Sequential Intra-Intercellular Delivery of Nanomedicine for Deep Drug-Resistant Solid Tumor Penetration

Cells in the center of solid tumors have always been an abyss untouched by treatments because of their deep location and increased drug resistance. Herein, we designed a rational strategy for sequential intra-intercellular delivery of nanomedicine to deep sites of drug-resistant solid tumors. In our formulation, dopamine and hemoglobin were polymerized to form a smart nanocarrier (PDA/Hb). Subsequently, the doxorubicin and nitric oxide donor were connected on the surface of PDA/Hb to obtain D/N-PDA/Hb. Ultimately, the hyaluronic acid was combined with D/N-PDA/Hb to form D/N-PDA/Hb@HA. Concretely, acidic and neutral environments of tumor cells were treated as a switch to turn on or off the drug release of a nanodrug. Meanwhile, the generation of nitric oxide in situ was exploited to favor the lysosomal escape of nanocarriers and overcome the drug resistance of deep solid tumor cells. The results indicated that the nanodrug based on sequential intra-intercellular delivery showed exciting penetration efficiency and resistance reversal of solid tumors. Conventional nanodrug delivery was highly dependent on the enhanced permeability and retention (EPR) effect and limited by tumorous interstitial fluid pressure. Plenty of drugs stayed on the surface of solid tumors, and the infiltrated drugs were inefficient due to strict resistance. To conquer this dilemma, this work proposed a new mechanism reversing the EPR effect for drug delivery, leading to better penetration and resistance reversal of solid tumors.