Study Of PEGylated Irinotecan

Irinotecan (CPT-11) is a derivative of camptothecin. It can hamper the relinking ofsingle-strand DNA via inhibiting topoisomerase I, resulting in the antitumor effects.Clinically, irinotecan is broad-spectrum antitumor, but it suffers some side effects, such aspoor water solubility, short circulating half-time, and poor biocompatibility. Polyethyleneglycol(PEG) is a synthetic polymer, and is nontoxic, non-immunogenic, non-antigenic andamphiphilic. PEGylation indicates the conjugation of PEG and the drug by chemical orphysical method, in order to transfer its good properties to the conjugated polymer. In thisstudy, PEG of2kD、4kD and10kD were selected to conjugate with irinotecan throughchemical modification. The conjugated polymers were characterized and theirpharmaceutical properties were measured.1. Irinotecan was chemically modified with PEG through three chemical reactionsteps. First, PEG was activated with Succinic Anhydride; Second, to link with glycine, thecarboxylated PEG obtained was activated with NHS; In last step, the irinotecan was linkedwith PEG, then we obtained PEGylated irinotecan.2. The products obtained were characterized with melting test, ultravioletspectrophotometry, infrared spectroscopy, nuclear magnetic resonance, high performanceliquid chromatography and X-ray scattering, etc.3. Pharmaceutical properties of the conjugated polymers were studied.①In vitrorelease test showed that: irinotecan modified by PEG2000, PEG4000and PEG10000showed some sustained-release effect, which became more and more powerful with theincrease of the MW.②In MTT, we chose human colon cancer cells HT-29, and the resultswere as follows: at the irinotecan concentration of1μg·mL-1、10μg·mL-1and100μg·mL-1, when irinotecan was conjugated with PEG4000, it showed no significantdifference in cytotoxicity; But the cytotoxicity became significantly stronger whenirinotecan was conjugated with PEG2000and PEG10000.