Synthesis, Characterizaiton And Preclinical Studies Of A Novel Doxorubicin Prodrug PEG-DOX

Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic drug, but its clinical application is greatly limited by several disadvantages such as poor water solubility, low selectivity, severe side effects and induction of drug resistance after long-term use. In recent years, nanotechnology has been extensively studied to develop novel strategies to overcome these problems. There are many potential advantages for using nanotechnology to deliver anticancer drugs including doxorubicin. For example, nano-scaled drugs can be used for passive targeting by the EPR effect and be enriched in tumor sites to achieve targeted delivery. Targeted delivery of drugs could not only significantly enhance the efficacy of chemotherapeutic drugs, but also markedly reduce the toxic effects to normal tissues. Nanomedicine is becoming an important research area all over the world.In this project we utilized the short-chain polyethylene glycol (PEG) as drug carriers (as hydrophilic side), to react with doxorubicin (as both hydrophobic side of the carrier and the therapeutic drug), to synthesize a novel DOX prodrug, PEG-DOX. We demonstrated that in physiological environment, PEG-DOX could be self-assembled into nanoparticles to take the advantage of EPR effect for targeted drug delivery. Meanwhile. PEG-hydrazide is used to be reacted with carbonyl of doxorubicin to form acid-sensitive conjugate, which would remain stable in the blood circulation (alkaline environment) but rapidly release DOX once in the tumor site (usually acidic environment). This favorable property could further enhance the therapeutic efficacy while reducing the side effects of DOX. In vitro studies with cultured tumor cells revealed that PEG-DOX exhibited excellent antitumor activity and entered tumor cells through endocytosis. More importantly, the uptake and accumulation of DOX was significantlv increased in MDR tumor cells treated with PEG-DOX than DOX, indicating PEG-DOX may be capable of overcoming multidrug resistance. Further animal studies suggested that PEG-DOX vesicles possess significantly improved pharmacokinetic properties than DOX, largely reduce DOX’s toxicity to normal tissues and exhibit excellent antitumor activity in vivo. PEG-DOX holds great promise to become a novel DOX prodrug useful for clinics, and deserves further studies.