Intra-arterial Delivery Research Articles

Effective therapy with Bismuth-212 labeled macroaggregated albumin in orthotopic mouse breast tumor models.

Intravascularly administered radiation therapy using beta (β-)-emitting radioisotopes has relied on either intravenously injected radiolabeled peptides that target cancer or radiolabeled microspheres that are trapped in the tumor following intra-arterial delivery. More recently, targeted intravenous radiopeptide therapies have explored the use of alpha (α)-particle emitting radioisotopes, but microspheres radiolabeled with α-particle emitters have not yet been studied. Here, FDA-approved macroaggregated albumin (MAA) particles were radiolabeled with Bismuth-212 (Bi-212-MAA) and evaluated using clonogenic and survival assays in vitro and using immune-competent mouse models of breast cancer. The in vivo biodistribution of Bi-212-MAA was investigated in Balb/c and C57BL/6 mice with 4T1 and EO771 orthotopic breast tumors, respectively. The same orthotopic breast cancer models were used to evaluate the treatment efficacy of Bi-212-MAA. Our results showed that macroaggregated albumin can be stably radiolabeled with Bi-212 and that Bi-212-MAA can deliver significant radiation therapy to reduce the growth and clonogenic potential of 4T1 and EO771 cells in vitro. Additionally, Bi-212-MAA treatment upregulated γH2AX and cleaved Caspase-3 expression in 4T1 cells. Biodistribution analyses showed 87-93% of the Bi-212-MAA remained in 4T1 and EO771 tumors 2 and 4h after injection. Following single-tumor treatments with Bi-212-MAA there was a significant reduction in the growth of both 4T1 and EO771 breast tumors over the 18-day monitoring period. Overall, these findings showed that Bi-212-MAA was stably radiolabeled and inhibited breast cancer growth. Bi-212-MAA is an exciting platform to study α-particle therapy and will be easily translatable to larger animal models and human clinical trials.

The first endovascular rat glioma model for pre-clinical evaluation of intra-arterial therapeutics.

Several translational animal models have been described assessing intra-arterial (IA) treatments for malignant gliomas. We describe the first endovascular animal model that allows testing of IA drug delivery as a first-line treatment, which is difficult to do in actual patients. We report a unique protocol for vascular access and IA delivery in the rat model that, unlike prior reports, does not require direct puncture and opening of proximal cerebrovasculature which carries risk of ischemia in the animal brain post-delivery. Wistar rats underwent left femoral artery catherization with a Balt Magic 1.2F catheter or Marathon Flow directed 1.5F Microcatheter with an Asahi Chikai 0.008 micro-guidewire which was navigated to the left internal carotid artery under x-ray. 25% mannitol was administered to test blood brain barrier breakdown (BBBB). Additional rats were implanted with C6 glioma cells in the left frontal lobe. C6 Glioma-Implanted Rats (C6GRs) were monitored for overall survival and tumor growth. Tumor volumes from MRI images were calculated utilizing 3D slicer. Additional rats underwent femoral artery catheterization with Bevacizumab, carboplatin, or irinotecan injected into the left internal carotid artery to test feasibility and safety. A successful endovascular access and BBBB protocol was established. BBBB was confirmed with positive Evans blue staining. 10 rats were successfully implanted with C6 gliomas with confirmed growths on MRI. Overall survival was 19.75 ± 2.21 days. 5 rats were utilized for the development of our femoral catheterization protocol and BBBB testing. With regards to IA chemotherapy dosage testing, control rats tolerated targeted 10 mg/kg of bevascizumab, 2.4 mg/kg of carboplatin, and 15 mg/kg of irinotecan IA ICA injections without any complications. We present the first endovascular IA rat glioma model that allows selective catheterization of the intracranial vasculature and assessment of IA therapies for gliomas without need for access and sacrifice of proximal cerebrovasculature.

Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma

Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. Development of novel therapeutical strategies for this disease have been extremely limited owing to the rarity of the disease and the paucity of biologically relevant substrates. We conducted the first high-throughput screen (HTS) on a human patient-derived CPC cell line (Children Cancer Hospital Egypt, CCHE-45) and identified 427 top hits highlighting key molecular targets in CPC. Furthermore, a combination screen with a wide variety of targets revealed multiple synergistic combinations that may pave the way for novel therapeutical strategies against CPC. Based on in vitro efficiency, central nervous system (CNS) penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Pharmacokinetic assays established increased brain penetrance with intra-arterial (IA) delivery over intra-venous (IV) delivery and demonstrated a higher CNS penetrance for the combination melphalan/elimusertib. The mechanisms of synergistic activity for melphalan/elimusertib were assessed through transcriptome analyses and showed dysregulation of key oncogenic pathways (e.g. MYC, mammalian target of rapamycin mTOR, p53) and activation of critical biological processes (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). Importantly, IA administration of melphalan combined with elimusertib led to a significant increase in survival in a CPC genetic mouse model. In conclusion, this study is, to the best of our knowledge, the first that identifies multiple promising combinatorial therapeutics for CPC and emphasizes the potential of IA delivery for the treatment of CPC.

Algorithm for evaluating ophthalmic artery pseudo-occlusion during intra-arterial chemotherapy for retinoblastoma.

Intra-arterial chemotherapy infusion for retinoblastoma is typically performed via selective catheterization of the ophthalmic artery. Anastomoses between the external carotid and the ophthalmic arteries have also been utilized when the ophthalmic artery cannot be catheterized directly. However, these are not present in every patient. A 10-month-old boy presented with bilateral retinoblastoma and underwent one round of intra-arterial chemotherapy (IAC) via direct catheterization of the ophthalmic arteries. Combined with adjuvant laser therapy, they experienced symptomatic improvement and tumour regression. However, during subsequent treatment sessions both ophthalmic arteries did not have anterograde flow and attempts to catheterize their origin were unsuccessful. Unfortunately, no targetable anastomoses between the external carotid and ophthalmic arteries were identified for drug delivery. Due to the patient's anatomy, balloon occlusion of the ECA was felt to be unsafe. As a salvage technique, a balloon was inflated in the left internal carotid artery (ICA) distal to the ophthalmic take-off to redirect flow into the ophthalmic. Repeat angiography with the distal ICA occluded showed improved flow into the ipsilateral ophthalmic artery. IAC was then successfully delivered through the left ICA. This case illustrates the importance of utilizing creative endovascular techniques for targeted intra-arterial drug delivery when other conventional measures fail as these patients often have limited, and potentially higher risk, therapeutic alternatives.

Abstract CT084: Targeted intra-arterial gemcitabine vs. continuation of IV gemcitabine plus nab-paclitaxel following Induction with sequential IV gemcitabine plus nab-paclitaxel and radiotherapy for unresectable locally advanced pancreatic cancer (TIGeR-PaC) - phase III trial interim analysis

