Biomedical Engineering – From Theory to Applications

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368 Biomedical Engineering – From Theory to Applications Photofrin ® (HpD) has the longest clinical history and patient track record being the first commercial photosensitiser. It is actually a combination of monomers, dimers, and oligomers derived from chemical manipulation of hematoporphyrin (HpD). The complex mixture is required for clinical activity. In the US, Photofrin® is FDA approved for early and late endobronchial lesions as well as Barrett’s esophagus and esophageal obstructing lesions. The drug is approved worldwide for a number of additional uses, such as for treatment of bladder cancer. 5-Aminolevulinic acid (ALA) is a prodrug, a naturally occurring amino acid which is converted enzymatically to protoporphyrin. By topical administration the treatment can be selectively performed without associated light sensitization of the untreated regions. Systemic administration does not have this built in selectivity. The drug is active at 630 nm, which should give adequate depth penetration; however, when topically administered, the drug has a limited penetration capacity and therefore is less efficient for treating deep Porphyrin sensitizer molecular structure Porphyrin sensitizer name Absorption (nm) Localization Primary mechanism of action Most commonly light time irradiation interval First generation photosensitizers Second generation photosensitizers Photofrin Tookad Foscan 630 763 652 Golgi apparatus plasma membrane Vascular damage ischemic tumor cell necrosis Vasculature Vascular damage Direct tumor cytotoxicity Endoplasmic reticulum (ER) Mitochondria Vascular damage 24-48 h 15 min 96 h Status: Approved Esophageal cancer, lung Clinical trials Approved Applications cancer, gastric cancer, cervical dysplasia and cancer Prostate cancer Head and Neck cancer Local side effects Mild to moderate erythema - Swelling, bleeding, ulceration scarring Systemic side effects Photosensitivity, mild constipation - - Table 3. Examples of porphyrin sensitizers and their characteristics (adapted from O’Connor et al., 2009)
Trends in Interdisciplinary Studies Revealing Porphyrinic Compounds Multivalency Towards Biomedical Application lesions. ALA is not highly active, so relatively high light doses or long time treatments are needed. Despite using topical anesthetics, ALA PDT can be painful. ALA has been successful for esophageal treatment and with the oral form of drug this is convenient. Dysplastic epithelium can be reliably destroyed by ALA PDT. The methylated form of ALA (M-ALA), known commercially as Metvix® in Europe and Metvixia® in the US, has FDA approval for the treatment of non-hyperkeratotic actinic keratoses of the face and scalp, using a red-light source. Metvix also has EU approval for the treatment of superficial basal cell carcinomas. Both ALA and its methylated form proved clinical efficacy in the treatment of actinic keratoses and have also been used for photorejuvenation and inflammatory acne vulgaris. Verteporfin, known commercially as Visudyne, is a benzoporphyrin derivative, which is clinically active when formulated with liposomes. The photosensitizer is active at 690 nm, allowing deep tissue penetration and light activation. The drug is rapidly accumulated and cleared, so that skin photosensitization is minimal. Most of the clinical response induced by Verteporfin is based on vascular disruption and therefore, this drug seems ideal for lesions depending on neovasculature.Verteporfin has been successful as treatment for choroidal neovascularization due to serous chorioretinopathy. Table 3 presents some of the clinically available sensitizers together with their most relevant features in order to emphasize the influence of the chemical changes (among others, free base versus metallated form) on the characteristics and applications. 3.4 Selected aspects of the synthesis Synthesis of porphyrins has been extensively reviewed in literature (Kadish K., 2002). The hematoporphyrin derivatives (HpD) were the start line for the porphyrinic photosensitizers, the result consisting in several commercial products, as Photofrin®, which is a mixture of oligomers formed by ether and ester linkages of several porphyrin units, delivered as sodium porphimer. Their efficacy is linked also to the different proportions of monomers, dimers and oligomers (Mironov et al., 1990). The porphyrinic ring is β-pyrrolic substituted in this case. By changing the substitution on the meso positions, new photosensitizers can be generated, such as the tetraphenylsulphonated structures (TSPP or TSPP4-meso-tetrakis(4-sulfonatophenyl)porphyrin). Despite a few advantages, as solubility and low cost, the neurotoxicity, cytoskeletal abnormalities and nerve fiber degeneration in systemic administration, has oriented the compound only to topical use (Lapes M. et al., 1996; Winkelman J.W. et al., 1987). Meso-substituted porphyrins (Fig. 7) are more attractive compared to the naturally occurring beta substituted porphyrins for different applications including the biomedical field. Their synthesis is an ongoing subject of research (Halime Z. et al., 2006; Senge M.O., 2010, 2005; Lindsey J.S. 2010) being directed toward increasing efficacy in obtaining unsymmetric ABCD substituted structures, in larger quantities. One approach is the use of microwave (MW) irradiation which offers excellent yields within minutes. As shown in figure 7, the porphyrin ring can be substituted in its 5, 10, 15 and 20 positions respectively with R1, R2, R3 and R4. If the substituents are all hydrogen atoms, the structure is a symmetrical porphin; if the substituents are not hydrogens, but are identical to each other, the structure is a symmetrical meso porphyrin. Whenever one or more of R1 to R4 is not hydrogen, the structure is an unsymmetrical porphyrin. Porphyrins are said to have type A unsymmetrical structure when only R1 is not hydrogen; type A,B – 5, 10 or type A,B – 5, 15 when either R1 and R2 or R1 and R3 are not hydrogens; type ABC if only R4 is 369
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BIOMEDICAL ENGINEERING - FROM THEOR
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VI Contents Chapter 9 Targeted Magn
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X Preface stand-alone and readers c
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120 6. Conclusion Biomedical Engine
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150 5. Conclusions Biomedical Engin
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162 1 st phase : half year 4 2 nd p
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166 7. Innovative active training B
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172 12. Maturing projects’ story
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180 16. Acknowledgments Biomedical
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190 R* M M M M MR*M O O O O M O R*
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196 Fig. 9. Chemical structure of 5
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198 Relative Intensity (AU) Biomedi
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204 2. Preparation of IO nanopartic
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