Interventional real-time optical imaging guidance for complete tumor ablation.

The aim of this study was to develop an interventional optical imaging (OI) technique for intraprocedural guidance of complete tumor ablation. Our study employed four strategies: 1) optimizing experimental protocol of various indocyanine green (ICG) concentrations/detection time windows for ICG-based OI of tumor cells (ICG cells); 2) using the optimized OI to evaluate ablation-heat effect on ICG cells; 3) building the interventional OI system and investigating its sensitivity for differentiating residual viable tumors from nonviable tumors; and 4) preclinically validating its technical feasibility for intraprocedural monitoring of radiofrequency ablations (RFAs) using animal models with orthotopic hepatic tumors. OI signal-to-background ratios (SBRs) among preablation tumors, residual, and ablated tumors were statistically compared and confirmed by subsequent pathology. The optimal dose and detection time window for ICG-based OI were 100 µg/mL at 24 h. Interventional OI displayed significantly higher fluorescence signals of viable ICG cells compared with nonviable ICG cells (189.3 ± 7.6 versus 63.7 ± 5.7 au, P < 0.001). The interventional OI could differentiate three definitive zones of tumor, tumor margin, and normal surrounding liver, demonstrating significantly higher average SBR of residual viable tumors compared to ablated nonviable tumors (2.54 ± 0.31 versus 0.57 ± 0.05, P < 0.001). The innovative interventional OI technique permitted operators to instantly detect residual tumors and thereby guide repeated RFAs, ensuring complete tumor eradication, which was confirmed by ex vivo OI and pathology. In conclusion, we present an interventional oncologic technique, which should revolutionize the current ablation technology, leading to a significant advancement in complete treatment of larger or irregular malignancies.

Effects of microwave ablation on cysts and cystic neoplasms with tissue-mimicking model: an ex vivo study.

BACKGROUND AND PURPOSE: Microwave ablation (MWA) is a promising modality that needs to be further investigated for cystic lesions. The present study aimed to determine the effects of MWA on cysts and cystic neoplasms with a tissue-mimicking model. METHODS: Twenty New Zealand White rabbits were randomly divided into Group A (cyst mimic models, n = 10, φ = 5 cm) and Group B (cystic neoplasm mimicking models, n = 10, φ = 5 cm). For each group, ex vivo rabbit healthy bladder and VX2-implanted tumor bladder were fixed and embedded in agarose gel to mimic cyst and cystic neoplasm. In the MWA experimental subgroups, microwave antennas guided by computed tomography (CT) were introduced into these models. A system thermometer was placed at the outer edge of the bladder wall to monitor temperature changes. Immediately after MWA, ex vivo rabbit healthy bladders and VX2-implanted tumor bladders were harvested for gross anatomy and prepared for pathological evaluation. RESULTS: A total of twenty cyst and cystic neoplasm mimicking models were successfully developed. Ninety percent of the MWA procedures were successful, and no peri-procedural complications were encountered. The temperature of the cystic wall increased with duration in both MWA experimental subgroups and an effective ablation temperature (>60 °C) was achieved. Pathological examination of the cyst and cystic neoplasm mimic models revealed degenerative necrosis of the bladder wall mucosal epithelial cells, loss of bladder wall tissue structure and coagulative necrosis of VX2 tumor cells. CONCLUSION: Our data indicate that MWA could cause thermal damage to the tissue structure of cyst and cystic neoplasm, and it is an effective technique for treating cystic diseases.HIGHLIGHTSex vivo rabbit healthy bladder and VX2-implanted tumor bladder were fixed and embedded in agarose gel to mimic cyst and cystic neoplasm.The temperature of the cystic wall increased with MWA duration and an effective ablation temperature (> 60 °C) was achieved.MWA could cause thermal damage to the tissue structure of the cyst and cystic neoplasm and it is effective in treating cystic diseases, as assessed by histopathology.

Renal and hepatic artery embolization with Pickering gel emulsion of lipiodol in rabbit.

