (HCC) and colorectal cancer metastasis to the liver ( 14 ). We thus felt confident this model would also accurately simulate the structure and vascularity of a human renal tumor. Additionally, given the similarities in the size and physiology between humans and pigs, the oncopig is an ideal model to appraise the usefulness of novel procedures in interventional radiology (IR) and the results can be naturally translation into humans because the pig permitted the use of clinical techniques and equipment. Catheter-based therapies in IR are in current clinical use to treat hepatic tumors, these treatments have been extended to other organs such as the lungs and kidney in a limited number of patients ( 17 , 18 ). Three main categories of i.a. therapies exist: 1) “bland” transarterial embolization with embolic particles to completely restrict blood flow to tumor cells, 2) transarterial chemoembolization (TACE) where chemotherapy is either loaded onto beads or combined with a liquid embolic agent (ethiodized oil) to form an emulsion, concentrating the chemotherapeutic drug in the tumor and slowly releasing the drug locally into the mass, 3) transarterial radioembolization (TARE) when microspheres impregnated with 90 Y beta radiation are lodged into the vasculature after i.a. administration resulting in local brachytherapy via crosstalk radiation. The local i.a. administration of a SM for PRRT has the potential to broaden our ability to treat tumors beyond the liver, providing local infusion of a high dose of radiation via a tumor specific drug with the goal of local cure. Within the field of radiology and nuclear medicine, the use of an innovative theranostic approach to patient care has gained immense interest. Theranostics utilizes radiochemistry to produce functional probes for diagnosis and treatment. When an imaging radionuclide is conjugated, these tumor specific biomolecules are typically introduced systemically, permitting the drug to find and interact with its target for either Single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Subsequently, theranostics envisages the application of additional local brachytherapy by substituting a high energy radio-particulate emitting therapeutic radionuclide to the same molecule (Fig. 3 ). Theranostics, being a tumor specific non-invasive treatment for tumors can be a cost-effective treatment with results similar to surgical resection but provided on an outpatient basis. The biopharmaceutical circulating half-life is essential in calculating the potential therapeutic index of this drug. SM drugs have rapid accumulation at their target and excretion from the body and are thus attractive for clinical theranostics ( 19 , 20 ). Treating solid tumors presents barriers that must be overcome. These include tumor tissue heterogeneity, with many tumors being highly fibrotic, abnormal structures of the tumor vessels, absence of functional lymphatics, and high interstitial fluid pressure ( 21 ). Thus, systemic PRRT with SM have not been able to overcome these barriers and have only provided palliative results after i.v. injection, leading at best to only stable disease or changes in biomarkers ( 22 – 25 ). Achieving doses for a curative intent in a single local solid tumor has thus far largely been unsuccessful ( 26 ). For example, the measured radiation absorbed dose at the tumor after 177 Lu-PSMA-617 radioligand therapy in HCC, was reported to be at least 10-fold lower than that typically achieved by 1 cycle of external-beam radiation therapy ( 27 ). Ebbers et al. has recently published clinical trial results evaluting i.a. infusion of 177 Lu-DOTATATE into the hepatic artery for the treatment of patients with bilobed liver metastasis from neuroendocrine tumor, the procedure was safe but no significant change in the tumor-to-non-tumor (T/N) uptake ratio was identified with i.a compared to systemic infusion seen after the first pass ( 13 ). This stresses the need for additional embolization of the tumors feeding arteries, arterioles, and capillaries prior to the administration of the drug. We show that with PVI the slow flow within the tumor after embolization diminished the efferent return to the systemic venous vasculature via the capillaries and results in a significant increase in a SM drug within the tumor. A change in the treatment algorithm for PRRT must be considered, shifting from palliative systemic therapy to local delivery into induvial tumors for cure. Alternative methods must be established to successfully treat solid tumors and achieve a radiation dose that can be curative in solid tumors. Transcatheter procedures performed by IR are an appealing option to combine with SM PRRT. PVI functions to prevent the SM from entering the systemic system by diminishing flow through the tumor arteries via embolization with micron-sized articles. PVI was shown increase first pass uptake. We hypothesize the slow flow combined with an increase in the osmotic pressure within the tumors' already irregular and leaky neovascularity prolongs the interaction between the drug and the tumor antigens in the extracellular matrix of the tumor, facilitating greater interaction between the SM and its tumor specific antigen. We also revealed PVI with i.a. infusion diminished the radiation exposure of normal tissues from a circulating radioprobe, thus enabling the infusion of higher radiation doses at the tumor, potentially above the therapeutic index needed for complete necrosis of the tumor mass. We also believe local infusion will authorize the use of radionuclides that release Alpha-particles whose higher linear energy transfer when compared to Beta-emitting radioisotopes and overcome any treatment resistance ( 28 , 29 ). Our study has some limitations, firstly we use a large animal model of a renal tumor, this model has previously been employed to evaluate IR procedures in the liver, where the tumors vascularity was found to be similar to human liver tumors, The tumor vascularity has never been categorically characterized for renal tumors in this model, thus we cannot definitely state the similarity to a human RCC tumor vascularity. Using a tumor specific SM would have been ideal, however, this is a novel porcine model of a human RCC tumor, the presence of human tumor antigens that exactly mimic human RCC such as PSMA has not been identified in this tumor model, additionally the SM drug may nor interact with the porcine version of the antigen as it does in humans. Thus, a specific clinical SM tracer that has known uptake in human tumors was not utilized. Given the ubiquitous utilization of FDG in clinical practice we determined its use would be beneficial