Perfluorocarbon Nanoparticles Enhance The Efficacy Of Photodynamic Therapy

Photodynamic therapy (PDT) depends on the ability of photosensitizers (PS) to transfer energy from lasers to tumour-dissolved oxygen (O2) to generate cytotoxic singlet oxygen (1O2) for cancer treatment. However, the effectiveness of PDT is impaired by an inadequate oxygen supply in tumours. In most solid tumours, hypoxia is common because the oxygen supply is reduced by disturbed microcirculation and deteriorated diffusion. Moreover, PDT worsens hypoxia through oxygen consumption and vascular shutdown effects. Low oxygen content can reduce the photodynamic efficacy of PS, preventing PDT from achieving its full therapeutic potential.Traditional methods have attempted to optimize tumour oxygenation to ensure PDT efficacy. For example, dividing irradiation into light-dark circles and extending irradiation with a low fluence rate have both been investigated as techniques for better tumour reoxygenation by the blood. However, these approaches only affect PDT-induced oxygen depletion, whereas the pre-existing hypoxia cannot be reversed; moreover, vascular shutdown due to PDT would also result in severe hypoxia. Hyperbaric oxygen inhalation has also been used to actively increase the level of tumour oxygen.However, vascular damage during PDT still prevents further oxygenation from hyperbaric blood; moreover, the potential toxic effects of excessive oxygen are an impediment to its clinical use. To our knowledge, no existing techniques can effectively reverse the tumour oxygen content during PDT. Therefore, optimizing the efficacy with limited oxygen is of great importance for photodynamic therapy.To address this challenge, herein we load photosensitizer into perfluorocarbon nanodroplets to develop a novel oxygen selfenriched photodynamic therapy (Oxy-PDT). Because of its highoxygen capacity, perfluorocarbon can maintain a higher oxygen content than the tumour matrix at a given oxygen partial pressure. Thus, although the tumour oxygen content remains limited during PDT, sufficient O2 can always be enriched in the PFC droplet for photodynamic consumption by the loaded PS, thus obtaining improved efficacy. This type of enhancement is possible regardless of pre-existing hypoxia, photodynamic consumption, or vascular damage; moreover, it has been reported that the 1O2 lifetime in perfluorocarbon is much longer than in the cellular environment or in water, which results in long-lasting photodynamic effects. Therefore, Oxy-PDT might help PS to achieve its full therapeutic potential. In this study, we assessed the therapeutic efficacy of Oxy-PDT as a novel form of PDT in cancer models. First, we studied the photodynamic effect of Oxy-PDT on the generation of 1O2 and its cytotoxicity by incubating tumour cells with Oxy-PDT, which were then irradiated with laser beams. Next, we assessed the effect of Oxy-PDT on tumour growth by intratumoural injections in vivo. Last, we examined the passive targeting of Oxy-PDT by intravenous injections in vivo. We envision that this new approach may guide improvements in the clinical use of PDT.