OBJECTIVE: This research aimed to evaluate the feasibility of a novel liquid embolic agent Pickering gel emulsion of lipiodol (PGEL) for renal and hepatic artery embolization in the rabbit experimental model. METHODS: Embolization was performed in the right renal artery of 24 adult New Zealand White rabbits and 24 VX2 tumors in the left liver lobe. The rabbits were randomly allocated to four treatment groups (n = 6 per group): (A) normal saline (NS), (B) lipiodol, (C) 180-300 µm polyvinyl alcohol (PVA), and (D) PGEL. RESULTS: Renal artery embolization in normal rabbits and transarterial embolization (TAE) in VX2 tumor-bearing rabbits indicated that PGEL achieved a better embolization effect for a longer time than lipiodol and PVA. The tumor growth ratio of the PGEL group was significantly lower than that of the NS, lipiodol, and PVA groups at 3 (P < 0.001) and 7 (P < 0.001) days after embolization. In addition, hematoxylin and eosin and immunohistochemical staining revealed that the tumor necrosis ratio was higher in the PGEL group than in the NS, lipiodol, and PVA groups (P < 0.01), and the expression levels of HIF-1α, VEGF, and CD31 decreased after PGEL embolization compared with the lipiodol and PVA treatments. CONCLUSION: PGEL is an effective embolic material that provides immediate and total occlusion of the renal artery and may be a potential therapeutic embolic agent for TAE of HCC.

Pi-inducedin-situaggregation of sevelamer nanoparticles for vascular embolization.

Decades have witnessed rapid progress of polymeric materials for vascular embolic or chemoembolic applications. Commercially available polymeric embolics range from gelatin foam to synthetic polymers such as poly(vinyl alcohol). Current systems under investigation include tunable, bioresorbable microspheres composed of chitosan or poly(ethylene glycol) derivatives,in situgelling liquid embolics with improved safety profiles, and radiopaque embolics that are trackablein vivo. In this paper, we proposed a concept of 'responsive embolization'. Sevelamer, clinically proved as an inorganic phosphate binder, was ground into nanoparticles. Sevelamer nanoparticle is highly mobile and capable of swelling and aggregating in the presence of endogenous inorganic phosphate, thereby effectively occluding blood flow in the vessel as it was administered as an embolic agent for interventional therapy. Moreover, citrated sevelamer nanoparticles delayed the aggregation, preferable to penetrate deeply into the capillary system. On the rabbit VX2 liver cancer model, both sevelamer particles aggregates occlude the tumor feeding artery, but backflow was found for the pristine one, thereby citrate passivation of sevelamer nanoparticles endows it have potential from 'bench to bedside' as a new type of vascular embolic.

Cell-free DNA and circulating tumor cell kinetics in a pre-clinical head and neck Cancer model undergoing radiation therapy.

BACKGROUND: Monitoring circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), known as liquid biopsies, continue to be developed as diagnostic and prognostic markers for a wide variety of cancer indications, mainly due to their minimally invasive nature and ability to offer a wide range of phenotypic and genetic information. While liquid biopsies maintain significant promising benefits, there is still limited information regarding the kinetics of ctDNA and CTCs following radiation therapy which remains a vital treatment modality in head and neck cancers. This study aims to describe the kinetics of ctDNA and CTCs following radiation exposure in a preclinical rabbit model with VX2 induced buccal carcinoma. METHODS: Seven rabbits were inoculated with VX2 cells in the buccal mucosa and subjected to radiation. At selected time points, blood sampling was performed to monitor differing levels of ctDNA and CTC. Plasma ctDNA was measured with quantitative PCR for papillomavirus E6 while CTCs were quantified using an immunomagnetic nanoparticles within a microfluidic device. Comparisons of CTC detection with EpCAM compared to multiple surface markers (EGFR, HER2 and PSMA) was evaluated and correlated with the tumor size. RESULTS: Plasma ctDNA reflects the overall tumor burden within the animal model. Analysis of correlations between ctDNA with tumor and lymph node volumes showed a positive correlation (R = 0.452 and R = 0.433 [p < 0.05]), respectively. Over the course of treatment, ctDNA levels declined and quickly becomes undetectable following tumor eradication. While during the course of treatment, ctDNA levels were noted to rise particularly upon initiation of radiation following scheduled treatment breaks. Levels of CTCs were observed to increase 1 week following inoculation of tumor to the primary site. For CTC detection, the use of multiple surface markers showed a greater sensitivity when compared to detection using only EpCAM. Plasma CTC levels remained elevated following radiation therapy which may account for an increased shedding of CTCs following radiation. CONCLUSION: This study demonstrates the utility of ctDNA and CTCs detection in response to radiation treatment in a preclinical head and neck model, allowing for better understanding of liquid biopsy applications in both clinical practice and research development.

