Hybrid Dextran-gadolinium Nano-suitcases as High-relaxivity MRI Contrast Agents

Dextran-poly（glycidyl methacrylate） （Dex-PGMA） nano-suitcases were synthesized efficiently via a graft copolymerization induced self-assembly （GISA） approach. On this basis, the Dex-PGMA nano-suitcases were modified with hydrazide, and the attachment of multiple chelated Gd（III） ions to the interior of the nano-suitcases affords nanoscale MRI contrast agents with high relaxivity values. The highly fenestrated dextran shell of the nano-suitcases assures water exchange which readily occurs between the surrounding environment and the Gd（III） ions encapsulated within the hybrid nano-suitcases. The complexation between the hydrophilic hydrazide interior of the nano-suitcases and Gd（III） ions results in an impressive Gd payload at 22.6 wt% in the hybrid nano-suitcases. The longitudinal relaxivity （rl） of the hybrid nano-suitcases is reported as 44.4 L/（mmol-s）, which is 9-14 folds of that of commercial Gd-DTPA agents. In vivo MRI studies demonstrate that the hybrid nano-suitcases accumulated in the lymph node of the rat due to their nanoscale dimensions and displayed strong signals in vivo. The results indicated that the hybrid nano-suitcases provide a promising platform for the diagnosis of lymph node related diseases.

Therapeutic targeting miR130b counteracts diffuse large B-cell lymphoma progression via OX40/OX40L-mediated interaction with Th17 cells

MicroRNAs(miRNAs)are involved in lymphoma progression by regulating the tumor microenvironment.Serum miR130b is overexpressed in diffuse large B-cell lymphoma(DLBCL),inducing Th17 cell alterations.To further illustrate its biological significance and therapeutic rationale,miR130b was detected by quantitative real-time PCR in the serum samples of 532 newly diagnosed DLBCL patients.The mechanism of miR130b on lymphoma progression and the tumor microenvironment was investigated both in vitro and in vivo.Therapeutic targeting miR130b was also evaluated,including OX40 agonistic antibody and lipid nanoparticles(LNPs)-miR130b antagomir.The results showed that serum miR130b significantly correlated with tumor miR130b and serum interleukin-17,indicating lymphoma relapse and inferior survival of DLBCL patients.MiR130b overexpression altered tumor microenvironment signaling pathways and increased Th17 cell activity.As mechanism of action,miR130b downregulated tumor OX40L expression by directly targeting IFNAR1/p-STAT1 axis,recruiting Th17 cells via OX40/OX40L interaction,thereby promoting immunosuppressive function of Th17 cells.In co-culture systems of B-lymphoma cells with immune cells,miR130b inhibited lymphoma cell autophagy,which could be counteracted by OX40 agonistic antibody and LNPs-miR130b antagomir.In murine xenograft model established with subcutaneous injection of A20 cells,both OX40 agonistic antibody and LNPs-miR130b antagomir remarkably inhibited Th17 cells and retarded miR130b-overexpressing tumor growth.In conclusion,as an oncogenic biomarker of DLBCL,miR130b was related to lymphoma progression through modulating OX40/OX40L-mediated lymphoma cell interaction with Th17 cells,attributing to B-cell lymphoma sensitivity towards OX40 agonistic antibody.Targeting miR130b using LNPs-miR130b antagomir could also be a potential immunotherapeutic strategy in treating OX40-altered lymphoid malignancies.