to study the proof of concept for PVI and more select and specific SM drugs can be used in the future in clinical studies. FDG is on the order of 10x smaller than clinical SM drugs used in humans and has no interaction with a specific tumor antigen, FDG is only a marker for metabolism and inflammation, it is not tumor specific like a SM probe, we do expect greater first pass uptake and retention when applying an appropriate tumor specific SM during future studies. FDG is also trapped in the cell, unlike a SM probe but we still see a significant increase in the amount of FDG found in the tumor at the early time points which is higher than i.v. infusion which suggests a greater amount of the tracer is present within the tumor and its matrix with PVI followed by i.a. administration. Time points only up to 120 minutes were obtained, longer time points up to 24 or 48 hours would have been ideal for assessing SM probe biodistribution, but we were limited by the short half-life of 18 F. Conclusion A great interest exists to develop and utilize SM drugs for theranostics in various tumor types. SM drugs generally exhibit a favorable biopharmaceutical half-life which has allowed their use for PRRT with the substitution of predominantly β-emitting radionuclides. Thus far these treatments have only delivered palliative doses to solid tumors due to the exposure of normal tissues to radiation when given systemically. IR offers an alternative method to deliver and concentrate a SM drug into a tumor. We have studied this potential in a large animal oncopig and shown that the first pass uptake of the drug is significantly greater at the tumor when it is infused directly into the tumor's vascularity when compared to i.v. injection. We believe this method can be translated into humans to provide curative doses of radiation to solid tumors in various organs such as the kidney, prostate, lung, and pancreas. List Of Abbreviations Small Molecule (SM) Intravenous (i.v.) Intra-arterial (i.a.) Renal cell carcinoma (RCC) Vascular endothelial growth factor receptor (VEGFR) Mammalian target of rapamycin (mTOR) Peptide Receptor Radionuclide Therapy (PRRT) Pseudovascular isolation (PVI) Significantly significant (SS) Transarterial chemoembolization (TACE) Transarterial radioembolization (TARE) Single-photon emission computed tomography (SPECT) Positron emission tomography (PET) Interventional Radiology (IR) ¹⁸F-Fluorodeoxyglucose (FDG) French (Fr) Declarations Ethics approval and consent to participate This study was performed after approval by our Institutional Animal Care and Use Committee (IACUC) with ethical approval. Owners permission was received This original research has no overlap with other materials already published. Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests Funding Funding for this research was provided by internal funds from the Interventional Radiology section of UT Southwestern Authors' contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Samuel L Rice (SLR), Mhd Wisam Alnablsi (MWA), and Jamaal Benjamin (JLB). The first draft of the manuscript was written by SLR with input from all authors including Fernando Gómez Muñoz, (FGM), Rehan Quadri (RQ). All authors commented on previous versions of the manuscript, including Joseph R. Osborne (JRO), Regina Beets-Tan (RBT). All authors read and approved the final manuscript SLR, MWA, JLB, FGM, RQ, JRO, RBT. Acknowledgements Not applicable The authors of this manuscript have no disclosures of any conflict of interest—financial or otherwise—that may directly or indirectly influence the content of the manuscript submitted. References Mitri Z, Esmerian MO, Simaan JA, Sabra R, Zgheib NK. Pharmacogenetics and personalized medicine: the future for drug prescribing. Le J Med libanais Leban Med J. 2010;58(2):101–4. Landais P, Méresse V, Ghislain J-C, Arnaud O, Bibeau F, Cellier D, et al. Evaluation and validation of diagnostic tests for guiding therapeutic decisions. Therapies. 2009;64(3):195–201. Lin W. Molecular diagnostic renovates drug development: overcoming challenges of co-development of theranostics. Trends Bio/Pharm Ind. 2007;4:26–8. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. 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Poty S, Francesconi LC, McDevitt MR, Morris MJ, Lewis JS. α-Emitters for radiotherapy: from basic radiochemistry to clinical studies—part 1. J Nucl Med. 2018;59(6):878–84. Tables Tables 1 and 2 are available in the Supplementary Files section. Supplementary Files Tables.docx SLReditorreply.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 03 Jul, 2024 Editor invited by journal 23 Feb, 2024 Editor assigned by journal 23 Feb, 2024 First submitted to journal 21 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3918869","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":322084052,"identity":"7e1b4a8f-a9c7-4e76-b9a1-4e1f3763f5b6","order_by":0,"name":"Samuel L. Rice","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0009-2069-5640","institution":"UT Southwestern: The University of Texas Southwestern Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Samuel","middleName":"L.","lastName":"Rice","suffix":""},{"id":322084053,"identity":"5485cc85-505f-4701-b10b-ed3626fdff1a","order_by":1,"name":"Fernando Gómez Muñoz","email":"","orcid":"","institution":"Netherlands Cancer Institute: Antoni van Leeuwenhoek","correspondingAuthor":false,"prefix":"","firstName":"Fernando","middleName":"Gómez","lastName":"Muñoz","suffix":""},{"id":322084054,"identity":"3a934418-7278-4b8d-a5df-4c3156231ef5","order_by":2,"name":"Jamaal L. Benjamin","email":"","orcid":"","institution":"UT Southwestern: The University of Texas Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jamaal","middleName":"L.","lastName":"Benjamin","suffix":""},{"id":322084055,"identity":"a75452c0-303d-48e6-802e-7a389e2472a9","order_by":3,"name":"Mhd Wisam Alnablsi","email":"","orcid":"","institution":"UT Southwestern: The University of Texas Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Mhd","middleName":"Wisam","lastName":"Alnablsi","suffix":""},{"id":322084056,"identity":"1ae7bc8f-6aee-4e17-b847-f6dff642b17f","order_by":4,"name":"Rehan Quadri","email":"","orcid":"","institution":"UT Southwestern: The University of Texas Southwestern Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Rehan","middleName":"","lastName":"Quadri","suffix":""},{"id":322084057,"identity":"d13b0f91-c530-426e-857b-435c24374325","order_by":5,"name":"Joseph R. Osborne","email":"","orcid":"","institution":"Weill Cornell Physicians","correspondingAuthor":false,"prefix":"","firstName":"Joseph","middleName":"R.","lastName":"Osborne","suffix":""},{"id":322084058,"identity":"3dc7667a-120e-4563-aafa-f2796dcea42f","order_by":6,"name":"Regina