As one of the most professional providers, Creative Biolabs has decades of experience and abundant knowledge of drug discovery and development. Now, we offer perfect phenol mustard glucuronide as a prodrug for antibody-directed enzyme prodrug therapy (ADEPT) development such as the antibody-β-glucuronidase conjugate.
Phenol mustard glucuronide is a type of prodrug synthesized from phenol mustard and glucuronide. During the past, a glucuronide prodrug [(ρ-di-2-chloroethylaminophenol-β-D-glucopyranosid) uronic acid, HAMG] of ρ-hydroxyaniline mustard [N, N-di-(2-chloroethyl)-4-hydroxyaniline, HAM] has been used to cure mice bearing well-established PC5 plasma tumors which contain high levels of β-glucuronidase. The relatively nontoxic prodrug HAMG can be apparently formed in the liver of mice when treated with aniline mustard [N, N-di-(2-chloroethyl) aniline], and subsequently, convert to highly cytotoxic ρ-hydroxyaniline mustard by glucuronidase at the tumor site.
The prodrug phenol mustard glucuronide can be activated by β-glucuronidase hydrolysis, yielding the parent drug phenol mustard. Phenol mustard glucuronide is a latent form of phenol mustard that can be converted to phenol mustard by β-glucuronidase at neutral pH. Phenol mustard is a kind of inhibitor that can bind to the glutamic acid residue, and inhibit the synthesis of protein. Tumor cells expressing tumor-associated antigen on their surface can be selectively killed by targeting β-glucuronidase. Antibody-directed enzymatic activation of glucuronide prodrugs could lead to more specific chemotherapy treatments.
Fig.1 Prodrugs activated by hydrolysis of an aromatic or aliphatic glycosyl bond. (Niculescu-Duvaz, 2004)
Phenol Mustard Glucuronide-based ADEPT
ADEPT relies on an antibody directed at a tumor-associated antigen is used to deliver a specific enzyme to the tumor site. The tumor-located enzyme converts a subsequently administered prodrug (phenol mustard glucuronide) into an active cytotoxic agent (phenol mustard). A type of phenol mustard glucuronide prodrug (BHAMG) was activated at hepatoma ascites in Sprague-Dawley rats. Injection of RH1-βG, a conjugate formed between recombinant βG (β-glucuronidase) and monoclonal antibody RH1 with specificity for an antigen expressed on AS-30D rat hepatoma cells, into rats bearing AS-30D ascites resulted in a significant accumulation of conjugate in tumor cells after 2 hr. Treatment of rats bearing established hepatoma ascites with RH1-bG resulted in the cure of most animals. Treatment with antibody-βG conjugate and BHAMG produced significantly greater hematological toxicity when compared to treatment with RH1-bG and BHAMG alone. All cured rats were completely protected from rechallenge with AS-30D cells which show that successful treatment of animals induced protective immunity, and antibody-directed enzymatic activation of glucuronide prodrugs could lead to more specific chemotherapy treatments.
Fig 2. Mechanism of ADEPT action. (Thanki, 2015)
Creative Biolabs is dedicated to preparing high-quality phenol mustard glucuronide and helping customers develop ADEPT. Our prodrug is suitable for antibody-β-glucuronidase conjugate development through customized linkers or direct fusion protein manner in a cost-effective and timely method. We provide our clients with a wide range of prodrugs for your ADEPT development. Please contact us for more information and a detailed quote.
References
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