Tumor targeting: Activation of prodrugs by enzyme-monoclonal antibody conjugates

Lipoamino Acid Conjugates of Methotrexate with Antitumor Activity

“…8,11 It is however noteworthy than many R-substituted MTX derivatives showed interesting features as possible prodrugs in enzyme-assisted therapeutic schemes (e.g., ADEPT approach). 19,20 The activity of compounds 1e, 1f, 1j, 1m, 1n, 1r, and 1a were also tested against a CEM cell subline (CEM/R), which is defective in the physiological "reduced folate" carrier system (RFC). MTX (1a) is 100 times less potent against CEM/R than against the parental CEM cells.…”

“…H NMR (DMSO-d 6 ) δ 8.55 (1H, s, H-7), 7.99 (1H, br s, CONH-Glu), 7.72-7.70, 6.82-6.78 (4H, 2d, arom),6.57 (1H, s, CO-NH), 4.77 (2H, s, 9-CH 2 ), 4.40, 4.10 (2H, br, 2 R-CH), 3.19 (3H, s, NCH 3 ), 2.00-1.40 (4H, br m, CH 2 γ CH 2 CO),1.35 (4H, s, 2 -CH 2 ), 1.17 (24H, 3s, 12 CH 2 ), 0.82 (6H, t, 2 CH 3 ); FAB-MS (m/z, %) 837, 815 [M + 2Na, M + Na] + (10, 35), 794 [M + 1] + (54), 641 (18), 606 (12), 482 (68), 460 (100), 443 (29), 430 (72), 410 (56); EI-MS (m/ z, %) 662 (20), 648, 647 (26, 62), 631 (3), 530 (63), 515 (49), 441 (83), 337 (29), 320 (27), 276 (22), 219 (48), 136 (58), 121 (67), 109 (100). Methotrexate R,γ-bis[2-(2-aminodecanoyl)-aminodecanoic acid] (1k)s 1 H NMR (CDCl 3 -MeOD) δ 7.80, 6.85 (4H, br, arom), 4.89 (2H, s, 9-CH 2 ), 4.50 (4H, m, 4 R-CH), 3.31 (3H, s, NCH 3 ), 2.00-1.75 (4H, br m, CH 2 γ CH 2 CO), 1.37 (56H, s, 28 CH 2 ), 0.97 (12H, t, 4 CH 3 ); FAB-MS (m/z, %) 1197, 1176, 1154 [M + 3Na, + 2Na, + Na] + (12, 33, 100), 1132 [M + 1] + (37), 984 (16), 978 (12), 951 (11), 663(20), 646(15), 530(12).Methotrexate R,γ-bis(2-aminododecanoic acid) (1l)s 1 H NMR (CDCl 3 -MeOD) δ 8.60 (1H,s, H-7), 8.05 (1H, br, CONH-Glu), 7.77-6.80 (4H, 2d, arom), 6.65 (2H, br, NH 2 ), 4.83 (2H, s, 9-CH 2 ), 4.15 (2H, br, 2 R-CH), 3.40 (3H, s, NCH 3 ), 2.10-1.50 (4H, m, CH 2 γ CH 2 CO), 1.25 (36H, 2s, 18 CH 2 ), 0.90 (6H, t, 2 CH 3 ); FAB-MS (m/z, %) 916, 894, 872 [M + 3Na, +2Na, +Na] + (3, 11, 33), 849 [M + 1] + (18), 613 (11), 483, 482 (29, 65), 460 (100), 443 (25), 413 (27). Methotrexate R,γ-bis(2-aminotetradecanoic acid) (1m)s 1 H NMR (DMSO-d 6 ) δ 8.55 (1H, s, H-7), 8.00 (1H, m, CO-NH-Glu), 7.69, 6.79 (4H, 2d, arom), 7.40 (2H, bs, NH 2 ), 6.53 (1H, s, CO-NH), 4.75 (2H, s, 9-CH 2 ), 4.35, 4.11 (2H, m, 2 R-CH), 3.17 (3H, s, NCH 3 ), 2.2-1.5 (4H, m, CH 2 γ CH 2 CO), 1.18 (44H, s, 22 CH 2 ), 0.81 (6H, t, 2 CH 3 ); FAB-MS (m/z, %) 971, 949, 928 [M + 3Na, +2Na, +Na] + (13, 37, 100), 906 [M + 1] + (46), 881 (13), 753 (31), 663 (59), 649 (52), 590 (43), 530 (50), 491 (47), 469 (70), 460 (66), 441 (85), 421 (62), 412 (52).…”

Biopharmaceuticals, an overview

“…More recently, greater emphasis has been placed upon development of monoclonal antibody preparations used to detect or treat various cancers (55,56). Upon transformation, many cells express cell surface proteins which are either not normally present on the untransformed cell, or are expressed in ultra low quantities.…”

Novel Gene Therapeutic Approaches to Brain Cancer

“…Likewise conjugation of prodrugs to monoclonal antibodies may also be used for specific targeting (113)(114)(115). In antibody-directed enzyme prodrug therapy (ADEPT); the catalytic enzyme is covalently linked to an antibody, which recognizes tumor-specific antigen and binds to this specific surface antigen, causing its internalization together with the activating enzyme.…”