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The advance of anti-tumor nanomedicines is restricted in the delivery efficiency owing to a lack of insight into the intratumoral delivery mechanism, especially traversing biological barriers. Herein, we explore a...

Chemotherapy is one of the most effective methods of treating tumors in clinical study currently, but drug side effects usually are unbearable to the patient, which also makes it difficult to continue chemotherapy. Enhanced drug efficacy and reduced drug side effects are the main strategies for tumor therapy. Herein, based on biochemical regulation, theanine liposomes were designed to adjuvant doxorubicin (DOX) therapy, which can reduce the adverse reactions and enhance the effect of DOX. Stigmasterol was applied instead of traditional cholesterol for reducing the risk of cardiovascular disease. The as-prepared theanine liposomes by two methods had optimal sizes (154.8 and 169.0 nm), which can effectively accumulate in tumor tissues. In vitro experiments demonstrated that the theanine liposomes had a good effect of sustaining drug release. Cell uptake indicated that the presence of theanine can effectively inhibit glutathione (GSH) levels in cells and increase the uptake of DOX. In tumor bearing mice experiments, the combination of the theanine liposomes and DOX showed a better tumor inhibitory effect with a smaller tumor volume (2.7 fold) compared with that of the free DOX group. Meanwhile, under the mediation of theanine, the amount of doxorubicin was greatly reduced to achieve the same therapeutic effect, and the side effects of the drug were largely inhibited. Therefore, theanine liposomes have great application potential in tumor chemotherapy.

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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.