Abstract Background: Treatment of locally advanced pancreatic cancer (LAPC) remains a clinical challenge with a median survival of 16-18 months1. Control of local disease, beyond systemic therapy, is part of the treatment paradigm being investigated in this patient population. Double balloon mediated local delivery of intra-arterial gemcitabine (IAG) into the tumor has been demonstrated to be safe in this patient population2. TIGeR-PaC is an ongoing Phase III clinical trial comparing the efficacy of this approach compared to standard of care IV gemcitabine/nab-paclitaxel (GN) for patients with LAPC. Methods: The trial is designed with an induction phase for all patients of upfront systemic chemotherapy and radiation prior to randomization to IAG or continuation of GN. ECOG 0-1 LAPC patients receive 3 cycles of GN and 1 cycle of radiation (SBRT, 33 Gy in 5 fractions). Following induction, patients with non-progressive disease are randomized to receive IAG (8 treatments bi-weekly for 16 weeks) or continuation of GN for 4 cycles over 16 weeks. After the 16 weeks of randomized therapy, patients with non-progressive disease receive continuation systemic therapy of GN or low-dose oral capecitabine, per investigator’s preference until disease progression and are followed for survival only. The primary endpoint is the overall survival (OS), and the study is powered at an 80% power to detect a hazard ratio of 0.6 between the two arms. It is assumed that the hazard functions are proportional only during the randomized treatment period, after which the two hazard functions become approximately identical during the continuing treatment period. The primary endpoint of OS for the two treatment arms will be compared using a 2-sided Wilcoxon test. The first interim analysis of the trial for the ITT population is performed after the 26th out of an expected 86 events have occurred in the trial (30%). Clinical Endpoint Analysis: The first interim analysis of the primary endpoint of OS was conducted on Feb 2nd, 2023. This was based on a data lock on survival status of all patients after the sponsor became aware that the 26th event in the trial occurred on Dec. 21st, 2022. As of that date, 45 patients had been randomized in the trial and the survival status of all 45 subjects was used as of the date for analysis. Of the 45 patients randomized, 23 were randomized to IAG and 22 to continuation of IV GN. There were equal number of primary events, 13, in each arm. The median survival in the control arm is 10 months, versus 16 months in the IAG arm. The p-values based on Wilcoxson non-proportional hazard ratio is 0.051 between the 2 arms. The study continues to accrue patients with a second interim analysis (after 52 events) expected at end of 2024. 1. Hammel P, Huguet F, van Laethem JL, et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib. JAMA. 2016;315(17):1844. 2. Rosemurgy AS, Ross SB, Vitulli PL, et al. Safety Study of Targeted and Localized Intra-Arterial Delivery of Gemcitabine in Patients with Locally Advanced Pancreatic Adenocarcinoma. J Pancreat Cancer. 2017;3(1):58-65. Citation Format: Michael Pishvaian, Amer Zureikat, Charles Lopez, Kenneth Meredith, Emmanuel Zervos, Hassan Hatoum, Ki Chung, Daniel J. Berg, Antonio Ucar, Ripal Gandhi, Reza Nazemzadeh, Parikh Nainesh, Paula Novelli, Brian Kouri, Christopher Laing, Brian Boone, Thor Johnson, Susan Bates, Karyn Goodman, Ramtin Agah. Targeted intra-arterial gemcitabine vs. continuation of IV gemcitabine plus nab-paclitaxel following Induction with sequential IV gemcitabine plus nab-paclitaxel and radiotherapy for unresectable locally advanced pancreatic cancer (TIGeR-PaC) - phase III trial interim analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT084.

Intra-Arterial Delivery of Radiopharmaceuticals in Oncology: Current Trends and the Future of Alpha-Particle Therapeutics.

A paradigm shift is underway in cancer diagnosis and therapy using radioactivity-based agents called radiopharmaceuticals. In the new strategy, diagnostic imaging measures the tumor uptake of radioactive agent "X" in a patient's specific cancer, and if uptake metrics are realized, the patient can be selected for therapy with radioactive agent "Y". The X and Y represent different radioisotopes that are optimized for each application. X-Y pairs are known as radiotheranostics, with the currently approved route of therapy being intravenous administration. The field is now evaluating the potential of intra-arterial dosing of radiotheranostics. In this manner, a higher initial concentration can be achieved at the cancer site, which could potentially enhance tumor-to-background targeting and lead to improved imaging and therapy. Numerous clinical trials are underway to evaluate these new therapeutic approaches that can be performed via interventional radiology. Of further interest is changing the therapeutic radioisotope that provides radiation therapy by β- emission to radioisotopes that also decay by α-particle emissions. Alpha (α)-particle emissions provide high energy transfer to the tumors and have distinct advantages. This review discusses the current landscape of intra-arterially delivered radiopharmaceuticals and the future of α-particle therapy with short-lived radioisotopes.

893 Development of a Rabbit Human Glioblastoma Model for Testing of Endovascular Selective Intra-Arterial Infusion (ESIA) of Novel Stem Cell-Based Therapeutics