Beets-Tan","email":"","orcid":"","institution":"Netherlands Cancer Institute: Antoni van Leeuwenhoek","correspondingAuthor":false,"prefix":"","firstName":"Regina","middleName":"","lastName":"Beets-Tan","suffix":""}],"badges":[],"createdAt":"2024-02-01 22:06:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3918869/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3918869/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":61193069,"identity":"4bbb5d2b-eb5f-419e-af6d-3d529ef0affb","added_by":"auto","created_at":"2024-07-26 20:56:42","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":650082,"visible":true,"origin":"","legend":"\u003cp\u003eIntra-arterial (i.a.) administration with Pseudovascular Isolation (PVI). A) i.a. angiography of the renal tumor (red arrow). B) Post embolization angiography shows pruning of the vasculature with contrast seen only in artery feeding tumor. C) Renal tumor on ultrasound, curved white arrow points to biopsy needle through tumor. \u0026nbsp;D) Post i.a. infusion of the SM radiotracer, thick black arrow shows post infusion tumor blush, thin black arrow shows coaxial needle for obtaining samples for biodistribution. E) Contrast enhanced MRI images of the kidney with red arrowhead identifying the renal tumor, F) PET scan after intravenous infusion of FDG demonstrating intrinsic FDG uptake in the renal tumor.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3918869/v1/312454a34c6234205002f371.jpeg"},{"id":61193070,"identity":"b56e408b-1345-4079-bcb8-981abae15cef","added_by":"auto","created_at":"2024-07-26 20:56:42","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":224519,"visible":true,"origin":"","legend":"\u003cp\u003eGraph of acute biodistribution. A) Uptake within the tumor after intra-arterial (i.a. green,) and intravenous (i.v., red) infusion of the small molecule (SM) radiotracer in %ID/g. B) %ID/g for uptake in various organs i.a. versus i.v. administration. C) Blood and urine %ID/g of SM radiotracer after i.a. and i.v. infusion.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3918869/v1/a748ba50a91db3dd16ff26fa.jpeg"},{"id":61193071,"identity":"40352e24-5350-4cdd-a363-18108ef1619e","added_by":"auto","created_at":"2024-07-26 20:56:42","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":564444,"visible":true,"origin":"","legend":"\u003cp\u003eIllustration demonstrating the principle of Pseudovascular Isolation (PVI): Angiography is performed to localize the tumor and its arterial vascular supply. Microcatheter (Black arrowhead) selectively localizes the vessels supplying the tumor, particles (white spheres) are injected intra-arterially (i.a) into the tumor vessels, these become lodged into the distal arterioles. After embolization with the microspheres, i.a. infusion of the LM theranostic agent is performed through the microcatheter (yellow arrow) with the theranostic agent exiting through the endothelium of the vessels into the extracellular matrix where it interacts with the tumor specific antigen.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3918869/v1/28352bbcaeec873d74025df6.jpeg"},{"id":61193072,"identity":"adf5ff45-7b43-4e79-a0b6-7d76832752d5","added_by":"auto","created_at":"2024-07-26 20:56:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1805754,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3918869/v1/6b61d710-3839-4968-9f69-c44b2fa6c878.pdf"},{"id":61193068,"identity":"eaefb39d-206c-4a99-a343-02c9a7dad324","added_by":"auto","created_at":"2024-07-26 20:56:42","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":362205,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-3918869/v1/a5314db886408b299114b416.docx"},{"id":61193067,"identity":"aebf0870-e159-4b74-8824-e00fa35e7efc","added_by":"auto","created_at":"2024-07-26 20:56:42","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":14214,"visible":true,"origin":"","legend":"","description":"","filename":"SLReditorreply.docx","url":"https://assets-eu.researchsquare.com/files/rs-3918869/v1/a8c3a4af4fbefe0b005e6e5a.docx"}],"financialInterests":"","formattedTitle":"Local and systemic biodistribution of a small molecule radiopharmaceutical probe after transcatheter embolization and intra-arterial delivery in a porcine orthotopic renal tumor model","fulltext":[{"header":"Introduction","content":"\u003cp\u003eUntil only recently, we have possessed a narrow understanding of cancer and thus could only implement systemic medicines that indiscriminately targeted cells undergoing threshold growth. A priority in oncology has always been to tailor specific drugs to different tumor types with the goal of a \u0026ldquo;magic bullet\u0026rdquo; which targets only cancer cells. As our knowledge and understanding of the variations in the molecular and genetic changes displayed within individual tumor populations has grown, the field of oncology has begun to apply the use of a personalized medicine approach, exploiting custom-made drug therapies based on precise variations expressed by tumor cells. The overall objective of this novel approach to cancer therapy is to render greater safety and more efficient pharmacotherapy (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRenal cell carcinoma (RCC) is an excellent example of this paradigm shift. RCC proved to be resistant to chemotherapy and radiation, with treatment focused on early surgical resection (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Improved understanding of the molecular divers of RCC have resulted in the development and utilization of therapies for RCC that target vascular endothelial growth factor receptor (VEGFR), mammalian target of rapamycin (mTOR), or immune checkpoint inhibitors inducing a tumoricidal immune response, improving the overall survival (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMany of these drugs are small molecule (SM) peptides that are tumor specific and site-directed to target certain cancers. Theranostics have adapted these drugs for functional molecular imaging and to directly treat tumors via Peptide Receptor Radionuclide Therapy (PRRT). These SM drugs typically have suitable biopharmaceutical half-lives which result in rapid accumulation at the tumor and excretion usually via the kidneys. Systemic brachytherapy therapy with PRRT has been successfully used to palliatively treat various tumors with either alpha or beta emitting radionuclides (\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). However, obtaining a therapeutic index to provide curative radiation doses has not been feasible due to radiation dose limits required to prevent systemic toxicity from circulating non-target radiation.