title: Balancing polymer hydrophobicity for ligand presentation and siRNA delivery in dual function CXCR4 inhibiting polyplexes.
abstract: In the present study, a series of copolymers (PAMD-Ch) was synthesized by grafting polymeric Plerixafor/AMD3100 (PAMD) with different amounts of cholesterol and the effect of cholesterol modification on siRNA delivery was investigated. PAMD-Ch/siRNA polyplexes exhibited improved colloidal and enzymatic stability when compared with PAMD/siRNA polyplexes containing no cholesterol. PAMD-Ch with low (17 wt%) and medium (25 wt%) cholesterol content exhibited CXCR4 antagonism comparable to unmodified PAMD. Cholesterol modification increased cell uptake of siRNA polyplexes and significantly decreased sensitivity of siRNA transfection to the presence of serum. When used to deliver anticancer siRNA against polo-like kinase 1 (PLK1), polyplexes based on PAMD-Ch with 17 wt% cholesterol exhibited the highest cancer cell killing activity both in serum-free and serum-containing conditions. Overall, the results of this study validate cholesterol modified PAMD as dual-function delivery vectors suitable for efficient delivery of anticancer siRNA and simultaneous CXCR4 inhibition for combined anticancer therapies.
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA. ; Department of Chemistry, University of Nebraska, Lincoln, NE, USA. ; Department of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China.
authors.forename: D
authors.initials: D
authors.lastname: Oupický
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001596:Benzylamines; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D002784:Cholesterol / Q000737:chemistry*; D000080027:Cyclams; D016503:Drug Delivery Systems; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects*; D008024:Ligands; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014162:Transfection; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D001596:Benzylamines; D018797:Cell Cycle Proteins; D002784:Cholesterol; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008024:Ligands; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D011108:Polymers; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D000097869:Polo-Like Kinase 1; C527276:CXCR4 protein, human; C088327:plerixafor
keywords: CXCR4; PLK-1; cancer; polyplexes; siRNA