INTRODUCTION: Poor outcomes for glioblastoma (GBM) are partly due to the inability to deliver therapeutic agents to the tumor because of the blood brain barrier (BBB) as well as ineffective agents. We have evaluated bone marrow-derived mesenchymal stem cells (MSCs) as transport vehicles of biological therapeutics, particularly Delta-24-RGD (D24), an engineered tumor-selective oncolytic adenovirus that replicates and lyses only in human tumor cells. In mice, we have shown that MSCs loaded with D24 (MSCs-D24) home to GBMs after intra-arterial (IA) carotid infusion, resulting in widespread distribution in the tumor and oncolysis. Intravenous infusion is ineffective, rendering IA delivery the only effective systemic option. To understand the applicability of IA infusions of MSCs-D24 requires a large animal, human brain tumor model recapitulating the challenges of clinical use. METHODS: Rabbits underwent stereotactic xenoimplantation of human GBM cell lines. Tumor creation was confirmed on magnetic resonance imaging (MRI), histologic and immunohistochemistry analysis. Selective internal carotid artery MSCs-D24 infusion ipsilateral to the tumor was performed assess efficacy and safety. RESULTS: We report on successful xenoimplantation of human glioblastoma cell lines (U87, GSC17, and GSC8-11) in 28 immunosuppressed rabbits using Mycophenolate Mofetil, Dexamethasone, and Tacrolimus. The implanted rabbits were followed for 35 days prior to tumor assessment with MRI, angiography, and histological analysis. On MRI, the tumors were hyperintense on T2-weighted image and enhanced (evidence of BBB breakdown). On histological analysis, tumors showed phenotypic traits of human GBM and display varying levels of vascularity, an important feature for testing IA therapy. Selective internal carotid artery MSCs-D24 infusion was safe in the model, and MSCs-D24 homed to the implanted tumor at 24 hours. CONCLUSIONS: The intracranial immunosuppressed rabbit human GBM model allows testing of ESIA infusion of novel therapeutics (eg. MSCs-D24) in a clinically relevant fashion.

Case Series of Precision Delivery of Methylprednisolone in Pediatric Inflammatory Bowel Disease: Feasibility, Clinical Outcomes, and Identification of a Vasculitic Transcriptional Program

Systemic steroid exposure, while useful for the treatment of acute flares in inflammatory bowel disease (IBD), is associated with an array of side effects that are particularly significant in children. Technical advancements have enabled locoregional intraarterial steroid delivery directly into specific segments of the gastrointestinal tract, thereby maximizing tissue concentration while limiting systemic exposure. We investigated the feasibility of intraarterial steroid administration into the bowel in a cohort of nine pediatric patients who had IBD. This treatment approach provided symptom relief in all patients, with sustained relief (>2 weeks) in seven out of nine; no serious adverse effects occurred in any patient. In addition, we identified patterns of vascular morphologic changes indicative of a vasculopathy within the mesenteric circulation of inflamed segments of the bowel in pediatric patients with Crohn's disease, which correlated with disease activity. An analysis of publicly available transcriptomic studies identified vasculitis-associated molecular pathways activated in the endothelial cells of patients with active Crohn's disease, suggesting a possible shared transcriptional program between vasculitis and IBD. Intraarterial corticosteroid treatment is safe and has the potential to be widely accepted as a locoregional approach for therapy delivery directly into the bowel; however, this approach still warrants further consideration as a short-term "bridge" between therapy transitions for symptomatic IBD patients with refractory disease, as part of a broader steroid-minimizing treatment strategy.

Intraarterial Transplantation of Mitochondria After Ischemic Stroke Reduces Cerebral Infarction.

Transplantation of autologous mitochondria into ischemic tissue may mitigate injury caused by ischemia and reperfusion. Using murine stroke models of middle cerebral artery occlusion, we sought to evaluate feasibility of delivery of viable mitochondria to ischemic brain parenchyma. We evaluated the effects of concurrent focused ultrasound activation of microbubbles, which serves to open the blood-brain barrier, on efficacy of delivery of mitochondria. Following intra-arterial delivery, mitochondria distribute through the stroked hemisphere and integrate into neural and glial cells in the brain parenchyma. Consistent with functional integration in the ischemic tissue, the transplanted mitochondria elevate concentration of adenosine triphosphate in the stroked hemisphere, reduce infarct volume and increase cell viability. Additional of focused ultrasound leads to improved blood brain barrier opening without hemorrhagic complications. Our results have implications for the development of interventional strategies after ischemic stroke and suggest a novel potential modality of therapy after mechanical thrombectomy.

