Jia Zhu Li

Advance in Photosensitizers and Light Delivery for Photodynamic Therapy

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.

Synthesis of novel long wavelength cationic chlorins via stereoselective aldol-like condensation

Using stereoselective aldol-like condensation as a key methodology, a series of chlorophyll a-based long wavelength cationic chlorins were synthesized using methyl pyropheophorbide a (MPPa) and purpurin-18-N-methoxylimide methyl ester as starting materials. Such long wavelength cationic chlorins possess covalently linked cationic moieties (pyridinium or quinolinium) on the peripheral of their tetrapyrrole macrocycles. It was found that all long wavelength cationic chlorins showed their longest absorption maxima in the range of 712-763nm, making them potential photosensitizers in photodynamic therapy. The results of preliminary experiments probing in vitro photodynamic effects showed that the purpurinimide derivatives exhibit relatively high phototoxicity in HeLa cells as compared to MPPa derivatives.

Synthesis and Characterization of Novel Purpurinimides as Photosensitizers for Photodynamic Therapy

A series of novel purpurinimides with long wavelength absorption were designed and synthesized to develop novel and potential photosensitizers. These compounds were investigated through reduction, oxidation, rearrangement reaction and amidation reactions of methyl pheophorbide a. They demonstrated a considerable bathochromic shift of the major absorption band in the red region of the optical spectrum (695–704 nm). Newly synthesized purpurinimides were screened for their antitumor activities, and showed higher photodynamic efficiency against A549 cell lines as compared to purpurin-18 methyl ester. The results revealed the novel purpurinimides could be potential photosensitizers.

Efficient synthesis and in vitro photodynamic anticancer study of new purpurinimide-hydrazone conjugates

A series of new purpurinimide-hydrazone conjugates were synthesized, and their in vitro anticancer efficacy against A549 lung cancer cell lines was evaluated. It was found that the incorporation of the hydrazone group to the purpurinimide could increase their anticancer activities via a combination of photodynamic therapy and chemotherapy.

Synthesis of long-wavelength chlorins by chemical modification for methyl pyropheophorbide-a and their in vitro cell viabilities

A series of novel chlorophyll-a homologs with long wavelength absorption were synthesized via modification of methyl pyropheophorbide-a used as starting material. For introducing electron-withdrawing group methylenemalononitrile moiety was established on the periphery of modified chlorin by Knoevenagel reaction of malononitrile with formyl group at 3-, 15-position and 131-carbonyl group on the exocyclic ring. All of chlorins containing the methylenemalononitrile structure show Qy-absorption at more than 700 nm. Moreover, we have examined a preliminary in vitro photodynamic anticancer effect of these new derivatives on mouse sarcoma S-180 cell line.

Efficient photosensitization by a chlorin-polyoxometalate supramolecular complex.

The 4:1 supramolecular complexed ionic salt between pyridinium chlorin and polyanionic [α-SiMo12O40](4-) exhibits significantly enhanced photodynamic activity against A549 cell lines because of increased singlet oxygen photogeneration through high cellular penetration and localization of the chlorin molecules on the ionic salt into the cancer cell. Confocal laser scanning microscopy images clearly represent a higher uptake and photodynamic effect of this supramolecular complex corresponding to the lower IC50 value compared to the free chlorin.

Synthesis of isoxazoline-linked chlorins and their in vitro cell viabilities

A concise synthesis of isoxazoline-linked chlorins is described. This approach is carried out from methyl pyropheophorbide-a as the starting material via 1,3-dipolar cycloaddition of a vinyl group on the periphery with nitrile oxide to give regioselective products with excellent yields. This method represents an extensive and efficient entry into the functionalization of chlorins with a chlorophyll-α skeleton. Moreover, we have examined a preliminary in vitro effect of these new derivatives on mouse sarcoma S-180 cell line in photodynamic therapy.