Abstract
A novel poly( N-isopropylacrylamide) (PNIPAM) hydrogel containing different photosensitizers (protoporphyrin IX (PpIX), pheophorbide a (Pba), and protoporphyrin IX dimethyl ester (PpIX-DME)) has been synthesized with a significant improvement in water solubility and potential for PDT applications compared to the individual photosensitizers (PSs). Conjugation of PpIX, Pba, and PpIX-DME to the poly( N-isopropylacrylamide) chain was achieved using the dispersion polymerization method. This study describes how the use of nanohydrogel structures to deliver a photosensitizer with low water solubility and high aggregation tendencies in polar solvents overcomes these limitations. FT-IR spectroscopy, UV-vis spectroscopy, 1H NMR, fluorescence spectroscopy, SEM, and DLS analysis were used to characterize the PNIPAM-photosensitizer nanohydrogels. Spectroscopic studies indicate that the PpIX, Pba, and PpIX-DME photosensitizers are covalently conjugated to the polymer chains, which prevents aggregation and thus allows significant singlet oxygen production upon illumination. Likewise, the lower critical solution temperature was raised to ∼44 °C in the new PNIPAM-PS hydrogels. The PNIPAM hydrogels are biocompatible with >90% cell viability even at high concentrations of the photosensitizer in vitro. Furthermore, a very sharp onset of light-dependent toxicity for the PpIX-based nanohydrogel in the nanomolar range and a more modest, but significant, photocytotoxic response for Pba-PNIPAM and PpIX-DME-PNIPAM nanohydrogels suggest that the new hydrogels have potential for applications in photodynamic therapy.
Highlights
Photodynamic therapy (PDT) relies on the activation of a photosensitizer (PS) using visible or near-IR light to generate reactive oxygen species, such as singlet oxygen, as cytotoxic agents.[1,2] Porphyrins feature prominently among the clinically approved PDT drugs and typical examples of porphyrin-based drugs include Photofrin, Visudyne, and Foscan.[2,3] A recurring problem is the intrinsically low water solubility of many porphyrinoid PSs and their tendency to aggregate in polar solvents and biological media
The PpIX-porphyrin in a Nisopropylacrylamide (PNIPAM) hydrogel was synthesized using an in situ dispersion polymerization method which involves mixing organic and aqueous solvents
Poly(N-isopropylacrylamide)−PSs (PpIX, pheophorbide a (Pba), and PpIX-DME) hydrogels have been successfully synthesized with different percentages of photosensitizers as a copolymer in the hydrogel structure
Summary
Photodynamic therapy (PDT) relies on the activation of a photosensitizer (PS) using visible or near-IR light to generate reactive oxygen species, such as singlet oxygen, as cytotoxic agents.[1,2] Porphyrins feature prominently among the clinically approved PDT drugs and typical examples of porphyrin-based drugs include Photofrin (porfimer sodium), Visudyne (verteporfin), and Foscan (temoporfin).[2,3] A recurring problem is the intrinsically low water solubility of many porphyrinoid PSs and their tendency to aggregate in polar solvents and biological media. Absorption spectra for PpIX-PNIPAM in water clearly showed that PpIX exists as a monomer in the hydrogel, even at high concentrations (Figure 3c). Pba and PpIX-DME are hydrophobic compounds, insoluble in water or biological media Addition of these compounds as copolymers and incorporation into the PNIPAM hydrogel structure result in good water solubility. The singlet oxygen quantum yield of TPP in DMSO is 0.52;33 PpIX-PNIPAM, Pba-PNIPAM, and PpIXDME-PNIPAM gave values of 0.69, 0.62, and 0.58 in DMSO, respectively These are promising values as the individual PS are not very efficient 1O2 generators in water due to aggregation and excited state quenching.
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