Abstract TP243: Efficacy Of Intra-arterial Stem Cell Therapy In A Canine Model Of Ischemic Stroke: Role Of Anti-inflammatory Action In The Brain

Introduction: Stroke is the 2 nd leading cause of death globally. Despite the current standard of care for stroke, more than 50% of stroke survivors are chronically disabled, leading to more than $46 billion in annual economic burden in the US alone. It is therefore imperative to develop novel therapies for stroke. Preclinical studies in the past two decades have shown promise in cell therapies for stroke. Intra-arterial (IA) delivery of Mesenchymal Stem Cells (MSCs) is minimally invasive making it attractive for clinical translation. Recent studies from our lab have shown the safety and efficacy of IA-MSC treatment in rodent and canine ischemic stroke models. These studies from our group have established the precise timing and effective dosage of IA-MSC therapy that leads to improved stroke outcomes. It is believed that IA-MSCs exert their protective effects by mediating anti-inflammatory actions. However, this mechanism is not very well studied, specifically in the large animal brain. Methods: In this study we determined the expression pattern of microglia, astrocytes, the Nod-like receptor 3 (NLRP3) inflammasome pathway markers, inflammatory cytokines and the activity of Nuclear factor kappa B subunit 1 (NF-κB) in the large animal canine brain following IA MSC therapy after ischemic stroke. Immunohistochemistry staining and immunofluorescence imaging of the canine brain cortex and hippocampus were performed. Results: Numerical quantification showed significant reduction in astrocyte and microglia activation, reduced expression of NLRP3 and Interluekin-1beta at different doses of IA-MSCs (10, 20, and 40 million) at 30 days post-stroke. Results from this study showed a significant dose-dependent reduction in inflammation in the canine hippocampus and the cortex. There was a simultaneous increase in surviving neurons. Conclusions: These novel findings help us understand inflammation in the canine brain after stroke. Our data further reveal how IA-MSC therapy mediates its action via inflammatory changes. Overall, this approach contributes to developing more robust and engineered IA-MSCs therapies for stroke patients, leading to more effective translation.

Intra-arterial gemcitabine vs IV gemcitabine PK substudy in patients with locally advanced pancreatic cancer.

728 Background: Localized dual-balloon-mediated, intra-arterial delivery of Gemcitabine (IAG) directly into tumors/tissue can lead to higher local drug potency1. Furthermore, IAG may lead to decreased systemic drug concentration and associated side effects. In patients with Locally Advanced Pancreatic Cancer (LAPC), this approach is currently being tested in a contemporary Phase III clinical trial, TIGeR-PaC. Herein we report the results of a 10-patient PK analysis sub-study within TIGeR-PaC. Methods: We analyzed a total of 10 subjects from 5 sites who received intra-arterial gemcitabine with the RenovoCath dual balloon catheter at 1000mg/m2 over 20 minutes. The target treatment artery was either the celiac axis (n=5) or the superior mesenteric artery (n=5). Samples were drawn at T = -5, 10, 15, 20, 30, 40, 60, and 90 minutes from the onset of infusion. At each timepoint, we collected 2mL of blood in heparinized tubing containing 25 mcg/mL of tetrahydrouridine. The blood samples were then centrifuged collect, freeze, and ship the plasma to a reference lab to perform a gemcitabine assay. The PK parameters for a single dose was estimated for Cmax, AUC, clearance, and distribution volume based on the terminal phase. These values are compared to historical data for intravenous gemcitabine (IVG) infusion at 1000mg/m2 over 30 minutes2. Results: At this time, data has been analyzed for 4 of 8 collected samples. We expect to complete collection and analysis of all 10 samples by November of 2022. We show results available so far; historical values for IVG are given as a reference point. The results suggest that IAG is associated with decreased systemic exposure of gemcitabine compared to IVG. Conclusions: Localized dual-balloon-mediated, intra-arterial delivery of gemcitabine can lead to decreased systemic levels of gemcitabine. This approach increased local potency and may be beneficial in decreasing gemcitabine-related systemic side effects. 1. Farsad K, et al. 04:21 PM Abstract No. 392 . J Vasc Intervent Radiol 2019;30(3):S172. doi:10.1016/j.jvir.2018.12.467. 2. Chow ECY, Zirkelbach JF. Clinical Pharmacology and Biopharmaceutics Review(s) {209604Orig1s000}. FDA: Center for Drug Evaluation and Research. Clinical trial information: NCT03257033 . [Table: see text]

