title: Anti-CD22 antibody targeting of pH-responsive micelles enhances small interfering RNA delivery and gene silencing in lymphoma cells.
abstract: The application of small interfering RNA (siRNA) for cancer treatment is a promising strategy currently being explored in early phase clinical trials. However, efficient systemic delivery limits clinical implementation. We developed and tested a novel delivery system comprised of (i) an internalizing streptavidin-conjugated monoclonal antibody (mAb-SA) directed against CD22 and (ii) a biotinylated diblock copolymer containing both a positively charged siRNA condensing block and a pH-responsive block to facilitate endosome release. The modular design of the carrier facilitates the exchange of different targeting moieties and siRNAs to permit its usage in a variety of tumor types. The polymer was synthesized using the reversible addition fragmentation chain transfer (RAFT) technique and formed micelles capable of binding siRNA and mAb-SA. A hemolysis assay confirmed the predicted membrane destabilizing activity of the polymer under acidic conditions typical of the endosomal compartment. Enhanced siRNA uptake was demonstrated in DoHH2 lymphoma and transduced HeLa-R cells expressing CD22 but not in CD22 negative HeLa-R cells. Gene knockdown was significantly improved with CD22-targeted vs. nontargeted polymeric micelles. Treatment of DoHH2 cells with CD22-targeted polymeric micelles containing 15 nmol/l siRNA produced 70% reduction of gene expression. This CD22-targeted polymer carrier may be useful for siRNA delivery to lymphoma cells.
authors.affiliation: Clinical Research Division and Center for Intracellular Delivery of Biologics, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. cpalwes@u.washington.edu
authors.forename: Maria C
authors.initials: MC
authors.lastname: Palanca-Wessels
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Convertine
authors.forename: Richelle
authors.initials: R
authors.lastname: Cutler-Strom
authors.forename: Garrett C
authors.initials: GC
authors.lastname: Booth
authors.forename: Fan
authors.initials: F
authors.lastname: Lee
authors.forename: Geoffrey Y
authors.initials: GY
authors.lastname: Berguig
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Stayton
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D008823:Micelles; D011108:Polymers / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D019809:Streptavidin / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D008823:Micelles; D011108:Polymers; D034741:RNA, Small Interfering; D051918:Sialic Acid Binding Ig-like Lectin 2; D019809:Streptavidin