Ultralong Circulating Lollipop-Like Nanoparticles Assembled with Gossypol, Doxorubicin, and Polydopamine via π-π Stacking for Synergistic Tumor Therapy

Long blood circulation in vivo remains a challenge to dual-drug-loaded nanocarriers for synergistic chemotherapy. Herein, a novel strategy to prepare lollipop-like dual-drug-loaded nanoparticles (DOX-PDA-gossypol NPs) is developed based on the self-assembly of gossypol, doxorubicin (DOX), and polydopamine (PDA) via pi-pi stacking. Dopamine polymerizes to PDA and fills the gaps between the gossypol and DOX molecules to form the super compact long-circulating nanoparticles. The DOX-PDA-gossypol NPs show a suitable particle size of 59.6 +/- 9.6 nm, high drug loading of 91%, superb stability, high maximum-tolerated dose (MTD) of over 60 mg kg(-1), and negligible toxicity. These NPs also exhibit pH-dependent drug release and low combination index (0.23). Notably, they show dramatically ultralong blood circulation (>192 h) with elimination half times 458-fold and 258-fold longer than that of free DOX and free gossypol, respectively. These values are markedly higher than most of the reported results. Therefore, the DOX-PDA-gossypol NPs have a high tumor accumulation of 12% remaining on the 8th day postinjection. This characteristic contributes to the excellent tumor comprehensive synergistic therapeutic efficacy (TIR > 90%) with low administration dosage and is benefitted for widening the drug therapeutic window. Thus, the proposed strategy has remarkable potential for tumor synergistic therapy.