How to Develop Drug Delivery System Based on Carbohydrate Nanoparticles Targeted to Brain Tumors.

Brain tumors are the most difficult to treat, not only because of the variety of their forms and the small number of effective chemotherapeutic agents capable of suppressing tumor cells, but also limited by poor drug transport across the blood-brain barrier (BBB). Nanoparticles are promising drug delivery solutions promoted by the expansion of nanotechnology, emerging in the creation and practical use of materials in the range from 1 to 500 nm. Carbohydrate-based nanoparticles is a unique platform for active molecular transport and targeted drug delivery, providing biocompatibility, biodegradability, and a reduction in toxic side effects. However, the design and fabrication of biopolymer colloidal nanomaterials have been and remain highly challenging to date. Our review is devoted to the description of carbohydrate nanoparticle synthesis and modification, with a brief overview of the biological and promising clinical outcomes. We also expect this manuscript to highlight the great potential of carbohydrate nanocarriers for drug delivery and targeted treatment of gliomas of various grades and glioblastomas, as the most aggressive of brain tumors.

Nanomechanical Signatures in Glioma Cells Depend on CD44 Distribution in IDH1 Wild-Type but Not in IDH1R132H Mutant Early-Passage Cultures.

Atomic force microscopy (AFM) recently burst into biomedicine, providing morphological and functional characteristics of cancer cells and their microenvironment responsible for tumor invasion and progression, although the novelty of this assay needs to coordinate the malignant profiles of patients' specimens to diagnostically valuable criteria. Applying high-resolution semi-contact AFM mapping on an extended number of cells, we analyzed the nanomechanical properties of glioma early-passage cell cultures with a different IDH1 R132H mutation status. Each cell culture was additionally clustered on CD44+/- cells to find possible nanomechanical signatures that differentiate cell phenotypes varying in proliferative activity and the characteristic surface marker. IDH1 R132H mutant cells compared to IDH1 wild-type ones (IDH1wt) characterized by two-fold increased stiffness and 1.5-fold elasticity modulus. CD44+/IDH1wt cells were two-fold more rigid and much stiffer than CD44-/IDH1wt ones. In contrast to IDH1 wild-type cells, CD44+/IDH1 R132H and CD44-/IDH1 R132H did not exhibit nanomechanical signatures providing statistically valuable differentiation of these subpopulations. The median stiffness depends on glioma cell types and decreases according to the following manner: IDH1 R132H mt (4.7 mN/m), CD44+/IDH1wt (3.7 mN/m), CD44-/IDH1wt (2.5 mN/m). This indicates that the quantitative nanomechanical mapping would be a promising assay for the quick cell population analysis suitable for detailed diagnostics and personalized treatment of glioma forms.

Nanomechanical and Morphological AFM Mapping of Normal Tissues and Tumors on Live Brain Slices Using Specially Designed Embedding Matrix and Laser-Shaped Cantilevers.

Cell and tissue nanomechanics has been intriguingly introduced into biomedical research, not only complementing traditional immunophenotyping and molecular analysis, but also bringing unexpected new insights for clinical diagnostics and bioengineering. However, despite the progress in the study of individual cells in culture by atomic force microscopy (AFM), its application for mapping live tissues has a number of technical limitations. Here, we elaborate a new technique to study live slices of normal brain tissue and tumors by combining morphological and nanomechanical AFM mapping in high throughput scanning mode, in contrast to the typically utilized force spectroscopy mode based on single-point probe application. This became possible due to the combined use of an appropriate embedding matrix for vibratomy and originally modified AFM probes. The embedding matrix composition was carefully developed by regulating the amounts of agar and collagen I to reach optimal viscoelastic properties for obtaining high-quality live slices that meet AFM requirements. AFM tips were rounded by irradiating them with focused nanosecond laser pulses, while the resulting tip morphology was verified by scanning electron microscopy. Live slices preparation and AFM investigation take only 55 min and could be combined with a vital cell tracer analysis or immunostaining, thus making it promising for biomedical research and clinical diagnostics.

Cell and Tissue Nanomechanics: From Early Development to Carcinogenesis.

Cell and tissue nanomechanics, being inspired by progress in high-resolution physical mapping, has recently burst into biomedical research, discovering not only new characteristics of normal and diseased tissues, but also unveiling previously unknown mechanisms of pathological processes. Some parallels can be drawn between early development and carcinogenesis. Early embryogenesis, up to the blastocyst stage, requires a soft microenvironment and internal mechanical signals induced by the contractility of the cortical actomyosin cytoskeleton, stimulating quick cell divisions. During further development from the blastocyst implantation to placenta formation, decidua stiffness is increased ten-fold when compared to non-pregnant endometrium. Organogenesis is mediated by mechanosignaling inspired by intercellular junction formation with the involvement of mechanotransduction from the extracellular matrix (ECM). Carcinogenesis dramatically changes the mechanical properties of cells and their microenvironment, generally reproducing the structural properties and molecular organization of embryonic tissues, but with a higher stiffness of the ECM and higher cellular softness and fluidity. These changes are associated with the complete rearrangement of the entire tissue skeleton involving the ECM, cytoskeleton, and the nuclear scaffold, all integrated with each other in a joint network. The important changes occur in the cancer stem-cell niche responsible for tumor promotion and metastatic growth. We expect that the promising concept based on the natural selection of cancer cells fixing the most invasive phenotypes and genotypes by reciprocal regulation through ECM-mediated nanomechanical feedback loop can be exploited to create new therapeutic strategies for cancer treatment.