Multimodal doxorubicin loaded magnetic nanoparticles for VEGF targeted theranostics of breast cancer.

In presented paper we have developed new system for cancer theranostics based on vascular endothelial growth factor (VEGF) targeted magnetic nanoparticles. Conjugation of anti-VEGF antibodies with bovine serum albumin coated PEGylated magnetic nanoparticles allows for improved binding with murine breast adenocarcinoma 4T1 cell line and facilitates doxorubicin delivery to tumor cells. It was shown that intravenous injection of doxorubicin loaded VEGF targeted nanoparticles increases median survival rate of mice bearing 4T1 tumors up to 50%. On the other hand magnetic resonance imaging (MRI) of 4T1 tumors 24 h after intravenous injection showed accumulation of nanoparticles in tumors, thus allowing simultaneous cancer therapy and diagnostics.

Superior infectivity of the fiber chimeric oncolytic adenoviruses Ad5/35 and Ad5/3 over Ad5-delta-24-RGD in primary glioma cultures.

Ad5-delta-24-RGD is currently the most clinically advanced recombinant adenovirus (rAd) for glioma therapy. We constructed a panel of fiber-modified rAds (Ad5RGD, Ad5/3, Ad5/35, Ad5/3RGD, and Ad5/35RGD, all harboring the delta-24 modification) and compared their infectivity, replication, reproduction, and cytolytic efficacy in human and rodent glioma cell lines and short-term cultures from primary gliomas. In human cells, both Ad5/35-delta-24 and Ad5/3-delta-24 displayed superior infectivity and cytolytic efficacy over Ad5-delta-24-RGD, while Ad5/3-delta-24-RGD and Ad5/35-delta-24-RGD did not show further improvements in efficacy. The expression of the adenoviral receptors/coreceptors CAR, DSG2, and CD46 and the integrins αVß3/αVß5 did not predict the relative cytolytic efficacy of the fiber-modified rAds. The cytotoxicity of the fiber-modified rAds in human primary normal cultures of different origins and in primary glioma cultures was comparable, indicating that the delta-24 modification did not confer tumor cell selectivity. We also revealed that CT-2A and GL261 glioma cells might be used as murine cell models for the fiber chimeric rAds in vitro and in vivo. In GL261 tumor-bearing mice, Ad5/35-delta-24, armed with the immune costimulator OX40L as the E2A/DBP-p2A-mOX40L fusion, produced long-term survivors, which were able to reject tumor cells upon rechallenge. Our data underscore the potential of local Ad5/35-delta-24-based immunovirotherapy for glioblastoma treatment.

Study of possibility of cell recognition in brain tumors.

The brain has an exceptionally high requirement for energy metabolism, with glucose serving as the exclusive energy source. Cancers, including glioblastoma, have a high glucose uptake and rely on aerobic glycolysis for energy metabolism. The alternation of high-efficiency oxidative phosphorylation to a low-efficiency aerobic glycolysis pathway (Warburg effect) provides macromolecules for biosynthesis and proliferation. Current research indicates that the specific metabolism in the tumor tissue and normal brain tissue in the glioma allows the use of 5-aminolevulinic acid (5 ALA)-induced protoporphyrin IX (PpIX) and methylene blue (MB) to monitor and correct the development of the tumor. The focus is on the detection of the differences between tumor cells and tumor-associated macrophages/microglia using spectroscopic and microscopic methods, based on the fluorescent signals and the difference in the drug accumulation of photosensitizers (PSs). Since 5 ALA has long been used effectively in the clinic for fluorescent surgical navigation, it was employed as an agent to identify the localization of tumor tissue and study its composition, particularly tumor and immune cells (macrophages), which have also been shown to actively accumulate PpIX. However, since PpIX is photodynamically active, it can be considered effective as the main target of tumor tissue for further successful photodynamic therapy. MB was employed to visualize resident microglia, which is important for their activation/deactivation to prevent the reprogramming of the immune cells by the tumor. Thus, using two drugs, it is possible to prevent crosstalk between tumor cells and the immune cells of different geneses.