Репозиторий Университета

© 2019 Elsevier B.V. Brain delivery of drugs by nanoparticles is a promising strategy that could open up new possibilities for the chemotherapy of brain tumors. As demonstrated in previous studies, the loading of doxorubicin in poly(lactide-co-glycolide) nanoparticles coated with poloxamer 188 (Dox-PLGA) enabled the brain delivery of this cytostatic that normally cannot penetrate across the blood-brain barrier in free form. The Dox-PLGA nanoparticles produced a very considerable anti-tumor effect against the intracranial 101.8 glioblastoma in rats, thus representing a promising candidate for the chemotherapy of brain tumors that warrants clinical evaluation. The objective of the present study, therefore, was the optimization of the Dox-PLGA formulation and the development of a pilot scale manufacturing process. Optimization of the preparation procedure involved the alteration of the technological parameters such as replacement of the particle stabilizer PVA 30–70 kDa with a presumably safer low molecular mass PVA 9–10 kDa as well as the modification of the external emulsion medium and the homogenization conditions. The optimized procedure enabled an increase of the encapsulation efficiency from 66% to >90% and reduction of the nanoparticle size from 250 nm to 110 nm thus enabling the sterilization by membrane filtration. The pilot scale process was characterized by an excellent reproducibility with very low inter-batch variations. The in vitro hematotoxicity of the nanoparticles was negligible at therapeutically relevant concentrations. The anti-tumor efficacy of the optimized formulation and the ability of the nanoparticles to penetrate into the intracranial tumor and normal brain tissue were confirmed by in vivo experiments.

© 2019, The Author(s).  Objectives: Glioblastoma (GB) contains diverse histologic regions. Apparent diffusion coefficient (ADC) values are surrogates for the degree of number of cells within the tumour regions. Because an assessment of ADC values and volumes within tumour sub-compartments of GB is missing in the literature, we aimed to evaluate these associations. Methods: A retrospective cohort of 48 patients with GB underwent segmentation to calculate tumour region volumes (in cubic centimetre) and ADC values in tumour regions: normal tissue, enhancing tumour, proximal oedema, distal oedema, and necrosis. Correlation, Kaplan-Meier, and Cox hazard regression analyses were performed. Results: We found a statistically significant difference among ADC values for tumour regions: F (4, 220) = 166.71 and p ≤.001 and tumour region volumes (necrosis, enhancing tumour, peritumoural oedema): F (2, 141) = 136.3 and p ≤.001. Post hoc comparisons indicated that the only significantly different mean score was the peritumoural volume in oedema region (p <.001). We observed a positive significant correlation between ADC of distal oedema and peritumoural volume, r =.418, df = 34, and p =.011. Cox proportional hazards regression analysis considering only tumour region volumes provided an almost significant model: − 2 log-likelihood = 146.066, χ 2 (4) = 9.303, and p =.054 with a trend towards significance of the hazard function: p =.067 and HR = 1.077 for the non-enhancing tumour volume. Conclusions: ADC values together with volumes of oedema region might have a role as predictors of progression-free survival (PFS) in patients with GB; we recommend a routine MRI assessment with the calculation of these biomarkers in GB.