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

doi:10.21203/rs.3.rs-3918869/v1

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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

https://doi.org/10.21203/rs.3.rs-3918869/v1

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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.

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.

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 (10⁹ 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 ¹⁸F. 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.

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).

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 ⁹⁰Y 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 ¹⁷⁷Lu-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 ¹⁷⁷Lu-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 ¹⁸F.

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.

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)

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.

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

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