Development of a 3D-Printed Navigational Template for Establishing Rabbit VX2 Lung Cancer Model.

BACKGROUND: The CT-guided percutaneous puncture-inoculation for establishing the rabbit VX2 lung cancer model (LCM) is time-consuming, requires repeated CT scans, and has a high complication rate. Therefore, this study aimed to develop a navigational template using 3D technology to provide an alternative method for establishing the model with improved success and complication rates. MATERIALS AND METHODS: Ideal pressure was determined using chest CT data from 15 anesthetized rabbits fitted with sphygmomanometer cuff around their chests. Subsequently, a preliminary 3D template with a square window and cross-sign to facilitate precise installation was designed. Using another 20 rabbits fixed with the preliminary template, an ideal common puncture point and parameter were determined, a navigational tunnel was set up on the template surface, and the final puncture navigational template was printed out. Eight-four rabbits (42/group) were assigned to the experimental (template-guided puncture) and control (traditional puncutre) groups and underwent VX2 tumor-fragment inoculation to validate the template. Differences in various parameters between two groups were analyzed. RESULTS: The ideal pressure was 30 mmHg. All rabbits were inoculated successfully and the template adequately fit the rabbit chest. The experimental group displayed significantly better operation time (198.93±36.64 vs 735.14±91.19 seconds); number of CT scans (0 vs 7.19±1.64); pneumothorax (11.9% vs 35.7%), chest seeding (16.7% vs 35.7%), and mid-lung field tumor-bearing (88.1% vs 59.5%) rates than the control group (all, P <0.05). The groups did not differ in rib injury, tumor volume or survival time (all, P > 0.05). CONCLUSIONS: We successfully developed a puncture navigational template, providing an alternative method for establishing the rabbit VX2 LCM.

Imaging features of microwave-ablated lesions of the VX2 tumors in rabbit lungs on computed tomography and magnetic resonance images and their correlations with pathological examination.

PURPOSE: This study aimed to explore the accuracy of different imaging methods for lesion volume estimation pre- and post-microwave ablation (MWA) as compared with that of pathological examination. METHODS: We used the VX2 cell line to establish the VX2 lung tumor model in rabbits, followed by MWA of the tumor. The imaging features of the VX2 tumors were documented. The volume of the tumors and the ablated lesions were measured and compared across imaging methods, using the pathological examination as reference. RESULTS: Tumors were successfully developed in 11 rabbits (age, 13.91 ± 1.38 weeks; weight, 2.15 ± 0.56 kg). The mean volume of the tumors was 2.05 ± 1.88 cm3. CT showed the strongest correlation with the pathologic examination results (r = 0.998, p<.001). MWA created three-layered structures that were delineated on MRI. The mean volume of the post-ablation lesion was 10.39 ± 8.93 cm3, and the measurement of the post-ablation volume on 3D-VIBE-T1WI showed the strongest correlation with the pathologic examination results (r = 0.991, p<.001). CONCLUSION: Both CT and MRI are capable of depicting lung tumors. In terms of post-ablation evaluation, MR images could provide more versatile information. The 3D-VIBE-T1WI sequence provides more precise lesion volume evaluation after ablation compared with other methods.

