Development of a Highly Selective Cancer Prodrug
Cancer is the unregulated growth of abnormal cells in the body, leading to the formation of tumors and invasion of surrounding organs. According to the American Cancer Society, approximately 1.6 million people in the US will be diagnosed with cancer in 2011, and over 570,000 people will die of the disease. As the second highest cause of death in the US, early detection and effective treatment of cancer is a priority in the healthcare field. Although there are several drugs on the market used to treat cancer, many suffer from undesirable and intolerable side effects. The use of prodrugs, which are pharmacologically inactivated forms of a drug, can often offer better selectivity to their targets and more desirable properties than the parent drug. For example, SN38 is an active metabolite of and more potent agent than irinotecan. SN38 inhibits an enzyme that is responsible for DNA unwinding, thereby preventing cells from multiplying. By designing prodrugs based on this potent metabolite, cancer drugs with better pharmacological properties may be developed.
Synthesis of SN38 Prodrug
The synthesis of a highly soluble SN38 prodrug is described. An elongated spacer N, N’-methylethylenediamine was incorporated between the indolequinone linker moiety and the drug in order to reduce the steric interference between the drug and the linker and thus enhance the release rate. Carbomate bonds between the indolequinone and naloxone made the structure stable in buffer conditions. The SN38 prodrug exhibited significantly increased in vitro against SKBR3 and KB cancerous cell lines in comparison to free SN38. The prodrug complex is also capable of comprising one or more functional groups selected from a targeting agent, trigger agent, and an imaging agent.
Applications and Advantages
- Cancer therapeutic
- Multi-functional agent (imaging, targeting, and trigger)
- Highly water soluble
- Not hydrolyzed by esterases
- Not hydrolyzed in liver – delayed glucuronidation
- Dual tumor specificity (hypoxia and high DT Diaphorase)
- Easily linked to a targeting molecule, nanoparticle