Phenotyping of Macrophages After Radiolabeling and Safety of Intra-arterial Transplantation Assessed by SPECT/CT and MRI

Cell therapy is an integral modality of regenerative medicine. Macrophages are known for their sensitivity to activation stimuli and capability to recruit other immune cells to the sites of injury and healing. In addition, the route of administration can impact engraftment and efficacy of cell therapy, and modern neuro-interventional techniques provide the possibility for selective intra-arterial (IA) delivery to the central nervous system (CNS) with very low risk. The effects of radiolabelling and catheter transport on differentially activated macrophages were evaluated. Furthermore, the safety of selective IA administration of these macrophages to the rabbit brain was assessed by single-photon emission computed tomography/computed tomography (SPECT/CT) and ultra-high-field (9.4 T) magnetic resonance imaging (MRI). Cells were successfully labeled with (111In)In-(oxinate)3 and passed through a microcatheter with preserved phenotype. No cells were retained in the healthy rabbit brain after IA administration, and no adverse events could be observed either 1 h (n = 6) or 24 h (n = 2) after cell administration. The procedure affected both lipopolysaccharide/gamma interferon (LPS/IFNγ) activated cells and interleukin 4 (IL4), interleukin 10 (IL10)/transforming growth factor beta 1 (TGFβ1) activated cells to some degree. The LPS/IFNγ activated cells had a significant increase in their phagocytotic function. Overall, the major impact on the cell phenotypes was due to the radiolabeling and not passage through the catheter. Unstimulated cells were substantially affected by both radiolabeling and catheter administration and are hence not suited for this procedure, while both activated macrophages retained their initial phenotypes. In conclusion, activated macrophages are suitable candidates for targeted IA administration without adverse effects on normal, healthy brain parenchyma.

Current Indications for Intraarterial Chemotherapy in Neurointerventional Surgery

Background In pursuit of a cure for cancer, it is imperative to utilize every tool, resource, and strategy. Included under this umbrella is the optimization of drug delivery. Broadly speaking, anti‐cancer treatment has been perpetually hindered by off‐target activity, systemic toxicity, and other adverse reactions. Intraarterial (IA) delivery of therapeutics is an approach that has garnered increased attention in recent years. This approach can deliver drug directly to the desired site with the potential to minimize systemic toxicity. Methods In this review, we briefly cover existing IA indications for peripheral solid tumors as a base from which we can learn, followed by trials and procedural considerations of IA drug delivery for neck, head, and central nervous system tumors. Results While the bulk of IA research and clinical trials have focused on drug delivery outside of the central nervous system, there have been recent encouraging results in IA tumor treatment within the neurointerventional arena, such as head and neck tumors, retinoblastoma, glioblastoma multiforme, and central nervous system lymphoma. Conclusion This review highlights the need for increased clinical research on IA chemotherapeutic delivery as a multi‐disciplinary approach involving neurointerventional surgeons.

Modern view on the treatment of oncological diseases by endovascular methods

In recent decades, the multidisciplinary development of medicine has led to an improved understanding of the molecular mechanisms of the development of oncological diseases. The idea of malignant neoplasms as heterogeneous objects containing cells with different genetic backgrounds made it possible to explain the selective effectiveness of one type of treatment for a certain part of the tumor cells in a patient. Numerous targeted therapies have formed the cornerstone in the treatment of various malignancies, alone or in combination with other treatments such as chemotherapy, radiation therapy, surgery and interventional radiology.Interventional oncology covers both diagnostics and treatment. Its methods are minimally invasive and highly specific to the patient. Currently, personalized procedures are actively develop and allow to detect cancer cells, selectively contact and treat them. Another important problems is to evaluate drug delivery and uptake in order to make adjustments to the treatment based on the received data from the procedures and, ultimately, to predict the response. Here we will consider such interventional oncological procedures and innovative methods that are under development as transarterial chemoembolization (TACE), oily transarterial chemoembolization (cTACE), catheter intra-arterial delivery of nanoparticles etc. Thus, interventional oncology has unique opportunities for selective impact on tumor lesions not only for diagnostic purposes, but also for a wide range of minimally invasive percutaneous treatments.