Irreversible electroporation ablation against subcutaneously implanted VX2 tumors in rabbits: findings of shearwave ultrasound elastography.

PURPOSE: This study aimed to evaluate stiffness changes of rabbit subcutaneous VX2 tumors before and after irreversible electroporation (IRE) ablationby shearwave ultrasound elastography (SWE). METHODS: IRE was performed on 20 subcutaneously implanted VX2 tumors in rabbits (R-SIVX2). Tumor stiffness was measured by SWE at different time points (before IRE,120minutes after IRE,7 days after IRE and 14 days after IRE). RESULTS: Before IRE, the mean stiffness (Emean) of tumors was (10.45 ± 1.07) KPa. 120 minutes after I RE, the Emean of tumors obviously rose to (70.53 ± 9.87) KPa. 7 days after IRE, the Emean of tumors decreased to (40.22 ± 9.01) KPa. 14 days after IRE, the Emean of tumors was (15.17 ± 1.00) KPa. A clear boundary was observed between the ablation area and the normal tissues in the pathological results. CONCLUSIONS: The stiffness of the VX2 tumors experienced a first rise process and tend to be normal in the procedure of IRE. SWE could provide tissue stiffness information of different IRE ablation period as a non-invasive method.

Pictorial Imaging-Histopathology Correlation in a Rabbit with Hepatic VX2 Tumor Treated by Transarterial Vascular Disrupting Agent Administration.

Cancer vasculature is immature, disorganized and hyperpermeable and can serve as a target for anti-cancer therapies. Vascular disrupting agents (VDAs) are tubulin protein binding and depolymerizing agents that induce rapid tumoral vascular shutdown and subsequent cancer necrosis. However, two clinical problems exist with all VDAs, i.e. 1) incomplete anticancer effect and 2) dose-dependent toxicity. To tackle these problems, in our ongoing research, a novel VDA C118P is applied by transarterial administration of half the intravenous dose in rabbits with implanted VX2 liver tumor to assess its therapeutic efficacy. Nearly complete tumor necrosis was achieved by only a single arterial dose of C118P at 5 mg/kg, which was documented in a representative case by in vivo digital subtraction arteriogram (DSA) and magnetic resonance imaging (MRI), and further confirmed by ex vivo microangiogram and histopathology. This convincing and promising preliminary outcome would warrant further comprehensive studies to explore the potentials of VDAs by transarterial administration either in mono-drug or in combination for management of solid cancers.

Combined microwave ablation and antiangiogenic therapy to increase local efficacy.

Purpose: We aim to evaluate the efficacy, safety and survival time of microwave ablation (MWA) with adjuvant antiangiogenic therapy-endostatin in animal models.Material and methods: A total of 40 rabbits successfully implanted with VX2 tumors were randomly assigned to four experimental groups: Group A underwent only microwave ablation of the tumors; Group B received only antiangiogenic drugs endostatin; Group C received endostatin immediately after MWA; Group D followed up without treatment.Results: Two months post-treatment, tumor sizes of Group A and Group C were reduced to 1.936 ± 0.373 cm3 and 1.592 ± 0.382 cm3, respectively. However, tumors grew to 15.091 ± 1.735 cm3 and 47.825 ± 7.664 cm3 in Group B and the control group. Three months post-treatment, tumor sizes in Group A and Group C maintained as 1.395 ± 0.394 cm3 and 1.482 ± 0.305 cm3, significantly smaller than Group B (35.277 ± 6.019 cm3). All animals in the control group died, while four (40%) survived in Group B (Endo Group). The numbers of survivals in Groups A and C were seven (70%) and eight (80%), respectively. The lowest metastasis rate (2/10, 20%) was observed in Group C (combination therapy).Conclusion: The combination of MWA and antiangiogenic therapy triggered a significant reduction in the growth rate and metastases of tumors and may potentially improve survivals.

