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We recently demonstrated the far-red light-activatable prodrug of paclitaxel (PTX), Pc-(L-PTX) 2 . Upon illumination with a 690 nm laser, Pc-(L-PTX) 2 showed combinational cell killing from rapid photodynamic therapy damage by singlet oxygen, followed by sustained chemotherapy effects from locally released PTX. However, its high lipophilicity (log D  7.4 &gt; 3.1) caused aggregation in aqueous solutions and has nonselectivity toward cancer cells. To solve these important problems, we prepared folic acid (FA)-conjugated and photoactivatable prodrugs of PTX with a polyethylene glycol (PEG) spacer of various chain lengths: FA-PEG  n  -Pc-L-PTX [ n = 0 (0k, 5 ), ∼23 (1k, 7a ), ∼45 (2k, 7b ), ∼80 (3.5k, 7c ), or ∼114 (5k, 7d )]. The PEGylated prodrugs 7a-d had a much improved hydrophilicity compared with the non-PEGylated prodrug, Pc-(L-PTX) 2 . As the PEG length increased, the hydrophilicity of the prodrug increased (log D  7.4 values: 1.28, 0.09, -0.24, and -0.59 for 1k, 2k, 3.5k, and 5k PEG prodrugs, respectively). Fluorescence spectral data suggested that the PEGylated prodrugs had good solubility in the culture medium at lower concentrations (&lt;1-2 μM), but showed fluorescence quenching due to limited solubility at higher concentrations (&gt;2 μM). Dynamic light scattering indicated that all of the prodrugs formed nanosized particles in both phosphate-buffered saline and culture medium at a concentration of 5 μM. The PEG length affected both nonspecific and folate receptor (FR)-mediated uptake of the prodrugs. The enhanced cellular uptake was observed for the prodrugs with medium-sized PEGs (1k, 2k, or 3.5k) in FR-positive SKOV-3 cells, but not for the prodrugs with no PEG or with the longest PEG (5k), which suggests the optimal range of PEG length around 1k-3.5k for effective uptake of our prodrug system. Consistent with the cellular uptake pattern, medium-sized PEGylated prodrugs showed more potent phototoxic activity (IC 50s , ∼130 nM) than prodrugs with no PEG or the longest PEG (IC 50 , ∼400 nM). In conclusion, we have developed far-red light-activatable prodrugs with improved water solubility and FR-targeting properties compared with the nontargeted prodrug.

Folate-PEG Conjugates of a Far-Red Light-Activatable Paclitaxel Prodrug to Improve Selectivity toward Folate Receptor-Positive Cancer Cells