2020-04-05 17:55:23

barrier blood Brain delivery antisense

责任者: BOADO, RJ 单位: UNIV CALIF LOS ANGELES,SCH MED,BRAIN RES INST,LOS ANGELES,CA 90095. 来源出处: ADVANCED DRUG DELIVERY REVIEWS, v 15, JUL 1995, p 73- 107 摘要: The blood-brain barrier evolved to protect the brain against peripheral neurotransmitters, cytotoxins and microorganisms. This barrier prevents the delivery to brain of antisense oligomers and other potential therapeutics for the treatment of viral infections, tumors, and other brain disorders. The brain represents a shelter for the human immunodeficiency virus (HIV), for low grade gliomas, and early stages of metastatic tumors to the brain. Non-invasive delivery systems for antisense oligodeoxynucleotide (ODN) therapeutics have been developed that include transcellular avidin-based delivery systems, such as conjugates of avidin analogues and the monoclonal antibody directed to the transferrin receptor (OX26), which targets all tissues expressing these receptors including the blood-brain barrier and liver. Although 3-biotinylation of phosphodies ter oligodeoxynucleotides provides complete protection against serum and cellular exonuclease-mediated degradation, the in vivo administration of unconjugated or vector-conjugated biotinylated PO-ODN results in a rapid degradation through an endonuclease-mediated mechanism, thus limiting the efficacy of this potential therapeutic for the brain. This rapid in vivo degradation also occurs with phosphorothioate-ODN containing a single internal phosphodiester bond. Alternatively, a biotinylated peptide nucleic acid (PNA) conjugated to the OX,26-streptavidin delivery system is metabolically stable in vivo and is transported to brain through the blood-brain barrier at a rate 28-fold higher than the oligomer alone. This results in a brain uptake comparable to that of morphine, a molecule well known for its pharmacological brain effects. In summary, this review discusses different approaches for delivery of antisense oligonucleotides to the brain and suggests that biotinylated PNA conjugated to avidin-based transcellular delivery system represents a model for the delivery of antisense therapeutics through the blood-brain barrier. 关键词: ENDOTHELIUM; BLOOD-BRAIN BARRIER; DRUG DELIVERY; ANTISENSE OLIGODEOXYNUCLEOTIDE; RNASE H; PHARMACOKINETICS; PHOSPHOROTHIOATE; OLIGODEOXYNUCLEOTIDE; RNASE H; PHARMACOKINETICS; PHOSPHOROTHIOATE; PEPTIDE NUCLEIC ACID PEPTIDE NUCLEIC ACID; HUMAN-IMMUNODEFICIENCY-VIRUS; PEPTIDE NUCLEIC-ACIDS; ANTI-SENSE OLIGODEOXYNUCLEOTIDES; DOXORUBICIN-LOADED NANOPARTICLES; OLIGODEOXYNUCLEOTIDES; DOXORUBICIN-LOADED NANOPARTICLES; THYMINE-SUBSTITUTED POLYAMIDE; SEQUENCE-SPECIFIC INHIBITION; AIDS THYMINE-SUBSTITUTED POLYAMIDE; SEQUENCE-SPECIFIC INHIBITION; AIDS DEMENTIA COMPLEX; HA-RAS ONCOGENE; GENE-EXPRESSION; CELLULAR UPTAKE DEMENTIA COMPLEX; HA-RAS ONCOGENE; GENE-EXPRESSION; CELLULAR UPTAKE