Programmed drug delivery system based on optimized “size decrease and hydrophilicity/hydrophobicity transformation” for enhanced hepatocellular carcinoma therapy of doxorubicin

The programmed drug delivery of GNPs-Dox-Lac from blood circulation to tumor cells. First, the GNPs-Dox-Lac (103 nm, -5.68 mV) were kinetically stable in blood circulation and inclined to accumulate at the tumor site both passively and actively. Second, the degradation of the nanoparticles triggered by tumor extracelluer matrix metalloproteinase-2 (MMP2) led to the release of small molecule prodrug Dox-Lac (Mw 898 Da) to facilitate the tumor tissue penetration and cellular uptake. Last, pH-responsive disassociation of Dox-Lac in tumor cells resulted in the free Dox (Mw 543 Da) release specifically inside tumor cells to induce toxicity.189