Synthesis And Release Of Novel PH-sensitive And Photo-sensitive Prodrugs

The pH value of some diseased tissues（such as inflammation, infection andmalignant tumor) is lower than that of normal tissues, making it possible to controldrug release of pH-sensitive prodrugs in pathological sites. As an external stimuli,light can spatiotemporally trigger drug release of photo-sensitive prodrugs,independent on the internal chemical environment. Targeted drug delivery system(TDDS) can effectively concentrate drug on diseased site, reducing the dosage andside effects. Based on the fact that biotin receptor is overexpressed in some cancercelllines and binding between biotin and its receptor is highly selective, biotin can beused as a targeting moiety to carry probes or toxic drugs sectively to cancerous tissuesfor cancer diagnosis or treatment.This work mainly invloves the following four parts:1. A cancer-targeted pH-sensitive prodrug of adriamycin was prepared withbiotin as the targeting moiety and acyl hydrazone as the pH-sensitive group(compound4). A pH-insensitive prodrug of adriamycin was prepared as control(compound6). HPLC analysis showed that the accumulative release of adriamycinfrom prodrug4in pH5.0and5.5buffer solution within24h was87.0%and53.7%respectively, while prodrug6was quite stable and no appreciable drug release wasobserved under the same conditions. The targeting effects of biotinwas proved by theuptake of prodrug4and6by SMMC-7721and Hela cells. MTT assay showed thatproliferation inhibition of prodrug4against SMMC-7721and Hela cells wassignificantly stronger than that of prodrug6. The in vivo selective antitumor activityis to be proved by further study.2. A2-nitrobenzyl-derived photo-sensitive prodrug for nitrogen mustard wasprepared (compounds10). The GC-MS analysis showed that the accumulative releaseof nitrogen mustard from prodrug10was10.1%after2h exposure to312nm UVlight.3. A cancer-targeted photo-sensitive prodrug of ibuprofen was prepared withbiotin as the targeting moiety and2-nitrobenzyl as the photo-sensitive group(compound16). HPLC analysis showed that prodrug16was stable in dark whiledecomposed in exposure to312nm UV light. The accumulative release of ibuprofenfrom prodrug16was42.2%after2h exposure to312nm UV light. 4. A new tetraphenylethylene derivative was prepared (compound22). Theaggregation-induced emission property of compounds22was proved by measuringthe fluorescence of various solutions of22in DMSO-H2O. A pH-sensitive prodrug ofadriamycin was prepared by conjugate adriamycin to22via acyl-hydrazone bond(compound23). When prodrug23was dissolved in pH5.5or6.5buffer solution thefluorescence of the solution increased with the extension of the incubation time,indicating the the release of adriamycin from prodrug23.