Targeting polysaccharide–methotrexate conjugates to the rat brain

Delivery of drugs to brain tumors is difficult due to the impermeability, and variable nature of the blood/tumor barrier. Of the various strategies designed to improve drug uptake‐intracellularly and into the brain, cationic carriers seem to offer an advantage. In the current investigation cationic polysaccharide–methotrexate conjugates were examined in the rat. Conjugates were prepared from N,O‐carboxymethyl chitosan (NOCC) and ³H‐methotrexate (MTX) by two different synthetic schemes, resulting in NOCCMTX‐1 and NOCCMTX‐2. NOCCMTX‐1 appeared to have a higher degree of cross‐polymerization than NOCCMTX‐2. Each conjugate and free MTX were administered intra‐arterially in a retrograde manner in the external carotid artery at a MTX dose of 1 mg/kg as a constant rate infusion over 30 min. Animals were sacrificed at various times after administration, and blood and tissue samples collected, processed in a sample oxidizer, and then measured for radioactivity. Brain MTX concentrations were 18‐ and 12‐fold greater at 15 min and 3 hr, respectively, following NOCCMTX‐1 administration compared to free MTX treatment. However, NOCCMTX‐1 resulted in animal death at about 12 hr after administration. NOCMTX‐2 was found to be non‐toxic, yet did not increase brain MTX concentrations compared to free drug administrations after correction for MTX in residual blood. Further investigations are planned to combine the positive drug targeting effect of NOCCMTX‐1 with the safety of NOCCMTX‐2.