Abstract 10858: Mesenchymal Stromal Cell Delivery via Cardiopulmonary Bypass Provides Neuroprotection in a Juvenile Porcine Surgical Model

Background: Neurodevelopmental impairment is one the most important challenges in children with congenital heart disease. Cardiopulmonary bypass (CPB) causes substantial oxidative/inflammatory stress and microglial activation. The present study tested CPB itself as a unique delivery system of bone marrow-derived mesenchymal stromal cells (BM-MSCs), known to possess significant immunomodulatory properties. Methods: Two-week old piglets were randomly assigned to one of three groups: Control, CPB, and CPB with BM-MSC administration. BM-MSCs (10x10 6 /kg) were delivered through CPB. In addition to cellular/molecular assays, structural and behavioral changes were assessed up to 4 weeks after surgery. Results: Intra-arterial delivery through CPB uniformly distributed BM-MSCs to most of the organs analyzed, including the brain, heart and kidney. In the brain, BM-MSCs were equally distributed between two hemispheres and within the cortex and white matter. While approximately half of the BM-MSCs were localized to parenchyma shortly after CPB, there were no residual MSCs at 4 weeks post-CPB. In the developing cortex, enhanced p53 and JAK-STAT3 pathway activation were revealed post-CPB. BM-MSCs suppressed CPB-induced microglial STAT3 phosphorylation, thereby inhibiting microglial activation. In addition to an increase in anti-inflammatory cytokines, BM-MSCs reduced caspase-3 activation in cortical neurons and limited the induction of apoptotic signals. BM-MSC-treated animals demonstrated improved post-operative recovery and reduced behavioral impairments due to cardiac surgery. Concurrently, CPB-induced structural alterations of the developing cortex were mitigated possibly through the inhibition of prolonged microglia activation by BM-MSCs. No evidence of any detrimental effects was observed. Our transcriptomic analyses suggest that BM-MSC exosome-derived micro-RNA, miR-21-5p, may be the key mediator of apoptosis suppression and reduced microglial activation. Conclusions: BM-MSC delivery via CPB minimizes inflammatory/oxidative stress and reduces neuronal caspase and microglial activation, with subsequent rescue of behavioral/structural impairments in children undergoing cardiac surgery.

Preclinical Therapeutic Evaluation of Lenvatinib-Eluting Microspheres for Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma.

To evaluate the preclinical in vivo therapeutic response of Lenvatinib-eluting microspheres (LEN-EM) transcatheter arterial chemoembolization (LEN-TACE) in an hepatocellular carcinoma (HCC) rat model. Magnetic resonance imaging (MRI) visible LEN-EM was fabricated with poly(lactide-co-glycolide) and iron oxide nanoparticles by a double-emulsion method. The morphology, LEN loading/release kinetics, and MRI contrast effect of LEN-EM were evaluated. For in vivo study, N1S1 HCC rats were treated with LEN-TACE (LEN: 2.4mg/kg, n = 5) using LEN-EM, systemic LEN (LEN: 0.4mg/kg, oral gavage daily for 7days, n = 5), control (intra-arterial (IA) saline infusion, n = 5), and non-tumor control (n = 3). Tumor size changes were measured for 2weeks. Histology, comparative LEN plasma concentration, hematologic markers, liver profile, and serum chemistry among the groups were measured. LEN-EM with 33µm in average size was prepared in an optimized emulsion process. LEN loading efficiency was 58.7%. LEN was continuously released for 500h. LEN-TACE showed the delivered LEN-EM surrounding tumor tissue in MRI-T2* images. The LEN-TACE group demonstrated a statistically significant larger tumor volume reduction compared to the other groups at 2weeks post-procedure. Quantification data of Terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells confirmed increased cancer cell death in the LEN-TACE group compared to control groups. Additional histology, hematologic markers, and liver profiles showed minimal side effects of LEN-TACE. LEN-TACE using IA delivery of LEN-EM demonstrated an effective therapeutic efficacy in an HCC rat animal model.

Site-Specific Considerations on Engineered T Cells for Malignant Gliomas.

