title: Endosomolytic anionic polymer for the cytoplasmic delivery of siRNAs in localizedin vivoapplications.
abstract: The use of small interfering RNAs (siRNAs) 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 widespread clinical use of siRNAs, however, is their entrapment and degradation within the endolysosomal pathway of target cells. Here we report the trafficking and function of PP75, a non-toxic, biodegradable, lipid membrane disruptive anionic polymer composed of phenylalanine derivatized poly(L-lysineiso-phthalamide). PP75 is readily endocytosed by cells, safely permeabilizes endolysosomes in a pH dependent manner and facilitates the transfer of co-endocytosed materials directly into the cytoplasm. The covalent attachment of siRNAs to PP75 using disulfide linkages generates conjugates that effectively traffic siRNAs to the cytoplasm of target cells bothin vitroandin vivo. In a subcutaneous malignant glioma tumor model, a locally delivered PP75-stathmin siRNA conjugate decreases stathmin expression in tumor cells and, in combination with the nitrosourea chemotherapy carmustine, is highly effective at inhibiting tumor growth. PP75 may be clinically useful for the local delivery of siRNAs, in particular for the treatment of solid tumors.
authors.affiliation: Surgical and Molecular Neuro-oncology Unit, NINDS, NIH, Bethesda, MD, 20892, USA ; Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Sariah
authors.initials: S
authors.lastname: Khormaee
authors.forename: Yong
authors.initials: Y
authors.lastname: Choi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shen
authors.forename: Biying
authors.initials: B
authors.lastname: Xu
authors.forename: Haitao
authors.initials: H
authors.lastname: Wu
authors.forename: Gary L
authors.initials: GL
authors.lastname: Griffiths
authors.forename: Rongjun
authors.initials: R
authors.lastname: Chen
authors.forename: Nigel K H
authors.initials: NK
authors.lastname: Slater
authors.forename: John K
authors.initials: JK
authors.lastname: Park
keywords: anionic polymer; endosome; glioblastoma; siRNA delivery; stathmin; tumor treatment