A novel nanoparticle-based drug carrier for photodynamic therapy is reported which can provide stable aqueous dispersion of hydrophobic photosensitizers, yet preserve the key step of photogeneration of singlet oxygen, necessary for photodynamic action. A multidisciplinary approach is utilized which involves (i) nanochemistry in micellar cavity to produce these carriers, (ii) spectroscopy to confirm singlet oxygen production, and (iii) in vitro studies using tumor cells to investigate drug-carrier uptake and destruction of cancer cells by photodynamic action. Ultrafine organically modified silica-based nanoparticles (diameter approximately 30 nm), entrapping water-insoluble photosensitizing anticancer drug 2-devinyl-2-(1-hexyloxyethyl) pyropheophorbide, have been synthesized in the nonpolar core of micelles by hydrolysis of triethoxyvinylsilane. The resulting drug-doped nanoparticles are spherical, highly monodispersed, and stable in aqueous system. The entrapped drug is more fluorescent in aqueous medium than the free drug, permitting use of fluorescence bioimaging studies. Irradiation of the photosensitizing drug entrapped in nanoparticles with light of suitable wavelength results in efficient generation of singlet oxygen, which is made possible by the inherent porosity of the nanoparticles. In vitro studies have demonstrated the active uptake of drug-doped nanoparticles into the cytosol of tumor cells. Significant damage to such impregnated tumor cells was observed upon irradiation with light of wavelength 650 nm. Thus, the potential of using ceramic-based nanoparticles as drug carriers for photodynamic therapy has been demonstrated.
Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.
We report a novel nanoformulation of a photosensitizer (PS), for photodynamic therapy (PDT) of cancer, where the PS molecules are covalently incorporated into organically modified silica (ORMOSIL) nanoparticles. We found that the covalently incorporated PS molecules retained their spectroscopic and functional properties and could robustly generate cytotoxic singlet oxygen molecules upon photoirradiation. The synthesized nanoparticles are of ultralow size ( approximately 20 nm) and are highly monodispersed and stable in aqueous suspension. The advantage offered by this covalently linked nanofabrication is that the drug is not released during systemic circulation, which is often a problem with physical encapsulation. These nanoparticles are also avidly uptaken by tumor cells in vitro and demonstrate phototoxic action, thereby highlighting their potential in diagnosis and PDT of cancer.
Low-temperature resonance Raman spectroscopy has been used to study the conformation and interactions of retinal within its opsin binding site in disk membrane vesicles formed from bovine retinal rod outer segments. At 80°K, laser irradiation within the visible absorp-7 From the
We have devised a method for obtaining the resonance Raman spectrum of a photolabile molecule before it is modified by light. The essence of this technique is that the sample is flowed through the light beam at a sufficiently high velocity so that the fraction of photoisomerized (or photodestroyed) molecules in the illuminated volume is very low.This rapid-flow technique has enabled us to measure the resonance Raman spectrum of unphotolyzed bovine rhodopsin in Ammonyx LO detergent solution and in sonicated retinal disc membranes. The major features of these spectra, which are very similar to one another, are the protonated Schiff base line near 1660 cm-1, the ethylenic line at 1545 cm-, lines due to skeletal modes at 1216, 1240, and 1270 cm-l, and a line due to C-H bending at 971 cm-'. The resonance Raman spectrum of unphotolyzed isorhodopsin formed by the addition of 9-cis-retinal to opsin was also measured. The spectrum of isorhodopsin is more complex and differs markedly from that of rhodopsin. In isorhodopsin, the ethylenic line is shifted to 1550 cm-l, and there are six lines between 1153 and 1318 cm-'. The rapid-flow technique described here makes it feasible to control the extent of interaction between light and any photolabile molecule. We present a theory for predicting the effective sample composition in the illuminated volume as a function of the flow rate, light intensity, and spectral characteristics of the photolabile species. Resonance Raman spectroscopy takes advantage of the selective enhancement in Raman scattering from vibrations coupled to an electronic transition when the excitation wavelength is within or near the corresponding absorption band (1, 2). This resonance effect makes it possible to specifically monitor the structure of chromophoric sites in macromolecules. Resonance Raman spectroscopy has recently been used to investigate colored metalloproteins (2-5), bacteriorhodopsin (6, 7), rhodopsin (8, 9), and enzymes with extrinsic chromophores (10, 11).Resonance Raman spectroscopy is a promising technique for elucidating the conformational changes in retinal during the initial stages of visual excitation (8, 9). There is a problem, however, in obtaining the spectrum of a photosensitive molecule such as rhodopsin. Raman scattering is a very weak process (1). Even with resonance enhancement, the probability that a molecule absorbs a photon is orders of magnitude greater than the probability that it scatters a photon by the resonance Raman process. It is convenient to express F in terms of the laser power P (photons sec'), which is equal to I 12. Also, we convert from a7A (cm2 molecule-') to the decadic extinction coefficient e (cm-l M-1), which are related by aA = 3.824 X 10-21 e.
