摘要： Background. We have developed ultrasmall porphyrin–high-density lipoprotein (HDL) nanoparticles (<20 nm), called “porphyrinHDL,” that have a high density of porphyrin molecules and dissociate rapidly upon tumor cell accumulation to become ?uorescent and photoactive. This is introduced as a novel activatable photosensitizer for image-guided photodynamic therapy (PDT). Here, we report the studies of these nanoparticles targeted to scavenger receptor class B type I (SR-BI) expressed on lung cancer cells as a ?rst step toward development of a minimally invasive treatment for peripheral lung cancer and metastatic lymph nodes of advanced lung cancer. Methods. The in vitro uptake of porphyrinHDL and the corresponding PDT ef?cacy were evaluated in both SR-BI–positive and SR-BI–negative lung cancer cell lines. A clinically relevant orthotopic lung cancer model in mice was used to examine ?uorescence activation and quanti?cation of uptake in tumor. In addition, we investigated the effect of porphyrinHDL-mediated PDT. Results. PorphyrinHDL promoted proper intracellular uptake in the H460 human lung cancer cell line. When irradiated with a 671-nm PDT laser, porphyrinHDL produced signi?cant therapeutic effectiveness in vitro. After systemic administration in mice with orthotopic lung cancer xenografts, porphyrinHDL demonstrated selective accumulation and photoactivation in tumor with signi?cantly enhanced disease-to-normal tissue contrast. Moreover, porphyrinHDL-PDT signi?cantly induced cell apoptosis in lung tumors (73.2%) without toxicity in normal tissues or damage to adjacent critical structures. Conclusions. SR-BI–targeted porphyrinHDL-mediated PDT of lung cancer is selective and effective in vitro and in vivo. These initial proof-of-principle studies suggest the potential of a “smart” PDT approach for highly selective tumor ablation.