Self‐Assembling Doxorubicin Prodrug Forming Nanoparticles and Effectively Reversing Drug Resistance In Vitro and In Vivo

Doxorubicin (DOX) is a widely used chemotherapeutic drug to treat a range of cancers. However, its unfavorable effects, particularly the cardiotoxicity and the induction of multidrug resistance (MDR), significantly limit its clinical applications. Herein, a novel doxorubicin prodrug, PEG2K‐DOX, is synthesized by conjugating a deprotonated doxorubicin molecule with the polyethylene glycol (PEG, MW: 2K) chain via pH‐responsive hydrazone bond, and its potential as a better alternative than doxorubicin is evaluated. The data show that the amphiphilic PEG2K‐DOX can self‐assemble into stable nanoparticles with a high and fixed doxorubicin loading content (≈20 wt%), a favorable size of 91.5 nm with a narrow polydispersity (PDI = 0.14), good stability, and pH‐dependent release behavior due to the acid‐cleavable linkage between PEG and doxorubicin. Although doxorubicin hardly accumulates in MDR cells, PEG2K‐DOX nanoparticles significantly increase the cellular uptake and cell‐killing activity of doxorubicin in two MDR cancer cell lines MCF‐7/ADR and KBv200, with the IC50 values dropped to 1.130% and 42.467% of doxorubicin, respectively. More impressively, PEG2K‐DOX nanoparticles exhibit significantly improved plasma pharmacokinetics, increased in vivo therapeutic efficacy against MDR xenograft tumors, and better in vivo safety compared with doxorubicin. PEG2K‐DOX nanoparticles hold the promise to become a better alternative than doxorubicin for cancer treatment, especially for MDR tumors.