\u003c/p\u003e \u003cp\u003eInterventional radiology (IR) provides an opportunity to identify the arterial vascularity that supplies a renal tumor via a transcatheter procedure. This has the potential to locally deliver and concentrate a SM drug directly into a tumors extracellular matrix which can hypothetically improve the first pass uptake. A clinical trial has evaluated i.a. infusion of PRRT for neuroendocrine liver metastasis and found no difference in the tumor-to-non-tumor (T/N) uptake ratio in liver masses directly treated by i.a. infusion and those that were exposed to secondary systemic circulation, thus direct arterial infusion alone appears similar to intravenous (i.v.) injection (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe report on the intra-arterial (i.a) infusion of a surrogate of a SM drug (\u0026sup1;⁸F-Fluorodeoxyglucose [FDG]) along with pseudovascular isolation (PVI) of a renal tumor in an oncopig model of a human tumor. We hypothesize PVI with embolization of a tumors arterioles can constrain the efferent blood flow from the capillaries of a tumor into the systemic venous system, prolonging the time a SM drug has to interact with a tumors antigens, improve the diffusion of the SM into the tumor and its extracellular matrix, increase the uptake of drug within the tumor, and thus decreasing the radiation exposure to systemic tissues when compared to i.v. injection.\u003c/p\u003e"},{"header":"Methods and Materials","content":"\u003cp\u003e The Institutional Animal Care and Use Committee (IACUC) approved all research procedures. The animals\u0026rsquo; housing facility was accredited by the AAALAC International and was in compliance with the United States Department of Agriculture Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals. Procedures were performed by a board-certified interventional radiologist.\u003c/p\u003e \u003cp\u003eFive, nine-week-old Oncopigs (transgenic pigs with Cre-inducible TP53R167H and KRASG12D mutations) with a mean body weight of 20\u0026ndash;25 kg were obtained from Sus clinicals Inc (Chicago, IL). The animals were allowed to acclimate to our animal facility for 5 days. Prior to any procedures the animals were fasted for 12 hours. Each pig was sedated with an intramuscular injection of solution containing ketamine hydrochloride, acepromazine, and atropine sulfate. Anesthesia was induced with isoflurane administered via mask. Once the pig was anesthetized, an endotracheal tube was inserted, and anesthesia was maintained with isoflurane, nitrous oxide, and oxygen.\u003c/p\u003e \u003cp\u003eTumor inoculation\u003c/p\u003e \u003cp\u003eUsing real-time ultrasound (US) guidance, an 18-gauge coaxial core biopsy of the right and left kidneys were obtained (Bard Mission, BD, Franklin Lakes, NJ). The tissue sample was allowed to incubate at room temperature for 20 mins with an adenoviral vector (10\u003csup\u003e9\u003c/sup\u003e pfu Ad5CMVCre, University of Iowa Viral Vector Core) in phosphate-buffered saline that contained 15 mM calcium chloride. Calcium chloride added to adenovirus in phosphate-buffered saline results in co-precipitation of adenovirus and calcium phosphate, which improves viral transduction. The virus carries the Cre recombinase gene and activates TP53R167H and KRASG12D expression. A slurry was fashioned from the 1 ml mixture and Gelatin sponge (Gelfoam, Pfizer) using a 3-way stopcock, and the mixture, containing virus, core biopsy, and gelatin was injected percutaneously back into the upper and lower poles of the kidney, through the coaxial needle which was kept in place after the initial tissue biopsy. Two sites were inoculated in each kidney, upper and lower poles were selected to be as far apart as possible, easy and safe to access, and deep enough to avoid leakage of injected material into the peritoneum.\u003c/p\u003e \u003cp\u003eAngiography with pseudovascular isolation\u003c/p\u003e \u003cp\u003eEmploying real-time US image guidance, a 21-gauge needle was advanced into the femoral artery, using Seldinger technique this was exchanged for a 5 French (Fr) vascular sheath. Selective angiograms of the left and right renal artery were performed, using a 5 Fr glide cobra catheter and a coaxially inserted 2.4 Fr Prograt (Terumo Medical, Somerset NJ) microcatheter selected segmental artery images were obtained. 40 \u0026micro;m calibrated Embozene particles (Varian Medical Systems, Palto Alto, CA) were mixed with Omnipaque\u0026trade; (iohexol) (GE, Healthcare, Chicago, Il). The embolic mixture was injected slowly and intermittently under fluoroscopic monitoring, the injection was continued until near complete filling of the capillary bed was achieved.\u003c/p\u003e \u003cp\u003eSmall Molecule Theronostics Surrogate Radiotracer Infusion\u003c/p\u003e \u003cp\u003eControl animals underwent i.v. administering of the SM radiotracer suspended in 2 mL of normal saline (n\u0026thinsp;=\u0026thinsp;2). After embolization, experimental animals (n\u0026thinsp;=\u0026thinsp;3) received i.a. infusion, the radiotracer was mixed with 2 mL Omnipaque contrast and slowly injected through the microcatheter into the renal artery supplying the renal tumor under real-time fluoroscopic guidance to ensure continued forward flow into the tumor without non-target reflux. Each injection occurred intermittently for 60 seconds. Approximately 266 Mbq (7.2 mCi) of \u0026sup1;⁸F-Fluorodeoxyglucose (FDG) was given to each animal.\u003c/p\u003e \u003cp\u003eEx vivo Biodistribution\u003c/p\u003e \u003cp\u003eBefore infusion of the radiotracer, real-time US was used to place an 18-gauge coaxial needle into the renal tumor; additional needles were placed with image guidance into the normal contralateral kidney, liver, spleen, and muscle tissue in the right thigh. A 5 Fr Yueh needle was inserted with image guidance into the bladder and urine was aspirated from the bladder until it was empty. After infusion of the radiotracer, coaxial biopsy tissue samples were taken at various time points: 1, 5, 15, 30, 60, 90, and 120 mins for blood; 5, 15, 30, 60, and 120 mins for urine; and 1, 10, 30, 60, and 120 mins for tissue biopsies. The tissues were subsequently rinsed in normal saline and placed into a weighed gamma counter tube. The tissue was weighed and counted in a gamma-counter for activity using a calibrated Perkin Elmer (Waltham, MA) Automatic Wizard2 Gamma Counter by using an energy window of 300\u0026ndash;700 keV for \u003csup\u003e18\u003c/sup\u003eF. The mass of radiotracer injected into each animal was measured and used to determine the total number of counts (counts per minute, [c.p.m.]) by comparison to a standard syringe containing and independently measured activity and mass. Count data were background and decay-corrected to the time of injection and the percent injected dose per gram (%ID/g) for each tissue sample calculated by normalization to the total activity injected.