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Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer.

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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4753416 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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Project description:The combination of Ce6, an acknowledged photosensitizer, and TPL, a natural anticancer agent, has been demonstrated as a useful strategy to reinforce the tumor growth suppression, as well as decrease the systemic side effects compared with their monotherapy. However, in view of the optimal chemo-photodynamic combination efficiency, there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL, and stimuli-responsively burst release drugs in tumor site. Herein, we described the synergistic antitumor performance of a pH-sensitive supramolecular nanosystem, mediated by the host-guest complexing between β-CD and acid pH-responsive amphiphilic co-polymer mPEG-PBAE-mPEG, showing the shell-core structural micelles with the tight β-CD layer coating. Both Ce6 and TPL were facilely co-loaded into the spherical supramolecular NPs (TPL+Ce6/NPs) by one-step nanoprecipitation method, with an ideal particle size (156.0 nm), acid pH-responsive drug release profile, and enhanced cellular internalization capacity. In view of the combination benefit of photodynamic therapy and chemotherapy, as well as co-encapsulation in the fabricated pH-sensitive supramolecular NPs, TPL+Ce6/NPs exhibited significant efficacy to suppress cellular proliferation, boost ROS level, lower MMP, and promote cellular apoptosis in vitro. Particularly, fluorescence imaging revealed that TPL+Ce6/NPs preferentially accumulated in the tumor tissue area, with higher intensity than that of free Ce6. As expected, upon 650-nm laser irradiation, TPL+Ce6/NPs exhibited a cascade of amplified synergistic chemo-photodynamic therapeutic benefits to suppress tumor progression in both hepatoma H22 tumor-bearing mice and B16 tumor-bearing mice. More importantly, lower systemic toxicity was found in the tumor-bearing mice treated with TPL+Ce6/NPs. Overall, the designed supramolecular TPL+Ce6/NPs provided a promising alternative approach for chemo-photodynamic therapy in tumor treatment.

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Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer.

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