Chemical modification of temoporfin – a second generation photosensitizer activated using upconverting nanoparticles for singlet oxygen generation

Abstract

In photodynamic therapy (PDT), the destruction of a target tissue (localized tumor) involves the combination of light of a specific wavelength, oxygen and a photosensitizer (PS). 1-3 Individually, these components are harmless; however, when combined, a putative cytotoxic agent, singlet oxygen ( 1 O 2 ), is generated. It is the 1 D g form of singlet oxygen that induces oxidation damages on cell components, resulting in cytotoxic reactions in the cells via necrosis or apoptosis, the self-destruction mechanisms of cells.The second generation PS, 5,10,15,20-tetra(m-hydroxyphenyl)-chlorin 4-6 (m-THPC, Foscan s , Temoporfin), with enhanced absorption of light in the red region (l max = 652 nm) has been found to be more specific than conventional porphyrins where skin photosensitization, usually a side effect of PDT, has been reported to be shorter. However, m-THPC does not make use of the optimal spectral biological window for tissue penetration in the 700-1000 nm range. Unfortunately, photons in this region are energetically too low for 1 O 2 generation. In addition to the band at 652 nm, which has a high molar extinction coefficient (e = 2.9 Â 10 4 cm À1 M À1 ), m-THPC has another absorption band in the blue region centered at 417 nm with a much higher molar absorption coefficient (e = 2.3 Â 10 5 cm À1 M À1 ). Excitation of m-THPC at 417 nm would eliminate the problem of low photon energy; however, direct excitation with high-energy blue light limits the use in biological applications due to its low tissue penetration depth. 7Lanthanide-doped upconverting nanoparticles (Ln 3+ -UCNPs) have been intensively studied in recent years. These nanoparticles can emit UV, visible and/or near-infrared (NIR) light upon NIR excitation (typically 980 nm) via a multiphoton process known as upconversion. The application of Ln 3+ -UCNPs as an energy source for exciting photosensitizers has been proposed. [8][9][10][11][12][13] The nanoconstructs, which were prepared using upconverting nanoparticles for the excitation of different photosensitizers, made use of the Er 3+ transitions, 2 H 11/2 , 4 S 3/2 -4 I 11/2 and 4 F 9/2 -4 I 11/2 . The transitions have one major disadvantage, the emission from these transitions does not overlap with the strongest absorption peak, the Soret band, of the photosensitizer presently used, which is at B400 nm. 14 The ideal modification would be to shift the Soret band of the photosensitizer to obtain the maximum overlap with the emission band(s) of the Ln 3+ -UCNPs. Temoporfin is one example of an approved second-generation photosensitizer. 15 Our group has recently synthesized LiYF 4 :Tm 3+ /Yb 3+ -UCNPs that showed stronger UV/blue emission following NIR excitation with 980 nm light compared to NaYF 4 . 16 Taking advantage of the high penetration depth and minimal autofluorescence of the NIR excitation light, LiYF 4 :Tm 3+ /Yb 3+ -UCNPs can be used as UV/blue excitation sources in biological applications.In this study we report on the functionalization of LiYF 4 :Tm 3+ / Yb 3+ -UCNPs with m-THPC to d...

Förster Resonance Energy Transfer‐Activated Processes in Smart Nanotheranostics Fabricated in a Sustainable Manner

“…[13] Capobianco'sg roup has modified as econd generation photosensitizer (m-THPC),a nd linked it to the Tm 3 + /Yb 3 +doped UCNPs surface,i no rder to increase the overlap between the blue emission spectra of the NPs and the absorption spectra of the PS agents. [14] Similar resultsw ere obtained for Tm 3 + /Yb 3 + -dopedU CNPs conjugated with Chlorin e6, [15] hypocrellin, [16] or doxorubicin [17,18] drugs. Changing the doping ion pair to Er 3 + /Yb 3 + furthere xtends the list of possible light-sensitive drugs to be conjugated with UCNPs.I nf act, av ery interesting approachw as proposed by Gao et al [19] who used stem cells as aU CNPs coating fore nhanced tumor targetingf unctionalities, whereas the conjugation with Bengal Rose (BR) allowed fore fficient energy-transfer-based photodynamic therapy (PDT) upon 980 nm excitation.I nteractionb etween Er 3 + /Yb 3 + -dopedU CNPs and BR was also applied for NIR-triggered PDT in neuroendocrine tumors.…”

Absolute upconversion quantum yields of blue-emitting LiYF4:Yb3+,Tm3+ upconverting nanoparticles

“…58 In security or bioimaging applications where the 794 nm emission is used, F UC,total is a good measure for the efficiency of LiYF 4 :Yb 3+ ,Tm 3+ UCNPs, because the upconverted emission spectrum is strongly dominated by the 794 nm band. However, in phototherapeutic applications where only the blue thulium emission is used, for example in the activation of bluelight sensitive anticancer compounds, 59 the actual efficiency of these UCNPs is one to three orders of magnitude lower than F UC,total . Thus, reporting only the latter would give a misleading evaluation of the amount of excitation light needed to obtain a measurable photochemical effect via NIR-to-blue upconversion.…”

Luminescence dynamics and enhancement of the UV and visible emissions of Tm3+ in LiYF4:Yb3+,Tm3+ upconverting nanoparticles

“…A number of studies using LiYF 4 :Yb 3+ ,Tm 3+ UCNPs with a nominal Tm 3+ concentration of 0.5% have been exploited, but optimization of Tm 3+ concentrations to achieve more intense UV emissions have not been reported in these systems. [10][11][12][13]19 In this study, we investigate the effects of slight changes in the Tm 3+ concentration on the UV, visible and NIR transitions. We also evaluate the sensitization mechanisms and the crossrelaxation processes that are involved in the higher energy emitting states of Tm 3+ (specically the 1 I 6 and 1 D 2 levels).…”