Photodynamic therapy (PDT) is a promising cancer treatment which involves a photosensitizer (PS), light at a specific wavelength for PS activation and oxygen, which combine to elicit cell death. While the illumination required to activate a PS imparts a certain amount of selectivity to PDT treatments, poor tumor accumulation and cell internalization are still inherent properties of most intravenously administered PSs. As a result, common consequences of PDT include skin photosensitivity. To overcome the mentioned issues, PSs may be tailored to specifically target overexpressed biomarkers of tumors. This active targeting can be achieved by direct conjugation of the PS to a ligand with enhanced affinity for a target overexpressed on cancer cells and/or other cells of the tumor microenvironment. Alternatively, PSs may be incorporated into ligand-targeted nanocarriers, which may also encompass multi-functionalities, including diagnosis and therapy. In this review, we highlight the major advances in active targeting of PSs, either by means of ligand-derived bioconjugates or by exploiting ligand-targeting nanocarriers.

Photodynamic therapy (PDT) is an anti-cancer therapy with proven efficacy; however, its application is often limited by prolonged skin photosensitivity and solubility issues associated with the phototherapeutic agents. Injectable hydrogels that can effectively provide intra-tumoral delivery of photosensitizers with sustained release is attracting increased interest for photodynamic cancer therapies. However, most of the hydrogels for PDT applications are based on systems with high complexity and often, pre-clinical validation is not provided. Herein, we provide a simple and reliable pH-sensitive hydrogel formulation that presents proper rheological properties for intra-tumoral injection. For this, Temoporfin (m-THPC), which is one of the most potent clinical photosensitizers, was chemically modified to introduce functional groups that act as cross-linkers in the formation of chitosan-based hydrogels. The introduction of -COOH groups gave rise to a water-soluble derivative, named as PS 2, that was the most promising candidate. Although PS 2 was not internalized by the target cells, its extracellular activation cause effective damage of the cancer cells which was likely mediated by lipid peroxidation. The injection of the hydrogel containing PS 2 in the tumors was monitored by high frequency ultrasounds and in vivo fluorescence imaging which confirmed the sustained release of PS 2 for at least 72 h. Following local administration, light exposure was conducted one (single irradiation protocol) or three (multiple irradiation protocol) times. The latter deliver the best therapeutic outcomes which included complete tumor regression and systemic anti-cancer immune responses. Immunological memory was developed as ~ 75% of the mice cured with our strategy rejected a second rechallenge with live cancer cells. Additionally, failure of PDT to treat immunocompromised mice bearing tumors reinforces the relevance of the host immune system. Finally, our strategy promotes anti-cancer immune responses that lead to the abscopal protection against distant metastases.