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData were analyzed by the unpaired, two-tailed Student\u0026rsquo;s t-test. Differences at the 95% confidence level (p\u0026thinsp;=\u0026thinsp;0.05) were considered to be statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTumor growth\u003c/p\u003e\n\u003cp\u003eTumor inoculation within the kidney of the oncopig was successful in all animals. After 20 days tumors were measured with ultrasound, the tumor mass used in this experiment varied in size from 2.2 to 2.8 cm in the longest axis.\u003c/p\u003e\n\u003cp\u003eAngiography and Pseudovascular isolation\u003c/p\u003e\n\u003cp\u003eAngiography and embolization were successful in 100% of the experimental animals. Distal embolization of the tumors arterial vasculature with 40 \u0026micro;m calibrated particles was performed with the goal of arteriole embolization with sluggish continued forward flow of blood into the tumor with 3 beat stasis within the vasculature supplying the tumor. This was verified with real time digital subtraction angiography. The volume of particles needed to achieve this degree of embolization was variable for each tumor and depended on the size of the vascular bed. Once embolization was accomplished, i.a. infusion into the tumor vessels was performed under real-time angiographic guidance (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). For control animals, the radiotracer was infused through an auricular vein and flushed with normal saline.\u003c/p\u003e\n\u003cp\u003eIn vivo Biodistribution of large molecule surrogate radiotracer\u003c/p\u003e\n\u003cp\u003eThe ability of i.a. administration of a surrogate SM radiotracer probe to be concentrated in a tumor with the assistance of vascular embolization was assessed by conducting acute biodistribution studies in a large animal orthotopic renal tumor model and later compared to the uptake after systemic i.v. injection of the same probe in our control pigs (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). At the earliest time point, 1 minute after injection, i.a. injection with SM is almost two times greater in the tumor than with i.v. infusion, this is significantly significant (SS), (%ID/g\u0026thinsp;=\u0026thinsp;44.41\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48 vs 23.19\u0026thinsp;\u0026plusmn;\u0026thinsp;4.65 p\u0026thinsp;=\u0026thinsp;0.0342). At 10 mins the difference in the amount of SM drug within the renal tumor after i.a. or i.v. infusion increases to four times which is also significant, 40.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.43 vs 10.94\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42 p\u0026thinsp;=\u0026thinsp;0.018 respectively. We identify washout of the tracer at later time points, but the trend towards increased uptake of the SM drug is at least three times as great for i.a., this continues but is not significant, up to 120 mins 31.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68 (i.a.) vs 9.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44 (i.v.), p\u0026thinsp;=\u0026thinsp;0.0874 (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe difference within other normal tissues between i.a. and i.v. infusion trends towards decreased uptake for the experimental group compared to the control but is nonsignificant (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eDifferences in the amount of radiotracer in the blood pool are significantly less with i.a. at one minute, 12.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76 vs 24.86\u0026thinsp;\u0026plusmn;\u0026thinsp;2.16 p\u0026thinsp;=\u0026thinsp;0.0181*. Over the next 120 minutes again we see a trend towards less uptake with i.a. compared to i.v. which is not SS (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our experiment we evaluated a novel transcatheter technique called PVI. Our goal was to block the efferent vascular flow from a tumor by embolizing the arterioles with micron sized particles to improve local drug delivery within the tumor of a SM radiotracer (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). We used a transgenic orthotopic renal tumor model for RCC in a porcine oncopig, and compared the biodistribution of a SM theranostic radiotracer surrogate, FDG, after two distinctive delivery approaches 1) control group with i.v. administration and 2) experimental group with local i.a. administration after PVI. We observed a SS increase in the tumor uptake with i.a. compared to i.v. infusions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe oncopig is a novel transgenic large animal orthotopic tumor model. This model has been previously used to study tumors in the liver, pancreas, and lungs (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In the evaluation of the liver tumors in this model, an assessment of the tumors vascularity, tumor perfusion, and embolization was performed, the model exhibited similarities to human hepatocellular carcinoma (HCC) and colorectal cancer metastasis to the liver (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). We thus felt confident this model would also accurately simulate the structure and vascularity of a human renal tumor. Additionally, given the similarities in the size and physiology between humans and pigs, the oncopig is an ideal model to appraise the usefulness of novel procedures in interventional radiology (IR) and the results can be naturally translation into humans because the pig permitted the use of clinical techniques and equipment.\u003c/p\u003e \u003cp\u003eCatheter-based therapies in IR are in current clinical use to treat hepatic tumors, these treatments have been extended to other organs such as the lungs and kidney in a limited number of patients (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Three main categories of i.a. therapies exist: 1) \u0026ldquo;bland\u0026rdquo; transarterial embolization with embolic particles to completely restrict blood flow to tumor cells, 2) transarterial chemoembolization (TACE) where chemotherapy is either loaded onto beads or combined with a liquid embolic agent (ethiodized oil) to form an emulsion, concentrating the chemotherapeutic drug in the tumor and slowly releasing the drug locally into the mass, 3) transarterial radioembolization (TARE) when microspheres impregnated with \u003csup\u003e90\u003c/sup\u003eY beta radiation are lodged into the vasculature after i.a. administration resulting in local brachytherapy via crosstalk radiation. The local i.a. administration of a SM for PRRT has the potential to broaden our ability to treat tumors beyond the liver, providing local infusion of a high dose of radiation via a tumor specific drug with the goal of local cure.