Immunotherapy has revolutionized cancer treatment. Despite the recent advances in immunotherapeutic approaches for several tumor entities, limited response has been observed in malignant gliomas, including glioblastoma (GBM). Conversely, one of the emerging immunotherapeutic modalities is chimeric antigen receptors (CAR) T cell therapy, which demonstrated promising clinical responses in other solid tumors. Current pre-clinical and interventional clinical studies suggest improved efficacy when CAR-T cells are delivered locoregionally, rather than intravenously. In this review, we summarize possible CAR-T cell administration routes including locoregional therapy, systemic administration with and without focused ultrasound, direct intra-arterial drug delivery and nanoparticle-enhanced delivery in glioma. Moreover, we discuss published as well as ongoing and planned clinical trials involving CAR-T cell therapy in malignant glioma. With increasing neoadjuvant and/or adjuvant combinatorial immunotherapeutic concepts and modalities with specific modes of action for malignant glioma, selection of administration routes becomes increasingly important.

Intra-arterial delivery of doxorubicin-loaded hollow gold nanospheres—photothermal ablation and chemoembolisation therapy in a rabbit VX2 liver cancer model

Hepatocellular carcinoma (HCC) is associated with a high mortality rate. In this study, we aimed to investigate the therapeutic effect and safety of hepatic arterial administration of doxorubicin (Dox)-loaded hollow gold nanospheres (Dox@HAuNSs) combined with photothermal ablation (PTA) in a rabbit VX2 liver cancer model established by implanting VX2 tumour cells into rabbit livers. Rabbits were randomly divided into four treatment groups: physiological saline solution (control); lipiodol and doxorubicin (Dox + Lp); lipiodol and Dox@HAuNS (Dox@PEG-HAuNS + Lp); and lipiodol, Dox@PEG-HAuNS, and photothermal ablation (Dox@PEG-HAuNS + Lp + PTA). Dox release from Dox@PEG-HAuNS in the tumour was detected using fluorescence microscopy. Tumour size and liver-kidney function were assessed in each rabbit preoperatively and on postoperative days 3, 7, and 14. Necrosis, proliferation, and micro-vessel density of VX2 tumours were estimated in peripheral tumour tissues. Dox release from Dox@PEG-HAuNS was increased with a subsequent increase in tumour necrosis in liver tumours after PTA, whereas the tumour volume and proliferation decreased. However, the aspartate aminotransferase and alanine aminotransferase levels indicated transient liver damage. Thus, intra-arterial delivery of Dox@PEG-HAuNS combined with PTA can suppress VX2 liver cancer growth. Dox@PEG-HAuNS + Lp + PTA is also associated with transient liver damage in rabbits. The combination of Dox@PEG-HAuNS chemoembolisation and PTA could be a potential therapeutic approach for HCC and it has broad application prospects.

DDEL-02. Intra-arterial Delivery for Novel Combinatorial Chemotherapies in Choroid Plexus Carcinoma

Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. New delivery routes such as intra-arterial (IA) route are being explored to limit toxicity and improve efficacy. To identify novel compounds that may be used in this context, we conducted a high-throughput screen (HTS) informing on the cytotoxicity of 2454 compounds, including some currently approved for IA in other brain tumors, that identified multiple active drugs on a human primary CPC cell line. Key molecular targets previously identified in CPC literature such as mTOR, PDGFR, ATR, CDK, FGFR1 and PI3K were enriched relative to other targets in the screen. Importantly, a combination screen with a wide variety of targets revealed multiple synergistic combinations. We examined two key combinations (topotecan/elimusertib and melphalan/elimusertib) based on mechanistic alignment and translational potential through extended in vitro validation and transcriptome analyses. Pharmacokinetic assays established increased drug brain penetrance with IA delivery when compared with intravenous delivery. Ultimately, a single intra-arterial administration of melphalan combined with systemic administration of elimusertib led to a significant increased survival in a CPC genetic mouse model. This study underscores the efficacy of IA delivery and identifies a promising therapeutic option for the treatment of CPC.

Abstract No. 338 Novel drug device combination for rectal carcinoma: rectal heating and intraarterial delivery of doxorubicin-loaded low temperature sensitive liposomes in a swine feasibility study

To establish a rectal hyperthermia (HT) model and evaluate plasma and tissue pharmacokinetics following systemic IV vs intra-arterial trans-catheter delivery of low temperature sensitive liposomes (LTSLs) loaded with doxorubicin during rectal HT