Mechanisms of Brain Tumor Chemoresistance

National Institute Of Neurological Disorders And Stroke

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Abstract

We have sought to develop a small interfering RNA (siRNA)-based strategy for the inhibition of stathmin expression in malignant gliomas. The use of siRNAs in general to down-regulate the expression of disease-associated proteins carries significant promise for the treatment of a variety of clinical disorders. One of the main barriers to the clinical use of siRNAs, however, is the inability to efficiently deliver siRNAs to the cytoplasm of target cells. The entrapment and degradation of siRNAs within the endolysosomal pathway has been especially problematic. We have developed a non-toxic, lipid membrane disruptive anionic polymer, phenylalanine derivatized poly(L-lysine iso-phthalamide) (PP75), that safely permeabilizes the endosomes of living cells and facilitates the transfer of endocytosed materials directly into the cytoplasm. The covalent attachment of PP75 to siRNAs using disulfide linkages generates conjugates that effectively traffic the siRNAs to the cytoplasm of target cells both in vitro and in vivo. In a subcutaneous malignant glioma tumor model, a PP75-stathmin siRNA conjugate, in combination with the nitrosourea chemotherapy carmustine, is highly effective at inhibiting tumor growth. PP75 may be clinically useful for the efficient cytoplasmic delivery of not only stathmin siRNAs but nucleic acids in general.