\u003c/p\u003e \u003cp\u003eWithin the field of radiology and nuclear medicine, the use of an innovative theranostic approach to patient care has gained immense interest. Theranostics utilizes radiochemistry to produce functional probes for diagnosis and treatment. When an imaging radionuclide is conjugated, these tumor specific biomolecules are typically introduced systemically, permitting the drug to find and interact with its target for either Single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Subsequently, theranostics envisages the application of additional local brachytherapy by substituting a high energy radio-particulate emitting therapeutic radionuclide to the same molecule (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Theranostics, being a tumor specific non-invasive treatment for tumors can be a cost-effective treatment with results similar to surgical resection but provided on an outpatient basis.\u003c/p\u003e \u003cp\u003eThe biopharmaceutical circulating half-life is essential in calculating the potential therapeutic index of this drug. SM drugs have rapid accumulation at their target and excretion from the body and are thus attractive for clinical theranostics (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Treating solid tumors presents barriers that must be overcome. These include tumor tissue heterogeneity, with many tumors being highly fibrotic, abnormal structures of the tumor vessels, absence of functional lymphatics, and high interstitial fluid pressure (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Thus, systemic PRRT with SM have not been able to overcome these barriers and have only provided palliative results after i.v. injection, leading at best to only stable disease or changes in biomarkers (\u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Achieving doses for a curative intent in a single local solid tumor has thus far largely been unsuccessful (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). For example, the measured radiation absorbed dose at the tumor after \u003csup\u003e177\u003c/sup\u003eLu-PSMA-617 radioligand therapy in HCC, was reported to be at least 10-fold lower than that typically achieved by 1 cycle of external-beam radiation therapy (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEbbers et al. has recently published clinical trial results evaluting i.a. infusion of \u003csup\u003e177\u003c/sup\u003eLu-DOTATATE into the hepatic artery for the treatment of patients with bilobed liver metastasis from neuroendocrine tumor, the procedure was safe but no significant change in the tumor-to-non-tumor (T/N) uptake ratio was identified with i.a compared to systemic infusion seen after the first pass (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). This stresses the need for additional embolization of the tumors feeding arteries, arterioles, and capillaries prior to the administration of the drug. We show that with PVI the slow flow within the tumor after embolization diminished the efferent return to the systemic venous vasculature via the capillaries and results in a significant increase in a SM drug within the tumor. A change in the treatment algorithm for PRRT must be considered, shifting from palliative systemic therapy to local delivery into induvial tumors for cure. Alternative methods must be established to successfully treat solid tumors and achieve a radiation dose that can be curative in solid tumors. Transcatheter procedures performed by IR are an appealing option to combine with SM PRRT. PVI functions to prevent the SM from entering the systemic system by diminishing flow through the tumor arteries via embolization with micron-sized articles. PVI was shown increase first pass uptake. We hypothesize the slow flow combined with an increase in the osmotic pressure within the tumors' already irregular and leaky neovascularity prolongs the interaction between the drug and the tumor antigens in the extracellular matrix of the tumor, facilitating greater interaction between the SM and its tumor specific antigen. We also revealed PVI with i.a. infusion diminished the radiation exposure of normal tissues from a circulating radioprobe, thus enabling the infusion of higher radiation doses at the tumor, potentially above the therapeutic index needed for complete necrosis of the tumor mass. We also believe local infusion will authorize the use of radionuclides that release Alpha-particles whose higher linear energy transfer when compared to Beta-emitting radioisotopes and overcome any treatment resistance (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur study has some limitations, firstly we use a large animal model of a renal tumor, this model has previously been employed to evaluate IR procedures in the liver, where the tumors vascularity was found to be similar to human liver tumors, The tumor vascularity has never been categorically characterized for renal tumors in this model, thus we cannot definitely state the similarity to a human RCC tumor vascularity. Using a tumor specific SM would have been ideal, however, this is a novel porcine model of a human RCC tumor, the presence of human tumor antigens that exactly mimic human RCC such as PSMA has not been identified in this tumor model, additionally the SM drug may nor interact with the porcine version of the antigen as it does in humans. Thus, a specific clinical SM tracer that has known uptake in human tumors was not utilized. Given the ubiquitous utilization of FDG in clinical practice we determined its use would be beneficial to study the proof of concept for PVI and more select and specific SM drugs can be used in the future in clinical studies. FDG is on the order of 10x smaller than clinical SM drugs used in humans and has no interaction with a specific tumor antigen, FDG is only a marker for metabolism and inflammation, it is not tumor specific like a SM probe, we do expect greater first pass uptake and retention when applying an appropriate tumor specific SM during future studies. FDG is also trapped in the cell, unlike a SM probe but we still see a significant increase in the amount of FDG found in the tumor at the early time points which is higher than i.v. infusion which suggests a greater amount of the tracer is present within the tumor and its matrix with PVI followed by i.a. administration. Time points only up to 120 minutes were obtained, longer time points up to 24 or 48 hours would have been ideal for assessing SM probe biodistribution, but we were limited by the short half-life of \u003csup\u003e18\u003c/sup\u003eF.