Enhanced Lymphatic Delivery of Mitomycin C Conjugated with Dextran

Absorption and lymphatic transfer of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), following i.m. injection were studied in rats in order to assess the feasibility of a macromolecular prodrug as a lymphotropic delivery system. Three types of MMC-D, conjugates with dextran with molecular weights of 10,000, 70,000 and 500,000, were synthesized, and the disposition of MMC was determined by bioassay. Following i.m. injection of MMC-D, MMC was retained at the injection site for a long period in a conjugated form while MMC administered as a free form disappeared rapidly. The disappearance was markedly influenced by the size of carrier dextran, because the remaining amount of MMC increased with an increase of molecular size. The lymphatic uptake of the drug was evaluated by determining the concentration in the regional lymph nodes and thoracic lymph fluid. In contrast to a slight lymphatic uptake following i.v. and i.m. injection of free MMC, MMC-D exhibited remarkable accumulation in the regional lymph nodes after i.m. injection which persisted up to 48 hr. MMC-D (Mr 10,000) appeared in the thoracic lymph as both the conjugated and the free form. Larger MMC-D gave a persistent supply of free MMC in thoracic lymph, suggesting that it was accumulated in the lymph node and supplying MMC continuously. These MMC-Ds suppressed the lymph node metastases introduced by a s.c. inoculation of L1210 leukemia cells. The usefulness of MMC-D as a lymphotropic delivery system for preventing lymphatic metastasis of cancer was suggested.