Plenat F, Klein-Monhoven N, Marie B, Vignaud J M, Duprez A
Laboratory Pathological Anatomy, Division of Medecine, Vandoeuvre les Nancy, France.
Am J Pathol. 1995 Jul;147(1):124-35.
Antisense oligonucleotides have the ability to inhibit individual gene expression in the potential treatment of cancer and viral diseases. However, the way parenterally administered oligonucleotides distribute themselves into healthy tissues or tumors is poorly understood. In this study, the cell and tissue distribution of two modified or unmodified phosphodiester pentadeca-beta-oligonucleotides intravenously administered to healthy or tumor-bearing nude mice was assessed by autoradiography as well as by direct fluorescence and immunoenzymatic histological methods. Resistance of oligonucleotides to degradation by nuclease activity was previously studied in vitro. Using these methods we were able to show the following: 1) within minutes, oligonucleotides permeate all cells and tissues with the exceptions of erythrocytes and intervertebral discs; 2) cell and tissue distribution does not depend on the sequence of the given oligonucleotide; 3) concentration of oligonucleotides is higher within the connective tissue cells than in the interstitial matrix; 4) after uptake, oligomers partition throughout all of the cellular compartments, including at the highest intracellular concentrations in the nuclei; 5) oligonucleotides penetrate easily the tumor cell compartments, oligonucleotide diffusion being unimpeded by the extracellular matrix.
反义寡核苷酸在癌症和病毒疾病的潜在治疗中具有抑制单个基因表达的能力。然而，人们对经肠胃外给药的寡核苷酸在健康组织或肿瘤中的分布方式了解甚少。在本研究中，通过放射自显影以及直接荧光和免疫酶组织学方法，评估了静脉注射给健康或荷瘤裸鼠的两种修饰或未修饰的磷酸二酯十五聚体β寡核苷酸的细胞和组织分布。此前已在体外研究了寡核苷酸对核酸酶活性降解的抗性。使用这些方法我们能够得出以下结果：1）在数分钟内，寡核苷酸可渗透到除红细胞和椎间盘外的所有细胞和组织中；2）细胞和组织分布不取决于给定寡核苷酸的序列；3）结缔组织细胞内的寡核苷酸浓度高于间质基质中的浓度；4）摄取后，寡聚物分布于所有细胞区室，包括细胞核内细胞内浓度最高的区域；5）寡核苷酸可轻易穿透肿瘤细胞区室，其扩散不受细胞外基质的阻碍。