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eA great interest exists to develop and utilize SM drugs for theranostics in various tumor types. SM drugs generally exhibit a favorable biopharmaceutical half-life which has allowed their use for PRRT with the substitution of predominantly β-emitting radionuclides. Thus far these treatments have only delivered palliative doses to solid tumors due to the exposure of normal tissues to radiation when given systemically. IR offers an alternative method to deliver and concentrate a SM drug into a tumor. We have studied this potential in a large animal oncopig and shown that the first pass uptake of the drug is significantly greater at the tumor when it is infused directly into the tumor's vascularity when compared to i.v. injection. We believe this method can be translated into humans to provide curative doses of radiation to solid tumors in various organs such as the kidney, prostate, lung, and pancreas.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cp\u003eSmall Molecule (SM)\u003c/p\u003e\n\u003cp\u003eIntravenous (i.v.)\u003c/p\u003e\n\u003cp\u003eIntra-arterial (i.a.)\u003c/p\u003e\n\u003cp\u003eRenal cell carcinoma (RCC)\u003c/p\u003e\n\u003cp\u003eVascular endothelial\u0026nbsp;growth factor receptor (VEGFR)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMammalian target of rapamycin (mTOR)\u003c/p\u003e\n\u003cp\u003ePeptide Receptor Radionuclide Therapy (PRRT)\u003c/p\u003e\n\u003cp\u003ePseudovascular isolation (PVI)\u003c/p\u003e\n\u003cp\u003eSignificantly significant (SS)\u003c/p\u003e\n\u003cp\u003eTransarterial chemoembolization (TACE)\u003c/p\u003e\n\u003cp\u003eTransarterial radioembolization (TARE)\u003c/p\u003e\n\u003cp\u003eSingle-photon emission computed tomography (SPECT)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePositron emission tomography (PET)\u003c/p\u003e\n\u003cp\u003eInterventional Radiology (IR)\u003c/p\u003e\n\u003cp\u003e\u0026sup1;⁸F-Fluorodeoxyglucose (FDG)\u003c/p\u003e\n\u003cp\u003eFrench (Fr)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed after approval by our Institutional Animal Care and Use Committee\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(IACUC) with ethical approval. Owners permission was received\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis original research has no overlap with other materials already published.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding for this research was provided by internal funds from the Interventional Radiology section of UT Southwestern\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Samuel L Rice (SLR), Mhd Wisam Alnablsi (MWA), and Jamaal Benjamin (JLB). The first draft of the manuscript was written by SLR with input from all authors including Fernando G\u0026oacute;mez Mu\u0026ntilde;oz, (FGM), Rehan Quadri (RQ). \u0026nbsp;All authors commented on previous versions of the manuscript, including\u0026nbsp;Joseph R. Osborne (JRO), Regina Beets-Tan (RBT). All authors read and approved the final manuscript SLR, MWA, JLB, FGM, RQ, JRO, RBT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eThe authors of this manuscript have no disclosures of any conflict of interest\u0026mdash;financial or otherwise\u0026mdash;that may directly or indirectly influence the content of the manuscript submitted.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMitri Z, Esmerian MO, Simaan JA, Sabra R, Zgheib NK. Pharmacogenetics and personalized medicine: the future for drug prescribing. Le J Med libanais Leban Med J. 2010;58(2):101\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLandais P, M\u0026eacute;resse V, Ghislain J-C, Arnaud O, Bibeau F, Cellier D, et al. Evaluation and validation of diagnostic tests for guiding therapeutic decisions. Therapies. 2009;64(3):195\u0026ndash;201.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin W. Molecular diagnostic renovates drug development: overcoming challenges of co-development of theranostics. Trends Bio/Pharm Ind. 2007;4:26\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2004;23(1):133\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25(7):884\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMotzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris PE, Zhernosekov K. The evolution of PRRT for the treatment of neuroendocrine tumors; What comes next? Front Endocrinol. 2022;13:941832.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaug AR. PRRT of neuroendocrine tumors: individualized dosimetry or fixed dose scheme? EJNMMI Res. 2020;10(1):1\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwekkeboom D. Perspective on 177Lu-PSMA therapy for metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57(7):1002\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSen I, Thakral P, Tiwari P, Pant V, Das SS, Manda D, et al. Therapeutic efficacy of 225Ac-PSMA-617 targeted alpha therapy in patients of metastatic castrate resistant prostate cancer after taxane-based chemotherapy. Ann Nucl Med. 2021;35(7):794\u0026ndash;810.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEbbers S, Barentsz M, de Vries-Huizing D, Versleijen M, Klompenhouwer E, Tesselaar M et al. Intra-arterial peptide-receptor radionuclide therapy for neuro-endocrine tumour liver metastases: an in-patient randomised controlled trial (LUTIA). Eur J Nucl Med Mol Imaging. 2023:1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNurili F, Monette S, Michel AO, Bendet A, Basturk O, Askan G, et al. Transarterial embolization of liver cancer in a transgenic pig model. J Vasc Interv Radiol. 2021;32(4):510\u0026ndash;7. e3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoas FE, Nurili F, Bendet A, Cheleuitte-Nieves C, Basturk O, Askan G, et al. Induction and characterization of pancreatic cancer in a transgenic pig model. PLoS ONE. 2020;15(9):e0239391.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhosn M, Elsakka AS, Petre EN, Cheleuitte-Nieves C, Tammela T, Monette S, et al. Induction and preliminary characterization of neoplastic pulmonary nodules in a transgenic pig model. Lung Cancer. 2023;178:157\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoas FE, Kemeny NE, Sofocleous CT, Yeh R, Thompson VR, Hsu M, et al. Bronchial or pulmonary artery chemoembolization for unresectable and unablatable lung metastases: a phase I clinical trial. Radiology. 