Synergism of wt-p53 and synthetic material in local nano-TAE gene therapy of hepatoma: comparison of four systems and the possible mechanism.

BACKGROUND: TAE-gene therapy for hepatoma, incorporating the tumor-targeted therapeutic efficacy of trans-arterial embolization, hydroxyapatite nanoparticles (nHAP) and anti-cancer wild-type p53 gene (wt-p53), was presented in our former studies (Int J Nanomedicine 8:3757-68, 2013, Liver Int 32:998-1007, 2012). However, the incompletely antitumoral effect entails defined guidelines on searching properer materials for this novel therapy. METHODS: Unmodified nHAP, Ca(2+) modified nHAP, poly-lysine modified nHAP and liposome were separately used to form U-nanoplex, Ca-nanoplex, Pll-nanoplex, L-nanoplex respectively with wt-p53 expressing plasmid. The four nanoplexs were then applied in vitro for human normal hepacyte L02 and hepatoma HePG2 cell line, and in vivo for rabbits with hepatic VX2 tumor by injection of nanoplexs/lipiodol emulsion into the hepatic artery in a tumor target manner. The distribution, superficial potential, physical structure, morphology and chemical compositions of nanoplexs were evaluated by TEM, SEM, EDS etc., with the objective of understanding their roles in hepatoma TAE-gene therapy. RESULTS: In vitro, L-nanoplex managed the highest gene transferring efficiency. Though with the second highest transfection activity, Pll-nanoplex showed the strongest tumor inhibition activity while maintaining safe to the normal hepacyte L02. In fact, only Pll-nanoplex can combine both the antitumoral effect to HePG2 and safe procedure to L02 among the four systems above. In vivo, being the only one with successful gene transference to hepatic VX2 tumor, Pll-nanoplex/lipiodol emulsion can target the tumor more specifically, which may explain its best therapeutic effect and hepatic biologic response. Further physical characterizations of the four nanoplexs suggested particle size and proper electronic organic surface may be crucial for nano-TAE gene therapy. CONCLUSION: Pll-nanoplex is the most proper system for the combined therapy due to its selectively retention in liver cancer cells, secondary to its morphological and physico-chemical properties of nanometric particle size, steady emulsion, proper organic and electronic surface.

Evaluation of the MR and pathology characteristics immediately following percutaneous MR-guided microwave ablation in a rabbit kidney VX2 tumor implantation model.

Purpose: This study aimed to evaluate the immediate efficacy of magnetic resonance (MR)-guided microwave ablation (MWA) in rabbit kidneys implanted with VX2 tumors.Materials and methods: MR-guided MWA was performed in eight VX2 tumor-bearing rabbits. MR images after ablation were obtained and analyzed. The differences between the tissue specimens and MR images obtained after ablation were compared.Results: On the three-dimensional volumetric interpolated breath-hold T1-weighted (3D-VIBE-T1WI) sequence, a low signal intensity indicated the primary tumor at the center of the ablation area, which was surrounded by a peripheral high-signal area. The signal for the primary tumor in the fast spin-turbo spin-echo T2-weighted (FS-TSE-T2WI) sequence was lower than before, and the ablation zone showed a low signal that completely covered the primary tumor. There was no significant difference in volume among the low-signal areas of the primary tumor on FS-TSE-T2WI before MWA, the central low-signal area on 3D-VIBE-T1WI after MWA, and the tumor coagulation necrosis area on the tissue specimens (p > 0.05). No significant difference was found in the volume of ablation zones among the tissue specimens, the high-signal area around the lesion on the 3D-VIBE-T1WI sequence, and the low-signal area covering the lesion on the FS-TSE-T2WI sequence (p > 0.05).Conclusion: Magnetic resonance imaging (MRI) is an effective method for immediate efficacy evaluation of rabbit renal VX2 tumors after MWA and can serve as a valuable reference for the clinical assessment of post-ablative renal tumors.

Perfusion Computer Tomography Assessment of the Effect of Angiotensin II On Blood Flow Distribution in Rabbits with Intrarenal VX2 Tumors.

