Intratumoral pharmacokinetics of oligonucleotides in a tissue-isolated tumor perfusion system.
The intratumoral pharmacokinetics of model oligonucleotides were studied in Walker 256 tissue-isolated tumor preparations using an in situ single-pass vascular perfusion technique. A 20-mer phosphodiester (PO) oligonucleotide, its fully phosphorothioated (PS) oligonucleotide counterpart, and an 18-mer phosphorothioated oligonucleotide containing four 2'-O-methylribonucleosides at both the 3'-end and 5'-end (PS-OMe) were used. These oligonucleotides were administered to the tumor in two ways, by constant arterial infusion and by direct intratumoral injection. In the case of constant arterial infusion, the experiments were carried out using perfusate with or without 4.7% bovine serum albumin (BSA). The protein binding of PO, PS, and PS-OMe to BSA was 46%, 87%, and 94%, respectively. No marked difference was observed between the degree of accumulation of the three types of oligonucleotides in the tumor when BSA was present in the perfusate. PS and PS-OMe showed higher degrees of accumulation in tumors compared with PO when no BSA was present. These results indicate that free (i.e., protein unbound) PS-OMe and PS have superior tumor accumulation characteristics. In the intratumoral injection experiments, PS-OMe was retained longer in tumor tissue compared with PS, suggesting that it might be useful for direct local injection into solid tumors. Thus, the present study provides useful information about the basic disposition characteristics of oligonucleotides in solid tumors.
Nakajima
S
S
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Koshino
Y
Y
Nomura
T
T
Yamashita
F
F
Agrawal
S
S
Takakura
Y
Y
Hashida
M
M
D000818:Animals; D002279:Carcinoma 256, Walker / Q000378:metabolism*; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods; D005260:Female; D007261:Infusions, Intra-Arterial; D015552:Injections, Intralesional; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation / Q000379:methods; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000493:pharmacokinetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense