Internally cationic polyamidoamine PAMAM-OH dendrimers for siRNA delivery: effect of the degree of quaternization and cancer targeting.
A novel cancer targeted, internally cationic and surface neutral polyamidoamine (PAMAM) dendrimer, was designed, synthesized, and evaluated as a nanocarrier for the targeted intracellular delivery of siRNA. The dendrimer contained a synthetic analog of Luteinizing hormone-releasing hormone as cancer targeting moiety. The proposed delivery system possesses the following advantages: (1) internal cationic charges for complexation with siRNA and enhanced siRNA protection; (2) low cytotoxicity; (3) lesser degree of quaternization offering free tertiary amines for potential proton sponge effect; and (4) targeting specifically to cancer cells for enhancing siRNA uptake and efficiency and potential limitation of adverse side effects of chemotherapy on healthy organs. Both nontargeted and targeted dendrimer-siRNA complexes formed compact nanometer size spherical particles, exhibited very low cytotoxicity even at the higher concentration, and efficiently penetrated cancer cells in vitro. However, only the targeted dendrimer-siRNA complex was able to substantially decrease the expression of a targeted BCL2 gene.
Patil
Mahesh L
ML
Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Zhang
Min
M
Taratula
Oleh
O
Garbuzenko
Olga B
OB
He
Huixin
H
Minko
Tamara
T
D045744:Cell Line, Tumor; D050091:Dendrimers; D016503:Drug Delivery Systems / Q000379:methods*; D019254:Genes, bcl-2 / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000187:drug effects; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy*; D011073:Polyamines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use
D050091:Dendrimers; C104700:PAMAM Starburst; D011073:Polyamines; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; D007987:Gonadotropin-Releasing Hormone