Normalizing Tumor Vessels To Increase the Enzyme-Induced Retention and Targeting of Gold Nanoparticle for Breast Cancer Imaging and Treatment

Abnormal tumor vessels impede the transport and distribution of chemotherapeutics, resulting in low drug concentration at tumor sites and compromised drug efficacy. Normalizing tumor vessels can modulate tumor vascular permeability, alleviate tumor hypoxia, increase blood perfusion, attenuate interstitial fluid pressure, and improve drug delivery. Herein, a novel strategy combining cediranib, a tumor vessel normalizing agent, with an enzyme responsive size-changeable gold nanoparticle (AuNPs-A&C) was developed. In vivo photoacoustic and fluorescence imaging showed that oral pretreatment with 6 mg/kg/day of cediranib for two consecutive days significantly enhanced the retention of AuNPs-A&C in 4T1 tumor. In vivo photoacoustic imaging for hemoglobin (Hb) and oxyhemoglobin (HbO 2 ), Evans blue assay, and immunofluorescence assay showed that cediranib pretreatment markedly increased tumor vascular permeability and tumor oxygenation, while distinctly decreased the tumor microvessel density, demonstrating normalized tumor vessels and favorably altered microenvironment. Additionally, the combination strategy considerably elevated the tumor targeting capacity of different nanoparticle formulations (AuNPs-PEG, AuNPs-A&C), while coadministration of cediranib and AuNPs-A&C achieved prevailing tumor targeting and antitumor efficacy in 4T1 tumor bearing mouse model. In conclusion, we report a novel combined administration strategy to further improve tumor diagnosis and treatment.