Local injection of anti-cancer drugs in an experimental model of colorectal cancer

Purpose: Endoscopic resection of colorectal lesions significantly decreases the risk of colorectal cancer (CRC) incidence and death. Patients with invasive neoplasia or metastatic CRC have an evident poorer prognosis. Next step could be a more personalized treatment strategy, as a targeted therapy by direct injection of active substances in a selected lesion. The aim was to evaluate the efficacy of intratumoral injection of a drug-eluting platform (CoverGel) with different anti-cancer drugs in a rat model of azoxymethane (AOM)-induced CRC. Methods: Experimental CRC was induced in 20 rats. Animals were randomized in five groups (four each): CoverGel + Aflibercept (AFL), CoverGel + Bevacizumab (BVZ), CoverGel + Cetuximab (CTX), CoverGel + Panitumumab (PNT) and CoverGel + Irinotecan (IRT). Endoscopic, histological and necrosis score (0-3 scale) test were performed during follow-up to evaluate clinical success. Results: All animals developed invasive neoplasia (NICE 3, JNET 3), 7.2 mm as mean size (range 6 - 8). Intratumoral injection was feasible in all animals with no adverse events. AFL, an angiogenesis inhibitor agent, in comparison with the other medications (BVZ, CTX, PNT and IRT) obtained the best results: significantly reduction in tumor size (-30% vs. -10%, -3%, +2% and + 2%; p < 0.05, respectively) and significantly higher necrosis score (3 vs. 1, 0.3, 0 and 0; p < 0.05, respectively). Conclusion: Angiogenesis inhibitors medications produced the higher cell necrosis and reduction in tumor size in an experimental model of CRC. Intratumoral injection of a drug-eluting platform could open a new way to manage invasive CRC.Medicin

Comparative study of electrical and rheological properties of different solutions used in endoscopic mucosal resection

Background and Aim: The study of electrical and rheological properties of solutions to carry out endoscopic resection procedures could determinate the best candidate. An ex vivo study with porcine stomachs was conducted to analyze electrical resistivity (R) and rheological properties (temperature, viscosity, height and lasting of the cushion) of different substances used in these techniques. Methods: Tested solutions were: 0.9% saline (S), platelet-rich plasma (PRP), Gliceol (GC), hyaluronic acid 2% (HA), Pluronic-F127 20% (PL), saline with 10% glucose (GS), Gelaspan (GP), Covergel-BiBio (TB) and PRP with TB (PRP+TB). Measurements of electrical and rheological properties were done at 0, 15, 30, 45 and 60 min after submucosal injection. Results: Solutions showed a wide variability of transepithelial R after submucosal injection. Substances able to maintain the highest R 60 min postinjection were TB (7 × 10 Ω), HA (7 × 10 Ω) and PL (7 × 10 Ω). Protective solutions against deep thermal injury (Tª lower than 60°C) were PL (47.6°C), TB (55°C) and HA (56.63°C). Shortest time to carry out resections were observed with GC (17.66″), PRP (20.3″) and GS (23.45″). Solutions with less cushion decrease (<25%) after 60 min were TB (11.74%), PL (18.63%) and PRP (22.12%). Conclusions: Covergel-BiBio, PL and HA were the best solutions with long-term protective effects (transepithelial R, lower thermal injury and less cushion decrease). Solutions with quicker resection time were GC, PRP and GS

Development and characterization of a new endoscopic drug-eluting platform with proven efficacy in acute and chronic experimental colitis

[Background and Aims]: Mucosal lesions refractory to biological treatments represent unmet needs in patients with inflammatory bowel disease (IBD) that require new treatment modalities. We developed and characterized a new endoscopic drug-eluting hydrogel (CoverGel) with proven efficacy in acute and chronic experimental colitis (EC) in rats.[Methods]: CoverGel was developed based on appropriate rheological, drug release, gelation, structural, and degradation property capacities to allow endoscopic application. Experimental colitis (EC) was induced by TNBS application in rats. In acute EC 40, rats were randomized in five groups (eight each): Sham, Control, CoverGel, CoverGel + Infliximab (IFX) and CoverGel + Vedolizumab (VDZ). In chronic EC, 12 rats were randomized in two groups (six each): IFX s.c. and CoverGel + IFX. Endoscopic, histological, and blood test were performed during follow-up to evaluate clinical success. Antibodies to IFX (ATIs) were evaluated in chronic EC animal study.[Results]: CoverGel is a biocompatible and bioadhesive reverse thermosensitive gelation hydrogel with a macroporous structure and drug release capacity. In acute EC animals treated with CoverGel + IFX or CoverGel + VDZ showed significantly clinical success (weight recovery, mucosal restoration, and bacterial translocation) as compared with controls and animals without a bioactive drug. In a chronic EC animal study, clinical efficacy was comparable in both groups. Levels of ATIs were significantly lower in animals treated with CoverGel + IFX vs. IFX s.c. (0.90 ± 0.06 μg/mL-c vs. 1.97 ± 0.66 μg/mL-c, p = 0.0025).[Conclusions]: CoverGel is an endoscopic vehicle to locally deliver biological drugs with proven efficacy in acute and chronic EC in rats and induce less immunogenicity reaction.This work was supported by project PI16/01928 given to VL-Z by the Health Institute Carlos III www.isciii.es and by the XIV GETECCU-Otsuka award given to VL-Z by the Spanish group for the study of Crohn and ulcerative colitis www.geteccu.org. ICN2 (MC-S) was supported by the Severo Ochoa program from Spanish MINECO (Grant No. SEV-2017-0706) www.mineco.gob.es.Peer reviewe

Rat CCl4-induced cirrhosis plus total portal vein ligation: A new model for the study of hyperammonaemia and brain oedema

Introduction: Animal models used to study hyperammonaemic disorders related to chronic liver disease are unsatisfactory. These animals only develop hyperammonaemia and brain oedema when fed with diets supplemented with amonium acetate. Aim: To develop a novel experimental model of hyperammonaemia and brain oedema in CCl4-induced cirrhosis in rats. Methods: Four groups were studied: rats with sham intervention (S), rats with total portal vein ligation (TPVL), cirrhotic rats (LC), and cirrhotic rats with TPVL (LC+TPVL). When ascites was diagnosed, oral glutamine challenge (OGC) test was performed. Blood, liver, lungs and brain samples were collected to quantify liver function parameters, plasmatic and cerebral ammonia, endotoxaemia, liver and brain histology, brain oedema and portosystemic shunting degree. Results: LC+TPVL rats showed a significant increase in portosystemic shunting when compared with LC group and a significant derangement in liver function when compared with TPVL group. These alterations resulted in a significant increase in plasmatic and brain ammonia concentrations and a higher plasmatic endotoxaemia as compared with others. Similarly, the area under OGC curve was significantly increased in LC+TPVL group as compared with the others, and correlates with portal shunting. Low-grade brain oedema was only observed in LC+TPVL group. All cirrhotic groups showed liver regeneration nodules and type-II Alzheimer astrocytes. Conclusion: LC+TPVL reproduce the main alterations - portosystemic shunting, plasmatic and cerebral hyperammonaemia and low-grade brain oedema - observed in cirrhotic patients with hepatic encephalopathy. © 2010 John Wiley & Sons A/S.This study has been supported by a grant from the Fondo de Investigaciones Sanitarias (Instituto de Salud Carlos III, FIS 051371). Ciberehd is funded by the Instituto de Salud Carlos III.Peer Reviewe