Potential of lectin-N-(2-hydroxypropyl)methacrylamide copolymer-drug conjugates for the treatment of pre-cancerous conditions

N-(2-Hydroxypropyl)methacrylamide (HPMA)-lectin (wheat germ agglutinin (WGA ), peanut agglutinin (PNA)) drug conjugates for treatment of the pre-cancer ous conditions ulcerative colitis and Barrett's esophagus are being develop ed. Cell-surface glycoproteins that are altered in disease and development bind lectins. PNA binds a-lactose and the Thomsen-Friedenreich (TF) antigen , a disease- and development-associated glycoprotein. PNA incorporation in conjugates may allow for preferential delivery to diseased over healthy tis sues. Conjugates were prepared by attaching lectins to HPMA copolymers via an amide linkage. Frontal affinity chromatography was used to measure disso ciation constants (K-d) of free and conjugated lectins. Animal models of co litis (DSS, TNBS/EtOH) were developed. Human biopsy specimens were obtained . Free and HPMA copolymer-conjugated FITC-labeled lectin and anti-TF antige n antibody binding patterns were examined in nor-mat neonatal. adult and di seased rodent tissues and normal and diseased human tissues. K-d values of free and conjugated lectins were similar (similar to 10(-5) M-1). Free and conjugated lectins had comparable binding patterns. In health, strong WGA b inding was seen in goblet cells PNA binding was minimal, occurring only in the supranuclear goblet cell region. In disease, WGA binding was not altere d, but PNA binding was increased in both human and rodent tissues; entire g oblets bound the lectin. Anti-TF antigen antibody binding was minimal, but did overlap with PNA binding patterns both in normal and diseased tissues. Conjugation of lectins to HPMA copolymers does not affect binding affinity. Alterations in glycoprotein structures in development and disease resulted in modified lectin binding patterns. In development and disease, the PNA b inding seen was to the TF antigen and other lactose-containing glycoprotein s. The results suggest that site-specific delivery of therapeutic agents su ch as cyclosporin A (CsA) for ulcerative colitis and mesochlorin e(6) for B arrett's esophagus may be achieved. P(HPMA)-lectin-CsA conjugates have been prepared and preliminary in vivo studies are underway. (C) 2001 Elsevier S cience BM All rights reserved.