Pancreatic tumors can be resistant to drug penetration due to high interstitial fluid pressure, dense stroma, and disarrayed vasculature. Ultrasound-induced cavitation is an emerging technology that may overcome many of these limitations. Low-intensity ultrasound, coupled with co-administered cavitation nuclei consisting of gas-stabilizing sub-micron scale SonoTran Particles, is effective at increasing therapeutic antibody delivery to xenograft flank tumors in mouse models. Here, we sought to evaluate the effectiveness of this approach in situ using a large animal model that mimics human pancreatic cancer patients. Immunocompromised pigs were surgically engrafted with human Panc-1 pancreatic ductal adenocarcinoma (PDAC) tumors in targeted regions of the pancreas. These tumors were found to recapitulate many features of human PDAC tumors. Animals were intravenously injected with the common cancer therapeutics Cetuximab, gemcitabine, and paclitaxel, followed by infusion with SonoTran Particles. Select tumors in each animal were targeted with focused ultrasound to induce cavitation. Cavitation increased the intra-tumor concentrations of Cetuximab, gemcitabine, and paclitaxel by 477%, 148%, and 193%, respectively, compared to tumors that were not targeted with ultrasound in the same animals. Together, these data show that ultrasound-mediated cavitation, when delivered in combination with gas-entrapping particles, improves therapeutic delivery in pancreatic tumors under clinically relevant conditions.

Genetic modification of genes such as recombination activating gene 2 (RAG2) or interleukin-2 receptor-γ (IL2RG) results in pigs exhibiting severe combined immunodeficiency (SCID). Pigs presenting a SCID phenotype are important animal models that can be used to establish xenografts and to study immune system development and various immune-related pathologies. However, due to their immunocompromised nature, SCID pigs have shortened lifespans and are notoriously difficult to maintain. The failure-to-thrive phenotype makes the establishment of a breeding population of RAG2/IL2RG double-knockout pigs virtually impossible. Here, to overcome this limitation, we investigated whether reconstituting the immune system of SCID piglets with a fetal bone allograft would extend their lifespan. Following intramuscular transplantation, allografts gave rise to lymphocytes expressing T cell (CD3, CD4 and CD8), B cell (CD79α) and natural killer cell (CD335) lineage markers, which were detected in circulation as well in the spleen, liver, bone marrow and thymic tissues. The presence of lymphocytes indicates broad engraftment of donor cells in the recipient SCID pigs. Unlike unreconstituted SCID pigs, the engrafted animals thrived and reached puberty under standard housing conditions. This study demonstrates a novel method to extend the survival of SCID pigs, which may improve the availability and use of SCID pigs as a biomedical animal model.

In a groundbreaking study recently published in Nature, Kai-Shan Tao and colleagues achieved the first successful heterotopic pigto-human liver xenotransplantation using a gene-edited Bama miniature pig carrying six targeted genetic modifications designed to suppress immunologic rejection and thrombosis. 1 The ability of the graft to maintain bile secretion, albumin synthesis, and histological integrity over 10 days in a brain-dead human recipient underscores the potential of xenotransplantation as a viable solution to the global shortage of donor livers for patients with acute or end-stage liver failure. 1 Central to the success of this approach was the precise engineering of the donor pig's genome. Researchers eliminated three major xenoantigen genes (GGTA1, CMAH, and B4GALNT2) encoding glycan epitopes widely recognized by human natural antibodies, effectively preventing hyperacute rejection. Simultaneously, three human transgenes (CD46, CD55, and hTHBD) were integrated to enhance complement regulation and minimize thrombosis. These combined modifications created a safer immunological and hemodynamic environment for the xenograft. The clinical protocol featured a heterotopic auxiliary liver transplantation technique, in which the porcine liver was implanted without removing the native human liver. This allowed careful monitoring of graft performance while minimizing surgical risks. Preoperative imaging ensured alignment of the porcine portal vein and hepatic artery with the recipient's vasculature, guaranteeing functional blood flow. Postoperatively, bile was diverted externally for direct measurement of secretory capacity. Within just 2 h of reperfusion, the graft began secreting bile-a reliable early indicator of hepatic viability. Throughout the 10-day period, the graft continuously secreted bile, indicating preserved exocrine capability (Fig. 1). Concurrently, metabolic activity was demonstrated through steadily increasing porcine-derived albumin levels in the recipient's circulation, confirming active hepatic protein synthesis. Serum biomarkers of liver injury remained largely stable, aside from a transient spike in aspartate aminotransferase (AST) shortly after transplantation. The authors suggested that the AST elevation could be cardiac in origin, partly supported by simultaneous rises in cardiac enzyme markers. Later increases in bilirubin and γ-glutamyl transpeptidase likely mirrored mild cholestatic changes in the native liver rather than the xenograft. These findings collectively indicated that the pig liver maintained structural and metabolic integrity without pronounced hepatocellular damage.

Jisoo Park, Hyebin Koh, Eunsu Jeon, Kyungjun Uh, Sangjune Kim, Jong-Hee Lee. IJSC -0001;0:. https://doi.org/10.15283/ijsc25020