In general, de novo solid
tumors are composed of phenotypically and functionally heterogeneous malignant cells. This heterogeneity interferes with the effectiveness of targeted molecular
cancer therapies. Even if most of the
tumor is killed by a targeted treatment, recurrences are common and can be lethal. In this study, a mixed
tumor model, which is predominantly a population of
epidermal growth factor receptor (EGFR)-positive A431 cells combined with a smaller population of EGFR-negative Balb3T3/
DsRed cells, was established. This mixed
tumor was then treated with photoimmunotherapy, a newly developed target-cell-selective
cancer therapy using a
monoclonal antibody (mAb)-
photosensitizer (IR700 fluorescence
dye) conjugate and exposure of near-infrared light. Although photoimmunotherapy successfully treated EGFR-positive A431 cells in the mixed
tumor, EGFR-negative Balb/
DsRed cells were not responsive. However, photoimmunotherapy also induced a large increase in
tumor permeability, known as the super-enhanced permeability and retention (SUPR) effect, which allowed a 5-fold increase in the accumulation of a liposomal
chemotherapy (DaunoXome) and resulted in more effective
therapy than either photoimmunotherapy or liposomal
daunorubicin alone. The liposomal
daunorubicin, administered 1 hour after EGFR-targeted photoimmunotherapy, was homogeneously distributed, allowing delivery to tiny surviving nests of EGFR-negative Balb3T3/
DsRed cells, resulting in prolonged survival of mice.