Self-assembling Doxorubicin Prodrug Forming Nanoparticles And Effectively Reversing Drug Resistance

Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic drug for the treatment of various types of tumors, but its clinical application and effectiveness were significantly limited by its poor water-solubility, low selectivity, severe side effects and induction of drug resistance. There are many potential advantages for using nanotechnology to deliver doxorubicin, including increasing drug solubility, improving the pharmacokinetics and targeting ability of the drug, as well as reducing the toxic side effects. However, most of the reported doxorubicin-delivery systems have obvious limitations, e.g. low drug-loading capability (usually less than 8 wt%), burst release of carried drug, limited anticancer activity and unsatisfied in vivo safety.In this project, we aimed to develop a novel type of doxorubicin-delivery system with significantly increased drug-loading capability, as well as significantly improved anticancer activity and in vivo safety. Herein, we utilized the short-chain polyethylene glycol (PEG, Mw:2000) 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, PEG2k-DOX. The amphiphilic PEG2k-DOX has a drug loading as high as 21 wt% and could self-assemble into nanoparticles under physiological conditions with an average size of 91.5nm and low PDI of 0.14, which may enable PEG2k-DOX nanoparticles to take the advantage of EPR effect and effectively target tumor sites. Moreover, as PEG-hydrazide was used to be reacted with carbonyl of DOX, the obtained acid-sensitive PEG2k-DOX conjugate exhibited pH-triggered release of DOX. That is to say, PEG2k-DOX nanoparticles remained stable in physiological conditions (e.g. pH 7.4) but rapidly release DOX once in the acidic environment (e.g. pH 4.0 and 5.0). This favorable property could further enhance the therapeutic efficacy while reducing the side effects of DOX.Moreover, in vitro studies with a panel of cultured tumor cell lines revealed that PEG2k-DOX exhibited excellent antitumor activity against all tested cell lines. Most importantly, the in vitro antitumor activity, the cellular uptake and accumulation of DOX was significantly increased in multidrug resistant (MDR) tumor cells treated with PEG2k-DOX than DOX. For instance, the IC50 value of PEG2k-DOX was only 1/50 of that of DOX in MDR cell line MCF-7/ADR. Further animal studies demonstrated that PEG2k-DOX nanoparticles exhibited significantly improved pharmacokinetic properties, as well as significantly increased antitumor activity against MCF-7/ADR xenograft tumors and in vivo safety when compared to DOX. These findings indicate that PEG2k-DOX holds great promise to become a novel DOX prodrug useful for clinics, especially for the treatment of resistant tumors.