Clin Endosc.  2013 Jan;46(1):7-23. 10.5946/ce.2013.46.1.7.

Advance in Photosensitizers and Light Delivery for Photodynamic Therapy

• Yoon I
• Li JZ
• Shim YK

• KMID: 1792635
• DOI: http://doi.org/10.5946/ce.2013.46.1.7

Abstract

The brief history of photodynamic therapy (PDT) research has been focused on photosensitizers (PSs) and light delivery was introduced recently. The appropriate PSs were developed from the first generation PS Photofrin (QLT) to the second (chlorins or bacteriochlorins derivatives) and third (conjugated PSs on carrier) generations PSs to overcome undesired disadvantages, and to increase selective tumor accumulation and excellent targeting. For the synthesis of new chlorin PSs chlorophyll a is isolated from natural plants or algae, and converted to methyl pheophorbide a (MPa) as an important starting material for further synthesis. MPa has various active functional groups easily modified for the preparation of different kinds of PSs, such as methyl pyropheophorbide a, purpurin-18, purpurinimide, and chlorin e6 derivatives. Combination therapy, such as chemotherapy and photothermal therapy with PDT, is shortly described here. Advanced light delivery system is shown to establish successful clinical applications of PDT. Phtodynamic efficiency of the PSs with light delivery was investigated in vitro and/or in vivo.

Keyword

Photochemotherapy; Photosensitizing agents; Chlorophyll and chlorins; Photothermal therapy; Light delivery

MeSH Terms

Chlorophyll
Dihematoporphyrin Ether
Family Characteristics
Light
Photochemotherapy
Photosensitizing Agents
Porphyrins
Triazenes
Chlorophyll
Dihematoporphyrin Ether
Photosensitizing Agents
Porphyrins
Triazenes

Figure

• 

  Fig. 1 Examples of second generation photosensitizer. (A) Tookad. (B) Antrin (Lu texaphyrin). (C) Benzoporphyrin derivative monocarboxylic acid (BPD-MA). (D) Purlytin. (E) Foscan. (F) Phthalocyanine.

• 

  Fig. 2 Modified Jablonski diagram. Photophysical processes involved in photodynamic therapy: 1) absorption, 2) fluorescence, 3) internal conversion, 4) intersystem crossing, 5) phosphorescence, 6) formation of free radicals by energy transfer from T1 photosensitizer to biological substrates, and 7) formation of singlet oxygen (1O2) by energy transfer from T1 photosensitizer to triplet oxygen (3O2). Adapted from Sternberg et al. Tetrahedron 1998;54:4151-4202, with permission from David Dolphin.12

• 

  Fig. 3 Comparative structures of porphyrin, chlorine, and bacteriochlorin. The bold lines indicate the 18π electron [18]-diazaannulene aromatic pathway.

• 

  Fig. 4 The structures of Chl a and b, and methyl pheophorbide a (MPa).

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  Fig. 5 Structures of some Chl derivatives as photosensitizers in photodynamic therapy. (A) Photochlor (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a, HPPH). (B) Taraporfin (Mono-L-aspartyl chlorin e6, NPe6). (C) Chlorin e6. (D) Purpurin (PP)-18. (E) Chlorin p6. (F) Purpurinimide. (G) Ketobacteriochlorin. (H) Zn-Benzochlorin. (I) Benzbaceriochlorin.

• 

  Fig. 6 Structures of photosensitizer-carbohydrate conjugates. (A) Pyropheophorbide 2-deoxyglucosamide (Pyro-2DG). (B) Purpurinimide-carbohydrate conjugate. (C) A 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH)-Gal.

• 

  Fig. 7 Synthesis of the basic chlorin derivatives having reactive groups. Reaction conditions: a) 5% H2SO4 in MeOH, N2, 12 hours. b) 2, 4, 6-collidine, N2, reflux, 2 hours; c) aq. LiOH, N2, 1.5 hours; d) KOH/1-propanol/pyridine/air, 2 hours; CH2N2; e) H2NCH2CH2R, CH2Cl2, 2 hours; f) CBr4, PPh3; g) OsO4, NaIO4, 6 hours. MP, methyl pheophorbide; MPP, methyl pyropheophorbide; PP, purpurin.

• 

  Fig. 8 Synthesis of purpurinimides having active groups. Reaction conditions: a) RNH2, pyridine, 5 hours; b) RNH2, Toluene, N2, reflux, 6 to 12 hours, c) from 16A to 17, TFA; from 15A to 18, CBr4, PPh3. MP, methyl pheophorbide; MDD, methy pyropheophorbide; PP, purpurin.

• 

  Fig. 9 Synthetic pathway of Pu-18-N-methyl-D-glucamine (NMGA) conjugated to gold nanoparticles (GNPs). PS, photosensitizer. Adapted from Lkhagvadulam et al. J Porphyr Phthalocyanines 2012;16:331-340, with permission from World Scientific Publishing Co.95

• 

  Fig. 10 Cell viability (%) of Pu-18-N-methyl-D-glucamine (photosensitizer, PS), PS-gold nanoparticles (GNPs) conjugate (PSGNPs), and citrate-GNPs (GNPs) (5.5 µg/mL concentration of PS) treated A549 cells by exposure to an irradiation at 670 to 710 nm (2 J/cm2) for 15 minutes. Error bars represent the standard deviation of three replicate experiments. Adapted from Lkhagvadulam et al. J Porphyr Phthalocyanines 2012;16:331-340, with permission from World Scientific Publishing Co.95

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