Examples of PEGylated small molecules in development

Small-molecule drugs in development can be coupled to large-molecular-weight PEGs as prodrugs. The potential benefits of using large-molecular-weight PEGs as prodrugs are:

• Increased circulating half life
• Modified biodistribution
• Improved safety
• Enhanced water solubility.

A molecule that would particularly benefit from this approach is irinotecan. Irinotecan is a $1-billion oncolytic drug with suboptimal pharmacokinetics that treats colorectal cancer and other solid tumors. Irinotecan is cleared from the body within a few hours, and its short half life necessitates high doses to achieve therapeutic drug levels. The drug consequently causes many side effects, including neutropenia and severe diarrhea. Dose reductions for patients who cannot tolerate the side effects compromise the drug's therapeutic efficacy.

Figure 1: The effects of irinotecan and PEG-irinotecan on the growth of irinotecan-resistant human colon tumor (HT29) in a mouse xenograft model. (FIGURES ARE COURTESY OF THE AUTHORS.)

Figure 2: Concentration of tumor SN38 in mice with HT29 tumors. (FIGURES ARE COURTESY OF THE AUTHORS.)

Figure 3: The effect of irinotecan and PEG-irinotecan on neutropenia in animals. (FIGURES ARE COURTESY OF THE AUTHORS.)

Small-molecule drugs can also be coupled to small-molecular-weight PEGs for CNS exclusion. The potential benefits of small molecular weight PEG technology are:

• Modified biodistribution
• Decreased transport
• Improved oral bioavailability
• Modified metabolism.