Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors

Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof

Surface engineering of polyester-degrading enzymes to improve efficiency and tune specificity

Certain members of the carboxylesterase superfamily can act at the interface between water and water-insoluble substrates. However, nonnatural bulky polyesters usually are not efficiently hydrolyzed. In the recent years, the potential of enzyme engineering to improve hydrolysis of synthetic polyesters has been demonstrated. Regions on the enzyme surface have been modified by using site-directed mutagenesis in order to tune sorption processes through increased hydrophobicity of the enzyme surface. Such modifications can involve specific amino acid substitutions, addition of binding modules, or truncation of entire domains improving sorption properties and/or dynamics of the enzyme. In this review, we provide a comprehensive overview on different strategies developed in the recent years for enzyme surface engineering to improve the activity of polyester-hydrolyzing enzymes