Finally, PEI/siRNA-mediated targeting of pleiotrophin (PTN) exerted strong antitumoral effects. PTN is a secreted growth factor which shows mitogenic, chemotactic, angiogenic and transforming activity [85] [86] [87] [88] [89] [90] [91] [92] [93] and which is markedly upregulated in several human tumors including cancer of the breast, testis, prostate, pancreas, and lung as well as in melanomas, meningiomas, neuroblastomas, and glioblastomas. The in vivo treatment of nude mice through systemic subcutaneous or IP application of PEI-complexed PTN siRNAs led to the delivery of intact siRNAs into subcutaneous tumor xenografts and a significant inhibition of tumor growth. Likewise, in a clinically more relevant orthotopic mouse glioblastoma model with U87 cells growing intracranially, the injection of PEI-complexed PTN siRNAs into the CNS exerted antitumoral effects. This establishes, also in a complex and relevant orthotopic tumor model, the potential of PEI/siRNA-mediated PTN gene targeting as a novel therapeutic option in GBM, and further extends the modes of delivery of PEI/siRNA complexes intrathecal strategies as employed in the therapy of glioblastomas with antisense oligonucleotides.