Polylysine conjugates of Bowman-Birk protease inhibitor as targeted anti-carcinogenic agents.
Bowman-Birk protease inhibitor (BBI), an 8000 mol. wt polypeptide with anti-carcinogenic activity, was coupled to poly(D-lysine) (BBI-SS-PDL) and poly(L-glutamate) (BBI-SS-PLG) with a disulfide-cross-linking agent, N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP). In vitro transformation assays showed that BBI-SS-PDL, but not BBI-SS-PLG, retained the full anticarcinogenic activity of BBI. When administered i.v. to Balb/c mice, a selective localization in the lungs was found with BBI-SS-PDL but not with BBI or BBI-SS-PLG. At 30 min, 3 h and 24 h after the injection of BBI-SS-PDL, the amounts of BBI in the lungs were 118%, 74% and 19% of the injected dose/g of tissue respectively. At the same time points, the amount of radioactivity in the lungs of mice injected with BBI was 5%, 3% and 1% of the injected dose/g of tissue respectively. Therefore, higher amounts of BBI could be targeted to the lungs by injecting BBI as a PDL conjugate. BBI-SS-PDL was also retained in the lungs for a longer period of time than free BBI. In previous studies, BBI has been shown to suppress lung carcinogenesis. The results presented here suggest that BBI-SS-PDL could be more effective than BBI as an anti-carcinogenic agent for the lung.
Persiani
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S
Drug Targeting Research, University of Southern California School of Pharmacy, Los Angeles 90033.
Yeung
A
A
Shen
W C
WC
Kennedy
A R
AR
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011107:Polylysine / Q000008:administration & dosage*; D014358:Trypsin Inhibitor, Bowman-Birk Soybean / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
D000970:Antineoplastic Agents; D014358:Trypsin Inhibitor, Bowman-Birk Soybean; D011107:Polylysine