Progression of solid tumors depends on vascularization and angiogenesis in a malignant tissue. Among a whole range of proangiogenic factors, a vascular endothelial growth factor A (VEGF-A) plays a key role. Blockade of VEGF may lead to regression of vascular network and inhibition of a tumor growth. In the present time, bevacizumab has been introduced into wide clinical practice in therapy of breast cancer, colorectal cancer and recurrent high-grade gliomas (HGGs). Coadministration of antiangiogenic therapy with irinotecan may increase probability of the response to the treatment and prolong progression-free survival rate (PFS). Moreover, bevacizumab is well tolerated and significantly improves patient's quality of life. However, in the case of brain tumors, the efficiency of such an approach is controversial. The antiangiogenic therapy can slightly delay tumor growth and does not lead to complete recovery. In addition, it contributes to enhanced tumor cell invasion into the normal brain. The mechanisms of resistance include activation of alternative proangiogenic signaling pathways, of an invasive population of tumor cells, metabolic change toward glycolysis and recruitment of myeloid bone marrow-derived cells to tumors. Obviously, that anti-VEGF therapy as monotherapy was not effective against HGGs. To enhance the antitumor treatment efficacy, it is necessary to develop a multi-target strategy to inhibit critical processes in malignancy progression such as angiogenesis, invasion, autophagy, metastatic spread, recruitment of bone marrow-derived endothelial cells and tumor stem-like cells. In addition, anti-VEGF antibodies have shown a promising result as a tumor-targeting vector for delivery therapeutic and diagnostic drugs in brain tumors.
Targeted delivery of anticancer drugs to brain tumors, especially glioblastoma multiforme, which is the most frequent and aggressive type, is one of the important objectives in nanomedicine. Vascular endothelial growth factor (VEGF) and its receptor type II (VEGFR2) are promising targets because they are overexpressed by not only core tumor cells but also by migrated glioma cells, which are responsible for resistance and rapid progression of brain tumors. The purpose of the present study was to develop the liposomal drug delivery system combining enhanced loading capacity of cisplatin and high binding affinity to glioma cells. This was achieved by using of highly soluble cisplatin analogue, cis-diamminedinitratoplatinum(II), and antibodies against the native form of VEGF or VEGFR2 conjugated to liposome surface. The developed drug delivery system revealed sustained drug release profile, high affinity to antigens, and increased uptake by glioma C6 and U-87 MG cells. Pharmacokinetic study on glioma C6-bearing rats revealed prolonged blood circulation time of the liposomal formulation. The above features enabled the present drug delivery system to overcome both poor pharmacokinetics typical for platinum formulations and low loading capacity typical for conventional liposomal cisplatin formulations.
Innate lymphoid cells (ILCs) are a heterogeneous family of immune regulators that protect against mucosal pathogens but can also promote intestinal pathology. Although the plasticity between ILCs populations has been described, the role of mucosal pathogens in inducing ILC conversion leading to intestinal pathology remains unclear. Here we demonstrate that IFNγ-producing ILCs are responsible for promoting intestinal pathology in a mouse model of enterocolitis caused by Campylobacter jejuni , a common human enteric pathogen. Phenotypic analysis revealed a distinct population of IFNγ-producing NK1.1 − T-bet + ILCs that accumulated in the intestine of C. jejuni -infected mice. Adoptive transfer experiments demonstrated their capacity to promote intestinal pathology. Inactivation of T-bet in NKp46 + ILCs ameliorated disease. Transcriptome analysis and cell-fate mapping experiments revealed that IFNγ-producing NK1.1 − ILCs correspond to ILC1 profile and develop from RORγt + progenitors. Collectively, we identified a distinct population of NK1.1 − ex-ILC3s that promotes intestinal pathology through IFNγ production in response to C. jejuni infection.
Bacterial nanocellulose (BNC) whose biosynthesis fully conforms to green chemistry principles arouses much interest of specialists in technical chemistry and materials science because of its specific properties, such as nanostructure, purity, thermal stability, reactivity, high crystallinity, etc. The functionalization of the BNC surface remains a priority research area of polymers. The present study was aimed at scaled production of an enlarged BNC sample and at synthesizing cellulose nitrate (CN) therefrom. Cyclic biosynthesis of BNC was run in a semisynthetic glucose medium of 10−72 L in volume by using the Medusomyces gisevii Sa-12 symbiont. The most representative BNC sample weighing 6800 g and having an α-cellulose content of 99% and a polymerization degree of 4000 was nitrated. The nitration of freeze-dried BNC was performed with sulfuric-nitric mixed acid. BNC was examined by scanning electron microscopy (SEM) and infrared spectroscopy (IR), and CN was explored to a fuller extent by SEM, IR, thermogravimetric analysis/differential scanning analysis (TGA/DTA) and 13C nuclear magnetic resonance (NMR) spectroscopy. The three-cycle biosynthesis of BNC with an increasing volume of the nutrient medium from 10 to 72 L was successfully scaled up in nonsterile conditions to afford 9432 g of BNC gel-films. CNs with a nitrogen content of 10.96% and a viscosity of 916 cP were synthesized. It was found by the SEM technique that the CN preserved the 3D reticulate structure of initial BNC fibers a marginal thickening of the nanofibers themselves. Different analytical techniques reliably proved the resultant nitration product to be CN. When dissolved in acetone, the CN was found to form a clear high-viscosity organogel whose further studies will broaden application fields of the modified BNC.
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