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      Characterization of Serine Protease Inhibitor from Solanum tuberosum Conjugated to Soluble Dextran and Particle Carriers

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      ACS Omega
      American Chemical Society

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          Abstract

          A serine protease inhibitor was extracted from potato tubers. The inhibitor was conjugated to soluble, prefractionated dextran and titanium dioxide and zinc oxide nanoparticles. Conjugation to dextran was achieved by periodate oxidation of the dextran, followed by Schiff base coupling to inhibitor amino groups, and finally reduction, whereas the conjugation to the oxide particles was carried out by aminosilanization and carbonyldiimidazole activation. The inhibitory effect of the conjugated inhibitor was compared to that of free inhibitor in solution and with gelatin gel as a direct substrate. A certain degree of inhibitory activity was retained for both the dextran-conjugated and particle-conjugated inhibitors. In particular, the apparent K i value of the dextran-conjugated inhibitor was found to be in the same range as that for free inhibitor. The dextran conjugate retained a higher activity than the free inhibitor after 1 month of storage at room temperature.

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          Most cited references32

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          Chemopreventive agents: protease inhibitors.

          Certain protease inhibitors, called the anticarcinogenic protease inhibitors in this review, are capable of preventing carcinogenesis in a wide variety of in vivo and in vitro model systems. The anticarcinogenic protease inhibitors are extremely potent agents with the ability to prevent cancer, with some unique characteristics as anticarcinogenic agents. The anticarcinogenic protease inhibitors have the ability to irreversibly suppress the carcinogenic process. They do not have to be continuously present to suppress carcinogenesis. They can be effective when applied in both in vivo and in vitro carcinogenesis assay systems at long time periods after carcinogen exposure, and are effective as anticarcinogenic agents at extremely low molar concentrations. While several different types of protease inhibitors can prevent the carcinogenic process, the most potent of the anticarcinogenic protease inhibitors on a molar basis are those with the ability to inhibit chymotrypsin or chymotrypsin-like proteases. The soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), is a potent chymotrypsin inhibitor that has been extensively studied for its ability to prevent carcinogenesis in many different model systems. Much of this review is focused on the characteristics of BBI as the anticarcinogenic protease inhibitor, as this is the protease inhibitor that has risen to the human trial stage as a human cancer chemopreventive agent. Part of this review hypothesizes that the Bowman-Birk family of protease inhibitors plays a role in plants similar to that of alpha1-antichymotrypsin in people. Both BBI and alpha1-antichymotrypsin are potent inhibitors of chymotrypsin and chymotrypsin-like enzymes, are highly anti-inflammatory, and are thought to play important roles in the defense of their respective organisms. It is believed that BBI will be shown to play a major role in the prevention and/or treatment of several different diseases, in addition to cancer.
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            Dextran conjugates in drug delivery.

            Dextran is a family of natural polysaccharides that is widely under investigation for use as polymeric carriers in novel drug delivery systems. The optimal drug delivery (and consequently maximum therapeutic effect) will be accomplished when carrier systems are used mainly for drugs with antitumoral activity, as they increase their blood permanence time, taking advantage of the increased mass that reduces kidney ultrafiltration. This review summarizes the attempts that have been made in the development of dextran conjugates and their application. The manuscript describes dextran hydrogels, the use of conjugates of dextran in bioadhesive oral delivery systems, colon drug delivery, reduction of ulcerogenicity of drugs, production of micelles, solubilization, long-circulating pharmaceutical carriers as anticancer drug carriers, non-viral vectors, stabilization of enzymes, functionalization of nanomaterials, diagnosis of solid tumors and hyperthermic treatment and liver targeting. Dextran conjugation has aided the design of new tailor-made polymers with different molecular weights, shapes, structures and with the functional groups needed for coupling at the desired positions in the chain. Dextran prodrugs are very useful systems for achieving controlled drug release and drug targeting. In particular, various dextran-antitumor drug conjugates enhance the effectiveness and improve the cytotoxic effects of chemotherapeutic agents. Future studies should concentrate on barriers for their clinical use and safety as a drug carrier.
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              The Bowman-Birk inhibitor from soybeans as an anticarcinogenic agent.

              Certain protease inhibitors are effective at preventing or suppressing carcinogen-induced transformation in vitro and carcinogenesis in animal model systems. One protease inhibitor, the soybean-derived Bowman-Birk inhibitor (BBI) is particularly effective in suppressing carcinogenesis. BBI is a protein of a molecular weight of 8000 with a well-characterized ability to inhibit trypsin and chymotrypsin. BBI has been extensively studied, both as purified BBI and as an extract of soybeans enriched in BBI called BBI concentrate (BBIC). Purified BBI and BBIC have comparable suppressive effects on the carcinogenic process in a variety of in vivo and in vitro systems. BBI appears to be a universal cancer preventive agent. Purified BBI and BBIC suppress carcinogenesis as follows: in 3 different species (mice, rats, and hamsters); in several organ systems and tissue types [eg, colon, liver, lung, esophagus, cheek pouch (oral epithelium), and cells of hematopoietic origin]; and in cells of epithelial and connective tissue origin when given to animals by several different routes of administration, including the diet, leading to different types of cancer (eg, squamous cell carcinomas, adenocarcinomas, and angiosarcomas), and induced by various chemical and physical carcinogens. About half of an oral dose of BBI is taken up into the bloodstream and distributed throughout the body, with excretion via the urine. Pharmacokinetic studies of BBI have been performed in animals with radioactively labeled BBI, whereas antibodies that react with reduced BBI are being used in pharmacokinetic studies in humans. The calculated serum half-life is 10 h in both rats and hamsters. BBIC achieved Investigational New Drug status from the FDA in April 1992 (IND no. 34671; sponsor, Ann R Kennedy), and studies to evaluate BBIC as an anticarcinogenic agent in human populations began. Both BBI and BBIC prevent and suppress malignant transformation in vitro and carcinogenesis in vivo without toxicity.
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                Author and article information

                Journal
                ACS Omega
                ACS Omega
                ao
                acsodf
                ACS Omega
                American Chemical Society
                2470-1343
                25 October 2019
                05 November 2019
                : 4
                : 19
                : 18456-18464
                Affiliations
                [1]Department of Chemistry—BMC, Uppsala University , P.O. Box 576, SE-751 23 Uppsala, Sweden
                Author notes
                [* ]E-mail: erika.billinger@ 123456kemi.uu.se . Phone: +46 18 471 43 12.
                Article
                10.1021/acsomega.9b02815
                6844106
                bbf965fd-ab07-4e65-aa59-d9bfeb24b35f
                Copyright © 2019 American Chemical Society

                This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

                History
                : 31 August 2019
                : 11 October 2019
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                ao9b02815

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