Abstract
Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff’s base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff’s base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy.
Highlights
The “low drug loading” nanocarrier could not completely overcome multidrug resistance caused by exposure to free drugs
The drug loading content was measured by UV-vis and the hydrodynamic diameter as well as the morphology of nanoparticles was determined by DLS and TEM, respectively
As Cur can increase the levels of topoisomerase II-mediated DNA cleavage in the cytoplasm through its natural antioxidant activity[39], the increased concentration of Cur in the cytoplasm may bring enhanced anticancer effects. These results indicated that PEG-DOX-Cur NPs could be efficiently uptaken by cancer cells, ensuring the consistent intracellular release of DOX and Cur
Summary
The “low drug loading” nanocarrier could not completely overcome multidrug resistance caused by exposure to free drugs. We adopted a “conjugation to” strategy[28,29,30,31,32] and designed, synthesized, and evaluated a simple yet efficient anti-tumor prodrug nanoparticle as cancer drug delivery system. Under the acidic environment that is often found in tumors, the Schiff ’s base groups within the nanoparticles would break and release both anti-cancer drugs at tumor sites (Fig. 1E). Our in vitro and in vivo anti-tumor studies revealed better inhibitory effect on tumor growth in the PEG-DOX-Cur NPs-treated animals than those treated by free DOX/Cur mixture. Drug accumulation and penetration studies indicated that the PEG-DOX-Cur NPs possessed prolonged blood circulation time, better local drug accumulation and enhanced drug penetration in tumors, further demonstrating a superior effect of the PEG-DOX-Cur NPs in cancer drug delivery
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