THE POTENTIAL OF WATER-SOLUBLE POLYMERIC CARRIERS IN TARGETED AND SITE-SPECIFIC DRUG DELIVERY

The design of targetable water-soluble polymeric drug carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers is described. Three types of conjugates have been studied: (a) HPMA copolymers containing oligopeptide side-chains terminated in anticancer drugs (daunomycin, adriamycin); (b) conjugates of HPMA copolymers with chlorin e6 (photoactivatable drug); and (c) HPMA copolymers for site-specific oral delivery of 5-aminosalicylic acid (5-ASA). Polymer-bound drugs (a) and (b) are lysosomotropic. When conjugated to a targeting moiety (galactosamine or antibody) their concentration in the target tissue is increased. It was shown that binding drugs to HPMA copolymers decreases their toxicity and immunogenicity. Two ways of drug activation in the lysosomal compartment are discussed: release by lysosomal cysteine proteinases (daunomycin, adriamycin) and activation by light (chlorin e6). Conjugates of chlorin e6 with HPMA copolymers and optionally galactosamine were synthesized and their photodynamic activity was tested in vitro on a human hepatoma cell line (PLC/PRF/5 cells). The conjugate containing galactosamine as the targeting moiety was more active compared to the conjugate without the targeting moiety. A new concept of oral drug delivery was proposed based on a combination of site-specific delivery of 5-ASA to the colon with bioadhesive properties of the carrier. HPMA copolymers containing saccharide units complementary to mucosal lectins of the GI tract are used as carriers. They also contain side-chains terminated in salicylic acid bound via an azo bond. Cleavage experiments were carried out using an isolated strain of bacteria commonly found in the colon. When incubated with Streptococcum faecium in vitro 5-ASA is released. Body distributions in guinea pigs after oral administration have shown that HPMA copolymers containing fucosylamine associate with the colon. Further experiments are necessary to verify the therapeutical importance of these observations and to develop water soluble polymers as carriers for site-specific oral delivery. © 1990.