Prodrug-Glucuronide Camptothecin

Creative Biolabs provides comprehensive antibody-directed enzyme prodrug therapy (ADEPT) development services to pharmaceutical, biotech, and agrochemical companies as well as governmental and academic research institutes. Aided by our specialized strategies and advanced platforms, glucuronide camptothecin can be used as a prodrug of antibody-purine nucleoside phosphorylase conjugate-based ADEPT.

Glucuronide Camptothecin

Glucuronide camptothecin is a type of prodrug produced from camptothecin and glucuronide. Glucuronide, which is also referred to as glucuronoside, is substance produced by linking glucuronic acid to another substance via a glycosidic bond. The prodrug could catalyze and produce the drug camptothecin (CPT), which was discovered in 1966. It is a topoisomerase inhibitor and a natural product isolated from the bark and stem of camptotheca acuminata (Camptotheca, Happy tree) which has been used as anticancer drugs. CPT shows significant anticancer activity in preliminary clinical trials. Due to its low solubility, numerous camptothecin such as 9-aminocamptothecin and 10-hydroxycamptothecin are synthesized. Furthermore, various derivatives could increase the treatment benefit of the chemical with good results.

Glucuronide prodrugs of 9-aminocamptothecin and 10-hydroxycamptothecin. Fig.1 Glucuronide prodrugs of 9-aminocamptothecin and 10-hydroxycamptothecin. (Tranoy-Opalinski, 2014)

MOA of Glucuronide Camptothecin

The β-glucuronidase enzyme catalyzes the cleavage of prodrug glucuronide camptothecin to produce effective camptothecin (CPT), which is a chemotherapy medication used to treat cancer. Camptothecin can directly destroy DNA structure and make DNA susceptible to endonuclease attack by binding to DNA. Simultaneously, it can also inhibit DNA polymerase activity and influence DNA replication. These functions mainly target proliferating cells. It is a cell cycle-specific drug mainly acting on S phase, and with a slight lethal effect to G1, G2 and M phase cells. It can inhibit a variety of animal tumors without cross-resistance to common antitumor drugs.

Glucuronide Camptothecin-based ADEPT

The use of glucuronide camptothecin as a prodrug of ADEPT is under active development. In this approach, monoclonal antibodies which retain the ability to target cancer cells antigen is linked to the β-glucuronidase enzyme and subsequently activate administered glucuronide camptothecin prodrug. Selective activation of glucuronide camptothecin at neoplastic cells can increase the concentration of the active drug (CPT) in tumors, reduce systemic toxicity, and allow bystander killing of antigen-negative cancer cells. Here, the glucuronide camptothecin prodrug has been designed to display increased water solubility for improved drug formulation. The design of the camptothecin prodrug suitable for targeted enzymatic activation at tumor cells is based upon four criteria: (1) improved water solubility, (2) stability in blood, (3) decreased cytotoxicity and (4) susceptibility to defined enzymatic cleavage.

Schematic structures of the drug conjugates before and after drug release. Fig 2. Schematic structures of the drug conjugates before and after drug release. (Seidi, 2018)

Creative Biolabs provides glucuronide camptothecin, an effective prodrug used in antibody-purine nucleoside phosphorylase conjugate-based ADEPT development. Our products and services will contribute greatly to the success of your projects. If you are interested in other various services regarding ADEPT development, please contact us for more information and a detailed quote.

References

  1. Tranoy-Opalinski, I.; et al. β-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: an update. European journal of medicinal chemistry. 2014, 74, 302-313.
  2. Seidi, F.; et al. Designing smart polymer conjugates for controlled release of payloads. Chemical Reviews. 2018, 118(7).

Other Antibody-β-glucuronidase Conjugate:

Related Sections

Antibody-directed Enzyme Prodrug Therapy (ADEPT): Antibody-enzyme Conjugates for Cancer Therapy: Services:
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