IGF-1 Conjugated Sub-5 nm Ultrafine Iron Oxide Nanoparticle Enhances Targeted Drug Delivery and Efficacy of DNA Topoisomerase Inhibitor SN38 for Pancreatic Cancer: An in Vitro Study

Background Pancreatic cancer remains one of the most lethal cancers largely due to the inefficient delivery of therapeutics. Nanomaterials have been extensively investigated as drug delivery platforms, showing improved drug pharmacodynamics and pharmacokinetics. However, their applications in pancreatic cancer have not yet been successful due to limited tumor delivery caused by dense tumor stroma and distorted tumor vasculatures. Meanwhile, smaller-sized nanomaterials have shown improved tumor delivery and retention in various tumors, including pancreatic tumors, suggesting their potential in enhancing drug delivery. Methods An ultrafine iron oxide nanoparticle (uIONP) was used to encapsulate 7-ethyl-10-hydroxyl camptothecin (SN38), the water-insoluble active metabolite of chemotherapy drug irinotecan for treating pancreatic cancer in clinic. Insulin-like growth factor 1 (IGF-1) was conjugated to uIONP as a ligand for targeting pancreatic cancer and stromal cells overexpressing IGF-1 receptor (IGF1R). The SN38 loading and release profile were characterized. The cancer cell targeting and induced apoptosis by developed nano-formulationIGF1-uIONP/SN38 were also investigated. Results IGF1-uIONP/SN38 demonstrated stable drug loading in physiological pH with the loading efficiency of 68.2 ± 3.5% (SN38/Fe, wt%) and <7% release for 24 hours. In tumor-interstitial- and lysosomal-mimicking pH (6.5 and 5.5), 52.2 and 91.3% of encapsulated SN38 were released over 24 hours. The IGF1-uIONP/SN38 exhibited specific receptor-mediated cell targeting and cytotoxicity to MiaPaCa-2 cells with IC50 of 11.8 ± 2.3 nM, but not to HEK293 human embryonic kidney cells. Conclusion The IGF1-uIONP significantly improved the delivery of SN38 to targeted pancreatic cancer cells, holding the potential for in vivo theranostic applications.

Cell Senescence as a Mediator of Age-Dependent Brain Inflammation

Cellular senescence and inflammation are interconnected causes and consequences of tissue aging. Here, we implemented orthogonal approaches to study their interaction in steady-state mature and aged mouse brain. Using single cell sequencing, we identified a putative senescent microglial population, which increased in abundance with age and was characterized by increased expression of p16 and chemotactic senescence associated secretory phenotype (SASP) factors. Using p16-INK-ATTAC transgenic mice to eliminate p16ink4a-positive senescent cells and mass cytometry, we show that p16ink4a-positive cell targeting reduced the abundance of activated inflammatory cells in the aged female brain. Age-dependent declines in executive cognitive function were improved following transgenic p16ink4a-positive cell targeting, and executive function robustly correlated with inflammatory brain cell composition in females. Collectively, our findings demonstrate fundamental differences in the age- and sex-dependent brain inflammatory landscape and implicate p16ink4a-positive senescent cell targeting as a therapeutic strategy to attenuate age-related inflammation and cognitive decline.

Cellular and Humoral Immune Response to SARS-CoV-2 mRNA Vaccines in Patients Treated with either Ibrutinib or Rituximab

Patients treated with B-cell targeting therapies like Rituximab or Ibrutinib have decreased serological response to various vaccines. In this study, we tested serological and cellular response to SARS-CoV-2 mRNA vaccines in 16 patients treated with Ibrutinib, 16 treated with maintenance Rituximab, 18 patients with chronic lymphocytic leukaemia (CLL) with watch and wait status and 21 healthy volunteers. In comparison to the healthy volunteers, where serological response was achieved by 100% subjects, patients on B-cell-targeting therapy (Ibrutinib and Rituximab) had their response dramatically impaired. The serological response was achieved in 0% of Rituximab treated, 18% of Ibrutinib treated and 50% of untreated CLL patients. Cell-mediated immunity analysed by the whole blood Interferon-γ Release immune Assay developed in 80% of healthy controls, 62% of Rituximab treated, 75% of Ibrutinib treated and 55% of untreated CLL patients. The probability of cell-mediated immune response development negatively correlates with disease burden mainly in CLL patients. Our study shows that even though the serological response to SARS-CoV-2 vaccine is severely impaired in patients treated with B-cell-targeting therapy, the majority of these patients develop sufficient cell-mediated immunity. The vaccination of these patients therefore might be meaningful in terms of protection against SARS-CoV-2 infection.

Magnetism-Induced Cell-Targeting Transplantation Improves Early Hematopoietic Reconstitution in a Murine Bone Marrow Transplantation Model

Background Early hematopoietic reconstitution is essential for improving survival and reducing complications after hematopoietic stem/progenitor cell (HSC/HPC) transplantation (HSCT/HPCT). Increasing HSC/HPC homing to the bone marrow is a potential approach for promoting hematopoietic reconstitution. Methods We proposed the transplantation of HSCs/HPCs with a magnetism-induced cell-targeting transplantation (MagIC-TT) strategy. HSCs/HPCs were magnetized with CD45 microbeads. The biological characteristics (morphology, proliferation, viability, and ferroptosis) and target migration ability of these cells were studied in vitro. The hematopoietic reconstitution experiments were constructed in vivo in autologous and allogeneic bone marrow transplantation models with grouping showed as Table 1. The therapeutic effects were assessed by survival, donor chimerism, routine blood examination and histological analysis. We also performed transcriptomic sequencing for further mechanistic studies. Results The biological characteristics was found no significant difference between the MagIC-TT and non-MagIC-TT groups, while migration ability was greatly improved with MagIC-TT (Data not showed). The survival rate was higher in the MagIC-TT group and significantly different in the allogeneic model (P&lt;0.05). Hematopoietic reconstitution of donor chimerism, WBCs, HGB, and PLTs was faster in the MagIC-TT groups (within 22 days) (Figure 1). Confocal observation showed that more donor cells (eGFP +) were retained in the injected femur of the MagIC-TT group than in the femur of the non-MagIC-TT group 7 days after transplantation (P&lt;0.05) (Figure 2). The severity of aGVHD (Assessed by survival, body weight, back arching, fur losting, diarrhea etc.) was reduced in the MagIC-TT groups in the allogeneic model (P&lt;0.05) (Data not showed). Transcriptome sequencing revealed differentially expressed genes (DEGs) involved in localization/locomotion and pathways, cytokine-cytokine receptor interactions and chemokine signaling pathways between the two groups (Figure 3). Conclusion The MagIC-TT strategy improves HSC/HPC homing, resulting in faster hematopoietic reconstitution in a murine bone marrow transplantation model. Key words Magnetism; Hematopoietic Stem Cell Transplantation (HSCT); Cell Homing; Hematopoietic Reconstitution; Ferroptosis Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.