Lentinan-Based Oral Nanoparticle Loaded Budesonide With Macrophage-Targeting Ability for Treatment of Ulcerative Colitis

Ulcerative colitis (UC) is a global, chronic, and refractory disease. Corticosteroids are first-line drugs for the treatment of UC but also cause adverse side effects. Budesonide (BUD), a corticosteroid with relatively low side effects, has been approved by the Food and Drug Administration for use as enteric capsules (Entocort EC) for the treatment of inflammatory bowel disease (IBD). However, this formulation lacks specific targeting ability to UC lesions. Herein, we describe the development of an advanced macrophage-targeted oral lentinan (LNT)–based nanoparticles (NPs) loaded BUD for treatment of UC. Briefly, LNT was used as a food source and natural carrier to load BUD by a simple solvent evaporation method to form LNT/BUD-NPs. LNT showed good loading capacity with high encapsulation and loading efficiencies to BUD of approximately 92.19 and 9.58%, respectively. Evaluation of the gastric stability of LNT/BUD-NPs indicated that LNT could effectively protect BUD from gastric acid and digestive enzymes. The release behavior and transmission electron microscopy image of LNT/BUD-NPs in the intestinal content of mice confirmed that intestinal flora can promote BUD release from LNT. Moreover, evaluation of cellular uptake showed that LNT/BUD-NPs could specifically target macrophages and enhance their uptake rate via the Dectin-1 receptor. In biodistribution studies, LNT/BUD-NPs were able to efficiently accumulate in the inflamed colon of mice. As expected, LNT/BUD-NPs could significantly alleviate inflammation by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Therefore, LNT/BUD-NPs have the advantages of good gastric stability, release mediated by mouse intestinal content, macrophage-targeting, and anti-UC effects. These advantages indicate LNT-based NPs are a promising oral drug delivery system for UC therapy.

Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Therapeutic Opportunities and Clinical Challenges

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of less than 10%. Macrophages are one of the earliest infiltrating cells in the pancreatic tumor microenvironment, and are associated with an increased risk of disease progression, recurrence, metastasis, and shorter overall survival. Pre-clinical studies have demonstrated an unequivocal role of macrophages in PDAC by contributing to chronic inflammation, cancer cell stemness, desmoplasia, immune suppression, angiogenesis, invasion, metastasis, and drug resistance. Several macrophage-targeting therapies have also been investigated in pre-clinical models, and include macrophage depletion, inhibiting macrophage recruitment, and macrophage reprogramming. However, the effectiveness of these drugs in pre-clinical models has not always translated into clinical trials. In this review, we discuss the molecular mechanisms that underpin macrophage heterogeneity within the pancreatic tumor microenvironment, and examine the contribution of macrophages at various stages of PDAC progression. We also provide a comprehensive update of macrophage-targeting therapies that are currently undergoing clinical evaluation, and discuss clinical challenges associated with these treatment modalities in human PDAC patients.

High Content Analysis of Macrophage-Targeting EhPIb-Compounds against Cutaneous and Visceral Leishmania Species

An immunostimulatory glycolipid molecule from the intestinal protozoan parasite Entamoeba histolytica (Eh) and its synthetic analogs derived from its phosphatidylinositol-b-anchor (EhPIb) previously showed considerable immunotherapeutic effects against Leishmania major infection in vitro and in vivo. Here, we describe a high content screening assay, based on primary murine macrophages. Parasites detection is based on a 90 kDA heat shock protein-specific staining, enabling the detection of several Leishmania species. We validated the assay using L. major, L. braziliensis, L. donovani, and L. infantum as well as investigated the anti-leishmanial activity of six immunostimulatory EhPIb-compounds (Eh-1 to Eh-6). Macrophages infected with dermotropic species were more sensitive towards treatment with the compounds as their viability showed a stronger reduction compared to macrophages infected with viscerotropic species. Most compounds caused a significant reduction of the infection rates and the parasite burdens depending on the infecting species. Only compound Eh-6 was found to have activity against all Leishmania species. Considering the challenges in anti-leishmanial drug discovery, we developed a multi-species screening assay capable of utilizing non-recombinant parasite strains, and demonstrated its usefulness by screening macrophage-targeting EhPIb-compounds showing their potential for the treatment of cutaneous and visceral leishmaniasis.