Often discovered at an advanced stage, ovarian cancer progresses to peritoneal carcinoma, which corresponds to the invasion of the serosa by multiple tumor implants. The current treatment is based on the combination of chemotherapy and tumor cytoreduction surgery. Despite the progress and standardization of surgical techniques combined with effective chemotherapy, post-treatment recurrences affect more than 60% of women in remission. Photodynamic therapy (PDT) has been particularly indicated for the treatment of superficial lesions on large surfaces and appears to be a relevant candidate for the treatment of microscopic intraperitoneal lesions and non-visible lesions. However, the impact of this therapy on immune cells remains unclear. Hence, the objective of this study is to validate the efficacy of a new photosensitizer [pyropheophorbide a-polyethylene glycol-folic acid (PS)] on human ovarian cancer cells and to assess the impact of the secretome of PDT-treated cells on human peripheral blood mononuclear cells (PBMC). We show that PS, upon illumination, can induce cell death of different ovarian tumor cells. Furthermore, PDT using this new PS seems to favor activation of the immune response by inducing the secretion of effective cytokines and inhibiting the pro-inflammatory and immunosuppressive ones, as well as releasing extracellular vesicles (EVs) prone to activating immune cells. Finally, we show that PDT can activate CD4+ and CD8+ T cells, resulting in a potential immunostimulating process. The results of this pilot study therefore indicate that PS-PDT treatment may not only be effective in rapidly and directly destroying target tumor cells but also promote the activation of an effective immune response; notably, by EVs. These data thus open up good prospects for the treatment of micrometastases of intraperitoneal ovarian carcinosis which are currently inoperable.

This study describes the employment of gold nanorods (AuNRs), known for their good reputation in hyperthermia-based cancer therapy, in a hybrid combination of photosensitizers (PS) and peptides (PP). We report here, the design and the synthesis of this nanosystem and its application as a vehicle for the selective drug delivery and the efficient photodynamic therapy (PDT). AuNRs were functionalized by polyethylene glycol, phototoxic pyropheophorbide-a (Pyro) PS, and a “KDKPPR” peptide moiety to target neuropilin-1 receptor (NRP-1). The physicochemical characteristics of AuNRs, the synthesized peptide and the intermediate PP-PS conjugates were investigated. The photophysical properties of the hybrid AuNRs revealed that upon conjugation, the AuNRs acquired the characteristic properties of Pyro concerning the extension of the absorption profile and the capability to fluoresce (Φ_f = 0.3) and emit singlet oxygen (Φ_Δ = 0.4) when excited at 412 nm. Even after being conjugated onto the surface of the AuNRs, the molecular affinity of “KDKPPR” for NRP-1 was preserved. Under irradiation at 652 nm, in vitro assays were conducted on glioblastoma U87 cells incubated with different PS concentrations of free Pyro, intermediate PP-PS conjugate and hybrid AuNRs. The AuNRs showed no cytotoxicity in the absence of light even at high PS concentrations. However, they efficiently decreased the cell viability by 67% under light exposure. This nanosystem possesses good efficiency in PDT and an expected potential effect in a combined photodynamic/photothermal therapy guided by NIR fluorescence imaging of the tumors due to the presence of both the hyperthermic agent, AuNRs, and the fluorescent active phototoxic PS.