Purpose: In superficial basal cell carcinomas treated with photodynamic therapy with topical y-aminolevulinic acid, we examined effects of light irradiance on photodynamic efficiency and pain. The rate of singlet-oxygen production depends on the product of irradiance and photosensitizer and oxygen concentrations. High irradiance and/or photosensitizer levels cause inefficient treatment from oxygen depletion in preclinical models. Experimental Design: Self-sensitized photobleaching of protoporphyrin IX (PpIX) fluorescence was used as a surrogate metric for photodynamic dose. We developed instrumentation measuring fluorescence and reflectance from lesions and margins during treatment at 633 nm with various irradiances. When PpIX was 90% bleached, irradiance was increased to 150 mW/cm 2 until 200 J/cm 2 were delivered. Pain was monitored. Results: In 33 superficial basal cell carcinomas in 26 patients, photobleaching efficiency decreased with increasing irradiance above 20 mW/cm 2
Purpose: The ATP-binding cassette protein ABCG2 (breast cancer resistance protein) effluxes some of the photosensitizers used in photodynamic therapy (PDT) and, thus, may confer resistance to this treatment modality. Tyrosine kinase inhibitors (TKI) can block the function of ABCG2. Therefore, we tested the effects of the TKI imatinib mesylate (Gleevec) on photosensitizer accumulation and in vitro and in vivo PDTefficacy. Experimental Design: Energy-dependent photosensitizer efflux and imatinib mesylate's effects on intracellular accumulation of clinically used second-and first-generation photosensitizers were studied by flow cytometry in murine and human cells with and without ABCG2 expression. Effects of ABCG2 inhibition on PDT were examined in vitro using cell viability assays and in vivo measuring photosensitizer accumulation and time to regrowth in a RIF-1tumor model. Results: Energy-dependent efflux of 2-(1-hexyloxethyl)-2-devinyl pyropheophorbide-a (HPPH, Photochlor), endogenous protoporphyrin IX (PpIX) synthesized from 5-aminolevulenic acid, and the benzoporphyrin derivative monoacid ring A (BPD-MA, Verteporfin) was shown in ABCG2+ cell lines, but the first-generation multimeric photosensitizer porfimer sodium (Photofrin) and a novel derivative of HPPH conjugated to galactose were minimally transported. Imatinib mesylate increased accumulation of HPPH, PpIX, and BPD-MA from 1.3-to 6-fold in ABCG2+ cells, but not in ABCG2À cells, and enhanced PDTefficacy both in vitro and in vivo. Conclusions: Second-generation clinical photosensitizers are transported out of cells by ABCG2, and this effect can be abrogated by coadministration of imatinib mesylate. By increasing intracellular photosensitizer levels in ABCG2+ tumors, imatinib mesylate or other ABCG2 transport inhibitors may enhance efficacy and selectivity of clinical PDT.Photodynamic therapy (PDT) is used for the treatment of many cancers. Photosensitizers are taken up by tumor cells and then activated by light (1), generating reactive oxygen species that cause cell death by necrosis or apoptosis (2). Expression of ATP-binding cassette (ABC) transport proteins renders tumor cells resistant to chemotherapy drugs that are substrates of these proteins (3), and the effect of these transporters on intracellular photosensitizer accumulation has been examined as a potential cause of resistance to PDT. The ABC family transport protein that has been most thoroughly investigated is ABCB1, or P-glycoprotein, but photosensitizers were found not to be substrates for this pump (4 -8), nor were they substrates for ABCC1, or multidrug resistance-associated protein-1 (8). In contrast, another ABC family transport protein, ABCG2 or breast cancer resistance protein, has been found to transport some photosensitizers and to decrease intracellular photosensitizer accumulation (8). Jonker et al. (9) showed that ABCG2 knock-out mice were photosensitive because of increased protoporphyrin IX (PpIX) levels. Robey et al. found that pheophorbide a is a specific substrate for...
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