Do folate-receptor targeted liposomal photosensitizers enhance photodynamic therapy selectivity?

Abstract

Photodynamic therapy (PDT) requires photosensitizer, light, and oxygen to induce cell death. The majority of efforts to advance PDT focus only on the first two components. Here, we employ perfluorocarbon nanoemulsions to simultaneously deliver oxygen and photosensitizer. We find that the implementation of fluorous soluble photosensitizers enhances the efficacy of PDT. Phototherapeutics are emerging avenues to mitigate side-effects of treatments due to the spatiotemporal control that can be achieved with light. 1 Photodynamic therapy (PDT), a classic phototherapeutic, employs a photosensitizer to generate reactive oxygen species (ROS) that induce local cell death (Figure 1A). 1 Current clinical uses of PDT include treatment of actinic keratosis, small cell carcinoma, pleural mesothelioma, oesophageal, non-small cell lung and skin cancer with other applications on the horizon as new photosensitizers and endoscopic technologies are developed. 2 Photosensitizer optimization and expanding the scope of tissue that can be irradiated with light contribute to the majority of advancements in PDT. 3 These are critical components; however, the direct therapeutic effect of PDT is a result of ROS such as singlet oxygen (1 O 2). 4 Hypoxia is a hallmark of many tumors 5 and limits the amount of ROS that can be generated even if ample light and photosensitizer are present. The ideal therapeutic for PDT is one that simultaneously delivers oxygen and photosensitizer to the disease site. Perfluorocarbon (PFC) nanoemulsions, droplets of fluorous solvent stabilized by a surfactant, are a compelling platform for PDT owing to the high oxygen content in perfluorocarbons (Figure 1B). 6 Previously, we have shown that fluorophores can be localized inside PFC nanoemulsions when fluorous chains are appended to the chromophore scaffold. 7 We imagined that a similar strategy could be employed to load PFC nanoemulsions with a photosensitizer to result in an exceptional nanomaterial for PDT (Figure 1C). Efforts to enhance PDT with perfluorocarbons began in 1988 when Henderson and co-workers co-injected a porphyrin photosensitizer with PFC nanoemulsions. 8 Despite promising results, this approach remained dormant for 25 years until cyanine dyes were embedded into the surfactant layer of PFC nanoemulsions to facilitate dual oxygen and photosensitizer delivery. 9 Contemporary variants of co-administration of photosensitizer and PFC nanoemulsions have also been pursued. 10 Figure 1. (A) Photodynamic therapy (PDT) involves the introduction of a photosensitizer which generates reactive oxygen species (ROS) upon irradiation with light to result in cell death. (B) Perfluorocarbon (PFC) nanoemulsions are droplets of fluorous solvent stabilized with surfactant. They have high oxygen content. (C) One step formulation of PFC nanoemulsions for PDT. Collectively, these reports demonstrate the potential of PFC nanoemulsions for PDT. However, organic photosensitizers are not compatible with the fluorous solvent, which can lead to inefficient photosensitization ...

Folic acid conjugated polymeric micelles loaded with a curcumin difluorinated analog for targeting cervical and ovarian cancers

“…HA conjugation gave HA-SMA-CDF the ability to accumulate in MIA PaCa-2 cells resulting in better anticancer activity. With the impressive results of HA-SMA-CDF, the aim of this study was to explore CDF’s anticancer activity further using folate-mediated delivery to cervical cancer cells (HeLa) and ovarian cancer cells (SKOV3)(Figure 1) [29–32]. For this purpose, SMA copolymer conjugated with folic acid (FA) as targeting ligand was employed.…”

Receptor-targeted, drug-loaded, functionalized graphene oxides for chemotherapy and photothermal therapy

“…Following pretreatment with FA, the cellular uptake of FITC-loaded FA-GO was reduced in KB cells, suggesting competitive inhibition of FA-GO uptake by KB cells. 41 FA did not affect the uptake of FA-GO by A549 cells, likely reflecting the folate receptor deficiency in these cells. 42 Qualitative cellular uptake studies were also performed using confocal microscopy.…”

“…KB cells express high levels of the folate receptor, which facilitates FA-GO uptake, resulting in higher SF-mediated cytotoxicity. 41 On the contrary, FA-GO/SF was less cytotoxic to A549 cells, as compared to free SF. This may reflect the folate receptor deficiency in this cell line, resulting in less uptake of FA-GO/SF.…”

Can nanotechnology potentiate photodynamic therapy?

“…The overexpression of folate receptor (FR) on a variety of epithelial cancer cells including cancers of ovary, lung, kidney, breast, brain, and colon [272] and the high affi nity of folate for its receptor has attracted wide attention as a targeting agent for tumor selectivity. Folate-decorated liposomes [273] , QD-folic acid conjugates [172] , pullulan/folate-PS nanogels [274] , or FR-targeted solid lipid nanoparticles [275] used the specifi c interaction with FR to assess superior cancer cell selectivity. FR cell selectivity greatly increases phototoxicity and cellular uptake compared with nonfunctionalized drug-delivery systems.…”