BACKGROUND/AIMS: Unlike other organs, which only have one set of capillary network, the renal microvasculature consists of two sets of capillary network series connected by efferent arterioles. Angiotensin II constricts the efferent glomerular artery. Hence, renal tumor blood flow (BF) distribution may be different from tumors in other organs. This study aims to investigate the effects of angiotensin II on the hemodynamics of intrarenal VX2 tumors using perfusion computed tomography(CT). METHODS: Twenty-four male New Zealand white rabbits were randomly divided into three groups: groups A (blank controls), group B (negative controls), and group C (angiotensin II-treated animals). Group B and C were established to the model of intrarenal VX2 tumors. Furthermore, perfusion CT of the kidney was performed in each group. Prior to perfusion CT scan in group C, the mean arterial blood was elevated to 150-160 mmHg by angiotensin II. The BF, blood volume (BV), mean transit time (MTT), capillary permeability-surface area product (PS), and relative permeability-surface area product (RPS) of tumors and renal tissues were calculated. RESULTS: Compared with normal renal cortex tissues in group A, the BF, BV and PS values of tumors in group B were significantly lower, MTT was prolonged and RPS increased. Compared with group B, only the RPS of these tumors increased from 83.23 ± 29.17% to 120.94 ± 31.84% by angiotensin II infusion. Angiotensin II significantly increased the RPS value of the renal cortex distant from the tumor (CDT) and the right renal cortex (RRC). CONCLUSIONS: Perfusion CT can accurately observe the influence of angiotensin II on normal and tumor BF in kidneys. This clarifies the effect of angiotensin II on intrarenal tumor hemodynamics.

Combination therapy comprising irreversible electroporation and hydroxycamptothecin loaded electrospun membranes to treat rabbit VX2 subcutaneous cancer.

Irreversible electroporation (IRE) is a kind of promising cancer treatment technology. However, local recurrence still occurs because of incomplete ablation. The aim of this study was to investigate the combined therapy of IRE and a hydroxycamptothecin loaded electrospun membrane (EM/HCPT) to treat rabbit VX2 subcutaneous cancer. HCPT loaded membranes were developed by electrospinning. Mechanical test and in vitro drug release study of EM/HCPT were performed. 24 rabbits with subcutaneous VX2 tumor were randomly divided into four groups: the control group, the EM/HCPT group, the IRE ablation group, and the IRE + EM/HCPT group. The tumor cells were ablated by IRE first, followed by subcutaneous implantation of EM/HCPT to release HCPT constantly in order to damage the residual cancer cells. The tumor inhibition efficacy was assessed by the tumor real-time monitoring, histological and immunofluorescent analyses, and transmission electron microscopy (TEM) examination. Assessment of the release from EM/HCPT showed that HCPT release lasted for about 7 days. The in vivo antitumor efficacy assessment, histological and immunofluorescent analyses, and TEM examination showed that IRE + EM/HCPT had the best tumor inhibition ability. In addition, the biochemical analyses and hematoxylin and eosin (H&E) staining of normal organs indicated that IRE + EM/HCPT treatment was safe. Our study provided a new concept in cancer treatment and might promote the application of IRE.

Establishment and evaluation of the VX2 orthotopic lung cancer rabbit model: a ultra-minimal invasive percutaneous puncture inoculation method.

The purpose of the present work is to establish an ultra-minimal invasive percutaneous puncture inoculation method for a VX2 orthotopic lung cancer rabbit model with fewer technical difficulties, lower mortality of rabbits, a higher success rate and a shorter operation time, to evaluate the growth, metastasis and apoptosis of tumor by CT scans, necropsy, histological examination, flow cytometry and immunohistochemistry. The average inoculation time was 10-15 min per rabbit. The tumor-bearing rate was 100%. More than 90% of the tumor-bearing rabbits showed local solitary tumor with 2-10 mm diameters after two weeks post-inoculation, and the rate of chest seeding was only 8.3% (2/24). The tumors diameters increased to 4-16 mm, and irregularly short thorns were observed 3 weeks after inoculation. Five weeks post-inoculation, the liquefaction necrosis and a cavity developed, and the size of tumor grew further. Before natural death, the CT images showed that the tumors spread to the chest. The flow cytometry and immunohistochemistry indicated that there was less apoptosis in VX2 orthotopic lung cancer rabbit model compared to chemotherapy drug treatment group. Minimal invasive percutaneous puncture inoculation is an easy, fast and accurate method to establish the VX2 orthotopic lung cancer rabbit model, an ideal in situ tumor model similar to human malignant tumor growth.