2021;301(2):474\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBi Y, Shi X, Ren J, Yi M, Han X. Transarterial chemoembolization of unresectable renal cell carcinoma with doxorubicin-loaded CalliSpheres drug-eluting beads. Sci Rep. 2022;12(1):8136.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEtrych T, Braunova A, Zogala D, Lambert L, Renesova N, Klener P. Targeted drug delivery and theranostic strategies in malignant lymphomas. Cancers. 2022;14(3):626.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSheikh A, Fatima S, Khurshid Z, Chiragh Z. Theranostics of Hematologic Disorders. Nuclear Med Immunol. 2022:359\u0026ndash;432.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThurber GM, Schmidt MM, Wittrup KD. Factors determining antibody distribution in tumors. Trends Pharmacol Sci. 2008;29(2):57\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaid M, Masud M, Zaini M, Salleh R, Lee B, Zainon R, editors. Lu-177 DOTATATE dosimetry for neuroendocrine tumor: single center experience. Journal of Physics: Conference Series; 2017: IOP Publishing.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang J, Song Q, Cai L, Xie Y, Chen Y. The efficacy of 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumours: a systematic review and meta-analysis. J Cancer Res Clin Oncol. 2020;146(6):1533\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcBean R, O'Kane B, Parsons R, Wong D. Lu177-PSMA therapy for men with advanced prostate cancer: Initial 18 months experience at a single Australian tertiary institution. J Med Imaging Radiat Oncol. 2019;63(4):538\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParida GK, Panda RA, Bishnoi K, Agrawal K. Efficacy and Safety of Ac-225 PSMA Radio Ligand Therapy in Metastatic Prostate Cancer. A Systematic Review and Metanalysis. Medical Principles and Practice. International Journal of the Kuwait University, Health Science Centre; 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZaheer J, Kim H, Lee Y-J, Kim JS, Lim SM. Combination radioimmunotherapy strategies for solid tumors. Int J Mol Sci. 2019;20(22):5579.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirmas N, Leyh C, Sraieb M, Barbato F, Schaarschmidt BM, Umutlu L, et al. 68Ga-PSMA-11 PET/CT improves tumor detection and impacts management in patients with hepatocellular carcinoma. J Nucl Med. 2021;62(9):1235\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57(12):1941\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePoty S, Francesconi LC, McDevitt MR, Morris MJ, Lewis JS. α-Emitters for radiotherapy: from basic radiochemistry to clinical studies\u0026mdash;part 1. J Nucl Med. 2018;59(6):878\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejre","sideBox":"Learn more about [EJNMMI Research](http://ejnmmires.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejre/default.aspx","title":"EJNMMI Research","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3918869/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3918869/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSmall molecule biomacromolecules target tumor specific antigens. They are employed as theranostic agents for imaging and treatment. Intravenous small molecule radioligands exhibit rapid tumor uptake and excretion.\u003c/p\u003e\n\u003cp\u003eHowever, systemically administration for peptide receptor radionuclide therapy brachytherapy lacks the therapeutic index to completely treat solid tumors beyond palliation. We study intra-arterial delivery with tumor embolization of a small molecule as a means to deliver local intertumoral brachytherapy for curative internal ablation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e¹⁸F-Fluorodeoxyglucose (FDG) was used as a surrogate for a small molecule theranostic agent in a porcine renal tumor model, this tumor model is not known to specifically express human tumor antigens, but the model demonstrates similar vascularity. Angiography and micron particle embolization of the tumor arterioles was performed in a renal tumor model. Significantly more, 2x to 4x more tumor uptake, for study intra-arterial. administration compared to i.v (%ID/g = 44.41 ± 2.48 vs 23.19 ± 4.65 p= 0.0342* at 1 min and 40.8 ± 2.43 vs 10.94 ± 0.42 p=0.018* 10 min). At later time points, up to 120 mins after injection, washout of the tracer from the tumor was observed, but percent injected dose per gram remained elevated, with 3x higher concentration of FDG with intra-arterial administration compared to intravenous, but the difference was not statistically significant. Trend towards diminished systemic percent injected dose per gram measured in the blood, liver, kidney, spleen, muscle, and urine for study intra-arterial \u0026nbsp;compared to intravenous administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCombining intra-arterial administration of a small molecule radioprobe surrogate with embolization of the tumor's arterioles extending the time for interaction of the drug within the tumor by diminishing flow out of the tumor via the efferent capillaries significantly increases the first pass uptake of the SM drug within a tumor and decreased the radiation to normal non-tumor tissues when compared to intravenous \u0026nbsp;injection of the same drug. The minimally invasive drug delivery allows tumor specific theranostic treatment of renal tumors with a brachytherapy absorbed dose of radiation that is potentially curative.\u003c/p\u003e","manuscriptTitle":"Local and systemic biodistribution of a small molecule radiopharmaceutical probe after transcatheter embolization and intra-arterial delivery in a porcine orthotopic renal tumor model","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-26 20:56:37","doi":"10.21203/rs.3.rs-3918869/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2024-07-03T07:47:08+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"EJNMMI Research","date":"2024-02-23T07:21:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-23T06:14:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"EJNMMI Research","date":"2024-02-21T19:39:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejre","sideBox":"Learn more about [EJNMMI Research](http://ejnmmires.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejre/default.aspx","title":"EJNMMI Research","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f7381912-e721-4f7c-98a8-5a90ea94f475","owner":[],"postedDate":"July 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-07-26T20:56:37+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-26 20:56:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3918869","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3918869","identity":"rs-3918869","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}