Dendronized heparin−doxorubicin conjugate based nanoparticle as pH-responsive drug delivery system for cancer therapy

Heparin drug conjugates are currently investigated as excellent candidates for drug delivery vehicles. In this study, we report the preparation and characterization of dendronized heparin–doxorubicin (heparin–DOX) conjugate as pH-sensitive drug delivery vehicle by combination of the features of dendrimer and heparin. Dynamic light scattering (DLS) and transmission electron microscope (TEM) studies demonstrated the dendronized heparin–DOX conjugate self–assembled into compact nanoparticles with negatively charged surface. The nanoparticles with 9.0 wt% (weight percent) of doxorubicin (DOX) showed pH-sensitive property due to the faster drug release rate at pH 5.0 and slow release rate at pH 7.4 aqueous. The nanoparticles were shown to effectively kill cancer cells in vitro. Notablely, the nanoparticles resulted in strong antitumor activity, high antiangiogenesis effects and induced apoptosis on the 4T1 breast tumor model due to the evidences from mice weight shifts, tumor weights, tumor growth curves, immunohistochemical assessment and histological analysis. It's also noteworthy that dendronized heparin and its nanoparticle with drug demonstrated no significant toxicity to healthy organs of both tumor–bearing and healthy mice, which was confirmed by histological analysis compared with free drug DOX. The dendronized heparin–DOX conjugate based nanopatilce with high antitumor activity and low side effects may be therefore a potential nanoscale drug delivery vehicle for breast cancer therapy.