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Photodynamic Therapy (PDT) holds great promise for the treatment of head and neck (H&N) carcinomas where repeated loco-regional therapy often becomes necessary due to the highly aggressive and recurrent nature of the cancers. Conventional surgery, chemotherapy and radiotherapy approaches cause significant cosmetic and functional damage to H&N tissue if repeated, whereas, PDT can allow a safe repeatable treatment alternative. While interstitial light delivery technologies are being refined for PDT of H&N and other cancers, a parallel clinically relevant research area is the formulation of photosensitizers in nanovehicles that allow systemic administration yet preferential enhanced uptake in the tumor. This approach can render dual-selectivity of PDT, by harnessing both the drug and the light delivery within the tumor. The broad long-term research objective is to develop an effective nanomedicine platform for targeted delivery of the photosensitizer drug Pc 4 to sites of head and neck cancer to enhance the clinical repertoire of Pc 4-induced photodynamic therapy (PDT) in these malignancies. The specific aims are to: (1) Determine encapsulation and release kinetics of Pc 4 in biocompatible block-copolymer micelles, (2) Modify micelle surface with EGFR-specific ligands and investigate cancer cell targeting of the surface-modified micelles in vitro, and, (3) Investigate targeted PDT effects on SCC cell lines in vitro and suitable animal models in vivo with Pc 4- loaded EGFR-targeted micelle formulations. Using fluorescence spectroscopy and confocal microscopy, it has been demonstrated in vitro that the EGFR-targeted Pc 4-nanoformulation undergoes faster and higher uptake in EGFR-overexpressing H&N cells. It is further demonstrated that this enhanced Pc 4 uptake results in significant cell-killing and drastically reduced post-PDT clonogenicity. Building on this in vitro data, it is shown that the EGFR-targeted Pc 4-nanoformulation results in enhanced intratumoral drug uptake and subsequent enhanced PDT response, in vivo, in SCC-15 xenografts in mice. Altogether our results show significant promise towards establishing a cell-targeted photodynamic nanomedicine for effective treatment of H&N carcinomas.