Laparoscopic subperitoneal injection of chemo-loaded particles lowers tumor growth on a rabbit model of peritoneal carcinomatosis.

The purpose of our study was to assess the effect of controlled-release chemotherapy on the growth and viability of peritoneal carcinomatosis treated by subperitoneal injection in a rabbit VX2 model. A model of peritoneal carcinomatosis was created by laparoscopic injection of VX2 tumor in the left and right broad ligaments of 12 White New Zealand rabbits. At day 12, each tumor was randomly treated with a peritumoral injection of 0.5 mL microspheres loaded with doxorubicin (DEM-DOX) or unloaded (DEM-BLAND). Seven days after treatment, tumor volume, tumor viability in histology, local tumor necrosis in contact with DEM, and doxorubicin concentration profile around the drug eluting microspheres (DEM) were measured. Tumor volume was significantly lower in the DEM-DOX group (3.6 ± 3.2 cm3) compared with the DEM-BLAND group (8.9 ± 5.4 cm3) (p = 0.0425). The percentage of viable tumor tissue was significantly lower in the DEM-DOX group (38% ± 17%) compared with the DEM-BLAND group (56% ± 20%) (p = 0.0202). Tissue necrosis was observed around all DEM-DOX up to a distance of 1.094 ± 0.852 mm and never observed around DEM-BLAND. Drug concentration was above the therapeutic level of 1.0 µM up to a distance of 1.4 mm from the DEM to the tumor. Laparoscopic subperitoneal injection of chemo-loaded particles is feasible and lowers tumor growth and viability in a rabbit model of peritoneal carcinomatosis after 1 week.

Targeted Yttrium 89-Doxorubicin Drug-Eluting Bead-A Safety and Feasibility Pilot Study in a Rabbit Liver Cancer Model.

The purpose of this article is to evaluate feasibility and safety of the cancer targeting (radio)-chemoembolization drug-eluting bead (TRCE-DEB) concept drug SW43-DOX-L-NETA(89Y) DEB for the intra-arterial treatment of VX2 rabbit liver tumors. The treatment compound comprises of the sigma-2 receptor ligand SW43 for cancer targeting, doxorubicin (DOX), and 89yttrium (89Y) as nonradioactive surrogate for therapeutic (yttrium-90, lutetium-177) and imaging (yttrium-86) radioisotopes via the chelator L-NETA. Ten New Zealand white rabbits with VX2 tumor allografts were used. SW43-DOX-89Y was synthesized, loaded onto DEB (100 µL; 100-300 µm), and administered intra-arterially in six rabbits at increasing doses (0.2-1.0 mg/kg). As controls, two rabbits each received either doxorubicin IV (0.3 mg/kg) or no treatment. Consecutive serum analysis for safety and histopathological evaluation after sacrifice were performed. One-Way ANOVA incl. Bonferroni Post-Hoc test was performed to compare groups. Targeted compound synthesis, loading onto DEB, and intra-arterial administration were feasible and successful in all cases. Serum liver enzyme levels increased in a dose dependent manner within 24 h and normalized within 3 days for 0.2/0.6 mg/kg SW43-DOX-89Y loaded onto DEB. The two rabbits treated with 1 mg/kg SW43-DOX-89Y had to be euthanized after 3/24 h due to worsening general condition. Histopathological necrosis increased over time in a dose depended manner with 95-100% tumor necrosis 3-7 days post treatment (0.6 mg/kg). SW43-DOX-89Y loaded onto DEB can be formulated and safely administered at a concentration of 0.6 mg/kg. Loading with radioactive isotopes (e.g., 86yttrium/90yttrium/177lutetium) to synthesize the targeted radio-chemoembolization drug-eluting bead (TRCE-DEB) concept drug is feasible.

