Therapeutic efficacy study of novel 5-FU-loaded PMM 2.1.2-based microspheres on C6 glioma

The aim of this study was to evaluate the potential of poly(methylidene malonate 2.1.2) as a new drug delivery system to the central nervous system. 5-Fluorouracil microspheres were formulated by an emulsion-extraction method, and evaluated on a C6 glioma model. Twenty-seven Sprague-Dawley female rats underwent implantation of various C6 cell concentrations. Magnetic resonance imaging was performed at day 10 to control the setting of the tumor, by using a T2-weighted sequence. At day 12, 18 animals received blank or 5-FU-loaded microspheres, while 9 animals were not implanted and constituted the controls. Thereafter, MRI was performed twice a week to follow the tumor growth. In 12 animals, an alloimmune rejection of the tumor was observed, showing the limitations of the C6 glioma model. When tumor developed, no relationship was observed between the number of C6 cells injected and the tumor volume. 5-FU microsphere efficacy could statistically be demonstrated by significantly improving the median survival of C6 glioma-bearing animals and also by decreasing tumor burden

The encapsulation of DNA molecules within biomimetic lipid nanocapsules

Most of DNA synthetic complexes result from the self-assembly of DNA molecules with cationic lipids or polymers in an aqueous controlled medium. However, injection of such self-assembled complexes in medium like blood that differ from that of their formulation leads to strong instability. Therefore, DNA vectors that have physico-chemical properties and structural organisation that will not be sensitive to a completely different medium in terms of ionic and protein composition are actively sought. To this end, the goal here was to discover and optimize a nanostructured system where DNA molecules would be encapsulated in nanocapsules consisting in an oily core and a shell covered by PEG stretches obtained through a nanoemulsion process in the absence of organic solvent. This encapsulation form of DNA molecules would prevent interactions with external hostile biological fluid. The results show the entrapment of lipoplexes into lipid nanocapsules, leading to the formation of neutral 110 nm-DNA nanocapsules. They were weakly removed by the immune system, displaying an increased blood half-life, and improved carcinoma cell transfection, in comparison to the parent lipoplexes. Our results demonstrate that the fabrication of nanocapsules encapsulating hydrophilic DNA in an oily core that meet criteria for blood injection is possible

Photocytotoxicity of mTHPC (Temoporfin) Loaded Polymeric Micelles Mediated by Lipase Catalyzed Degradation

Purpose. To study the in vitro photocytotoxicity and cellular uptake of biodegradable polymeric micelles loaded with the photosensitizer mTHPC, including the effect of lipase-catalyzed micelle degradation. Methods. Micelles of mPEG750-b-oligo(ɛ-caprolactone)5 (mPEG750-b-OCL5) with a hydroxyl (OH), benzoyl (Bz) or naphthoyl (Np) end group were formed and loaded with mTHPC by the film hydration method. The cellular uptake of the loaded micelles, and their photocytotoxicity on human neck squamous carcinoma cells in the absence and presence of lipase were compared with free and liposomal mTHPC (Fospeg ®). Results. Micelles composed of mPEG750-b-OCL5 with benzoyl and naphtoyl end groups had the highest loading capacity up to 30 % (w/w), likely due to π–π interactions between the aromatic end group and the photosensitizer. MTHPC-loaded benzoylated micelles (0.5 mg/mL polymer) did not display photocytotoxicity or any mTHPC-uptake by the cells, in contrast to free and liposomal mTHPC. After dilution of the micelles below the critical aggregation concentration (CAC), or after micelle degradation by lipase, photocytotoxicity and cellular uptake of mTHPC were restored. Conclusion. The high loading capacity of the micelles, the high stability of mTHPC-loaded micelles above the CAC, and the lipase-induced release of the photosensitizer makes these micelles very promising carriers for photodynamic therapy in vivo. KEY WORDS: drug release; enzymatic degradation; meta-tetra(hydroxyphenyl)chlorin (mTHPC); photodynamic therapy (PDT); polymeric micelles

IL-22 Is Produced by Innate Lymphoid Cells and Limits Inflammation in Allergic Airway Disease

Interleukin (IL)-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-deficient mice and found that they suffer from significantly higher airway hyperreactivity upon airway challenge. IL-22-deficiency led to increased eosinophil infiltration lymphocyte invasion and production of CCL17 (TARC), IL-5 and IL-13 in the lung. Mice treated with IL-22 before antigen challenge displayed reduced expression of CCL17 and IL-13 and significant amelioration of airway constriction and inflammation. We conclude that innate IL-22 limits airway inflammation, tissue damage and clinical decline in allergic lung disease

ILC3 function as a double-edged sword in inflammatory bowel diseases

Inflammatory bowel diseases (IBD), composed mainly of Crohn’s disease (CD) and ulcerative colitis (UC), are strongly implicated in the development of intestinal inflammation lesions. Its exact etiology and pathogenesis are still undetermined. Recently accumulating evidence supports that group 3 innate lymphoid cells (ILC3) are responsible for gastrointestinal mucosal homeostasis through moderate generation of IL-22, IL-17, and GM-CSF in the physiological state. ILC3 contribute to the progression and aggravation of IBD while both IL-22 and IL-17, along with IFN-γ, are overexpressed by the dysregulation of NCR− ILC3 or NCR+ ILC3 function and the bias of NCR+ ILC3 towards ILC1 as well as regulatory ILC dysfunction in the pathological state. Herein, we feature the group 3 innate lymphoid cells’ development, biological function, maintenance of gut homeostasis, mediation of IBD occurrence, and potential application to IBD therapy

NK cells and type 1 innate lymphoid cells: partners in host defense

Innate lymphoid cells (ILCs) are effectors and regulators of innate immunity and tissue modeling and repair. Researchers have identified subsets of ILCs with differing functional activities, capacities to produce cytokines and transcription factors required for development and function. Natural killer (NK) cells represent the prototypical member of the ILC family. Together with ILC1s, NK cells constitute group 1 ILCs, which are characterized by their capacity to produce interferon-γ and their functional dependence on the transcription factor T-bet. NK cells and ILC1s are developmentally distinct but share so many features that they are difficult to distinguish, particularly under conditions of infection and inflammation. Here we review current knowledge of NK cells and the various ILC1 subset