Targeted intracellular delivery of photosensitizers to enhance photodynamic efficiency

Abstract

IntroductionPhotodynamic therapy (PDT) is a relatively new cytotoxic treatment, predominantly used in anticancer approaches, that depends on the retention of photosensitizers (PS) in tumour cells and their activation within the tumour through irradiation with light of the appropriate wavelength. Photoactivated PS generate reactive oxygen species (singlet oxygen, 1 O 2 , and free radicals, such as ·OH, HO· 2 and ·O 2 -) which are able to damage cellular structures, meaning that PDT is particularly attractive as an alternative means to kill drug-and radioresistant tumour cells.1,2 Normal cells, however, are also able to accumulate PS and be damaged by them, so that prolonged skin photosensitization, light-sensitivity of the eye and other side-effects have proved to be severe limitations of PDT. When photoactivated, PS inflict damage on many types of biomolecules without any specificity, their action being mediated largely via the reactive oxygen species mentioned, none of which travel more than several tens of nanometers before reacting with a biomolecule. Keeping in mind that cell dimensions are of the order of micrometres or tens of micrometres, it is clear that the intracellular action of PS is restricted to the site of their subcellular location and the surrounding radius of not more than 40 nm.3-5 That uneven intracellular distribution of PS can lead to differences in toxicity has been shown using laser microbeam irradiation. 6In contrast to cell membranes and other cytoplasmic organelles, the cell nucleus 7-9 is known to be a very sensitive target for reactive oxygen species. In order to reduce the dose of PS administered to patients and hence minimize the harmful side-effects of PDT, new approaches have been devised to increase the effectiveness of tumour-cell killing through targeted delivery of PS to hypersensitive subcellular sites. These approaches are the focus of the present review. Subcellular distribution of photosensitizersInsomuch as most mammalian cells span tens of micrometres, it is clear that PS efficiency will depend not only on the relative distribution of PS between the tumour and surrounding tissues and between malignant and normal cells, but also on the intracellular distribution of the PS. Furthermore, membranes divide the interior of the eucaryotic cell into compartments that differ markedly in their sensitivity to reactions induced by PS-generated reactive oxygen species, in the ability of damaged molecules to be replaced/recycled and in the extent to which such damage affects cell viability and/or the capability of the cell to divide. It is noteworthy that preferential PS accumulation in tumours is itself not a guarantee of selective photoinduced tumour damage and successful PDT. In experiments on rats with gliosarcoma 9L, 10 for example, it has been found that despite a 13-fold higher accumulation of the PS Photofrin in the tumour compared with Summary Photodynamic therapy (PDT) is a novel treatment, used mainly for anticancer therapy, that depends on the retention of photosensitizer...

Photodynamic apoptosis and antioxidant activities of Brassica napus extracts in U937 and SK-HEP-1 cells

“…Results of our experiment revealed that the BNCE exhibits relatively high toxicity effect in U937 cells against SK-HEP-1 cells. This corresponds to a previous study reporting that the effects of photosensitizers depend on tissue distribution, affinity for certain cell types, penetration into various subcellular compartments, and accumulation [16]. Further, there was the difference between cells due to the various mechanisms involved in cell death [3,17,18].…”

Porphyrin-based cationic amphiphilic photosensitisers as potential anticancer, antimicrobial and immunosuppressive agents

“…Importantly, because of their efficient accumulation in mitochondria, they are expected to trigger immunogenic death. Of note is the fact that they are not significantly accumulated in the nucleus and hence do not cause extensive DNA damage (Rosenkranz et al 2000;Tovmasyan et al 2014), and are therefore not expected to be mutagenic themselves, which is an important feature for anticancer agents.…”

Magnetic and fluorescent Gd₂O₃:Yb³⁺/Ln³⁺ nanoparticles for simultaneous upconversion luminescence/MR dual modal imaging and NIR-induced photodynamic therapy

“…In this novel system, UCNs activate the PS by visible light emission generated from sequential multiphoton NIR excitation via an anti-Stokes process. [8][9][10] In 2007, Zhang et al first reported the use of NaYF 4 : Yb 3+ /Er 3+ UCNs for PDT application. 11 Since then, the UCNs have been used for PDT by many groups.…”

“…For effective PDT, the choice of the UCNs host is critical for obtaining good upconversion efficiency. A popular host material is NaYF 4 , which exhibits high upconversion efficiency due to the low phonon cutoff energy, 15 thus attracting much interest in UCNs-based PDT and upconversion luminescence (UCL) imaging. [16][17][18][19] Other fluorides containing Yb 3+ (NaYbF 4 ) and Gd 3+ (NaGdF 4 ) ions, which also function as computed tomography (CT) and magnetic resonance imaging (MRI) contrast agents, [20][21][22][23][24] have been utilized to achieve simultaneous dual-or multimodal bioimaging with high sensitivity and high spatial resolution.…”