Measurement of pO2 in a Pre-clinical Model of Rabbit Tumor Using OxyChip, a Paramagnetic Oxygen Sensor.

The objective of this work was to establish a novel and robust technology, based on electron paramagnetic resonance (EPR) oximetry, as a practical tool for measurement of tumor oxygen. Previously, we have reported on the development of oxygen-sensing paramagnetic crystals (LiNc-BuO) encapsulated in a biocompatible polymer, called OxyChip. In this report we present our recent data on the use of OxyChip for pO2 measurements in the tumor of a pre-clinical, large-animal rabbit model. The results establish that OxyChip is capable of noninvasive and repeated measurement of pO2 in a large animal model.

Doxorubicin nanobubble for combining ultrasonography and targeted chemotherapy of rabbit with VX2 liver tumor.

A new class of multifunctional nanobubble using poly(lactic-co-glycolic acid) (PLGA) has been developed as ultrasound imaging contrast agents, doxorubicin carriers, and enhancers of ultrasound-mediated drug delivery. The doxorubicin nanobubble (DOX-NB) wrapping carbon tetrafluoride gas was prepared with double emulsion method. We evaluated the enhanced ultrasonic function of the DOX-NB in vivo; its antitumor function was confirmed. The diameter of the prepared bubble was 500 nm, and the potential was -23 mV. The drug loading and encapsulation efficiency of the bubble were 78.6 and 7.4 %, respectively. Therefore, the DOX-NB greatly enhanced ultrasound imaging in vivo. Ultrasound combined with DOX-NB had significant antitumor effect. Compared with other groups, the tumor growth rate and the proliferation index were the lowest while the survival rate and apoptosis index were the highest.

Intravoxel incoherent motion diffusion-weighted MRI for characterizing regional variability and monitoring serial changes of parameters in rabbit VX2 liver tumors.

PURPOSE: To characterize intravoxel incoherent motion (IVIM) parameters in different regions of interest (ROIs) of rabbit VX2 liver tumors during a follow-up of 4 weeks. MATERIALS AND METHODS: This study was approved by the Institutional Animal Care and Use Committee. In 18 VX2 liver tumor-bearing rabbits, IVIM DW imaging was serially performed at the 2nd, 3rd, and 4th week separately after tumor implantation at 1.5T by using 12 b values. Three ROIs were drawn on the apparent diffusion coefficient (ADC) maps, including the whole lesion, the visibly most restricted diffusion area (MRDA), and peripheral area of tumor. For each ROI of tumors, serial changes in ADC and D, D*, and f at three timepoints were calculated. The differences of IVIM parameters in different ROIs of tumors at each timepoint were compared. RESULTS: Serial measurements of f in all three ROIs (P = 0.000, P = 0.002, and P = 0.000), ADC for the whole lesion, MRDA (P = 0.000 and P = 0.024), and D for MRDA (P = 0.001) from the 2nd to 4th week illustrated a statistical difference. The overall comparison of ADC (P = 0.000, P = 0.014, and P = 0.000), D (P = 0.000, P = 0.001, and P = 0.000), and f (P = 0.001, P = 0.001, and P = 0.000) for three tumor regions at weeks 2, 3, and 4 showed significant differences. D* in all three ROIs at each timepoint showed no significant differences (P = 0.612, P = 0.723, and P = 0.699; 95% confidence interval: 0.184-0.950). CONCLUSION: The peripheral area of tumor could be used as an alternative to the whole lesion as ROIs to assess the VX2 liver tumor with IVIM DW imaging, and in the period between weeks 2 and 3.