Anti-MAdCAM-1-Conjugated Nanocarriers Delivering Quantum Dots Enable Specific Imaging of Inflammatory Bowel Disease

Marta Truffi,1 Marta Sevieri,2 Lucia Morelli,3 Matteo Monieri,2 Serena Mazzucchelli,2 Luca Sorrentino,2 Raffaele Allevi,2 Arianna Bonizzi,2 Pietro Zerbi,2 Beatrice Marchini,2 Erika Longhi,2 Gianluca Matteo Sampietro,4 Francesco Colombo,4 Davide Prosperi,3 Miriam Colombo,3 Fabio Corsi2,5 1Nanomedicine and Molecular Imaging Laboratory, Istituti Clinici Scientifici Maugeri IRCCS, Pavia 27100, Italy; 2Department of Biomedical and Clinical Sciences “Luigi Sacco, Università degli studi di Milano, Milano, 20157, Italy; 3NanoBioLab, Department of Biotechnology and Biosciences, Università degli studi di Milano-Bicocca, Milano, 20126, Italy; 4IBD Surgery Unit, ASST Fatebenefratelli Sacco - Ospedale “Luigi Sacco” Polo Universitario, Milano, 20157, Italy; 5Surgery Department, Breast Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, 27100, ItalyCorrespondence: Fabio CorsiSurgery Department, Breast Unit, Istituti Clinici Scientifici Maugeri IRCCS, via Maugeri 4, Pavia 27100, ItalyTel +39 02 5031 9850Fax +39 02 5031 9846Email fabio.corsi@icsmaugeri.itPurpose: Assessment of inflammatory bowel disease (IBD) currently relies on aspecific clinical signs of bowel inflammation. Specific imaging of the diseased bowel regions is still lacking. Here, we investigate mucosal addressin cell adhesion molecule 1 (MAdCAM-1) as a reliable and specific endothelial target for engineered nanoparticles delivering imaging agents to obtain an exact mapping of diseased bowel foci.Materials and Methods: We generated a nanodevice composed of PLGA-PEG coupled with anti-MAdCAM-1 antibody half-chains and loaded with quantum dots (P@QD-MdC NPs). Bowel localization and systemic biodistribution of the nanoconjugate were analyzed upon injection in a murine model of chronic IBD obtained through repeated administration of dextran sulfate sodium salt. Specificity for diseased bowel regions was also assessed ex vivo in human specimens from patients with IBD. Potential for development as contrast agent in magnetic resonance imaging was assessed by preliminary study on animal model.Results: Synthesized nanoparticles revealed good stability and monodispersity. Molecular targeting properties were analyzed in vitro in a cell culture model. Upon intravenous injection, P@QD-MdC NPs were localized in the bowel of colitic mice, with enhanced accumulation at 24 h post-injection compared to untargeted nanoparticles (p< 0.05). Nanoparticles injection did not induce histologic lesions in non-target organs. Ex vivo exposure of human bowel specimens to P@QD-MdC NPs revealed specific recognition of the diseased regions vs uninvolved tracts (p< 0.0001). After loading with appropriate contrast agent, the nanoparticles enabled localized contrast enhancement of bowel mucosa in the rectum of treated mice.Conclusion: P@QD-MdC NPs efficiently detected bowel inflammation foci, accurately following the expression pattern of MAdCAM-1. Fine-tuning of this nanoconjugate with appropriate imaging agents offers a promising non-invasive tool for specific IBD diagnosis.Keywords: polymeric nanoparticles, inflamed bowel, adhesion molecule, targeted imaging