Intratumoral Pharmacokinetics of Oligonucleotides in a Tissue-Isolated Tumor Perfusion System

Abstract

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.

Lipid Carrier Systems for Targeted Drug and Gene Delivery

“…[21][22][23] This is a unique system, composed of a solid tumor with a pair of supplying arteries and a draining vein, and enabled us to study the intratumoral pharmacokinetics of a variety of materials, independent of the systemic circulation. The pharmacokinetics of anticancer drugs, macromolecular prodrugs and drug carriers following intraarterial infusion or direct injection into the tumor have been studied with this system.…”

“…[21][22][23] Approximately 50% of the naked pDNA was eliminated from the tumor 2 h after injection and intact pDNA was found in the venous outflow, while more than 90% of the pDNA was retained in the tumor when complexed with cationic liposomes (Lipofectin ® ), suggesting that the cationic liposomes increase the retention of pDNA in the tumor tissue due to electrostatic interaction which results in less appearing in the venous outflow.…”