Vasodilator Hydralazine Promotes Nanoparticle Penetration in Advanced Desmoplastic Tumors

Desmoplastic tumors are normally resistant to nanoparticle-based chemotherapy due to dense stroma and limited particle permeability inside the tumor. Herein, we reported that hydralazine (HDZ)—an antihypertension vasodilator—would dramatically promote nanoparticle penetration in advanced desmoplastic tumors. First, a HDZ–liposome system was developed for tumor-selective delivery of HDZ. After three injections of HDZ–liposomes at a dose of 15 mg/kg, the tumor stroma was remarkably reduced, along with ameliorated tumor hypoxia in murine models of desmoplastic melanoma (BPD6). Furthermore, HDZ–liposome treatment altered the immunosuppressive tumor microenvironment, which provided opportunities for applying this therapeutic system to aid immunotherapy in desmoplastic tumors. Using DiD-loaded liposome as a model nanoparticle, we showed that HDZ–liposome treatment significantly increased nanoparticle accumulation and penetration inside desmoplastic tumors. As a result, one single injection of doxorubicin–liposomes at a dose of 5 mg/kg resulted in strong tumor inhibition effect after HDZ–liposome pretreatment in the advanced desmoplastic melanoma with sizes over 400 mm3. Because HDZ is a widely used antihypertension drug, the findings here should be readily translatable for clinical benefits.