Upconversion in photodynamic therapy: plumbing the depths

Abstract

Photodynamic therapy (PDT) involves the combination of non-toxic dyes called photosensitizers (PS) and harmless visible light that interact with ambient oxygen to give reactive oxygen species (ROS) that can damage biomolecules and kill cells. PDT has mostly been developed as a cancer therapy but can also be used as an antimicrobial approach against localized infections. However even the longest wavelength used for exciting PS (in the 700 nm region) has relatively poor tissue penetration, and many PS are much better excited by blue and green light. Therefore upconversion nanoparticles (UCNPs) have been investigated in order to allow deeper-penetrating near-infrared light (980 nm or 810 nm) to be used for PDT. NaYF₄ nanoparticles doped with Yb³⁺ and Er³⁺ or with Tm³⁺ and Er³⁺ have been attached to PS either by covalent conjugation, or by absorption to the coating or shell (used to render the UCNPs biocompatible). Forster resonance energy transfer to the PS then allows NIR light energy to be transduced into ROS leading to cell killing and tumor regression. Some studies have experimentally demonstrated the deep tissue advantage of UCNP-PDT. Recent advances have included dye-sensitized UCNPs and UCNPs coupled to PS, and other potentially synergistic drug molecules or techniques. A variety of bioimaging modalities have also been combined with upconversion PDT. Further studies are necessary to optimize the drug-delivery abilities of the UCNPs, improve the quantum yields, allow intravenous injection and tumor targeting, and ensure lack of toxicity at the required doses before potential clinical applications.

Figure 1. Jablonski diagram illustrating the principles of PDT

A ground-state photosensitizer (⁰PS) absorbs a photon, transitions to the short-lived (nsec) excited singlet state (¹PS) that can lose energy by fluorescence, internal conversion to heat, or else can undergo intersystem crossing to the long-lived (μsec) excited triplet state (³PS). The³PS can relax to ground state by emitting phosphorescence, but can also undergo energy transfer with ground state triplet oxygen (³O₂) to form reactive singlet oxygen (¹O₂, Type 2) or else can undergo an electron transfer reaction to form hydroxyl radicals (HO•, Type 1). Both these ROS (¹O₂ and HO•) can efficiently kill cancer cells (see Figure 2).

Figure 2. Schematic illustration of the three mechanisms responsible for the PDT-mediated destruction of a tumor in vivo

Photosensitizer (PS) absorbs light and is excited to the long-lived triplet state PS* which produces excited state singlet oxygen ¹O₂. ¹O₂ can (1) directly kill tumor cells by necrosis and induction of apoptosis, (2) can cause destruction of tumor vasculature by shutting down microvessels, and (3) can produce an acute inflammatory response that attracts leukocytes such as dendritic cells (DC) and neutrophils (PMN) that stimulates immune response.

Figure 3. Two common energy transfer processes occurring in upconversion

(A) ESA, excited-state excitation; (B) ETU, energy transfer upconversion.

Figure 4. Emission spectra and energy levels of the two common types of UCNPs

(A) The Yb3+ and Er3+ pairing emitting green, red and NIR light (B) The Yb3+ and Tm3+ pairing emitting UVA, blue, red and NIR light

Figure 5. Chemical structures of some PS that have been employed in UCNPs

Zn-PC, zinc phthalocyanine; MC540, merocyanine 540; ce6, chlorin(e6); TMPyP4, tetra-(N-methyl-4-pyridyl)porphyrin tetratosylate; RF, riboflavin; HP, hematoporphyrin; RB, Rose Bengal; SPCD, silicon phthalocyanine dihydroxide; Hyp a, hypocrellin a; MB, methylene blue; PPA, pyropheophorbide a; C60-MA, C60 fullerene monomalonic acid.