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Poly(L-histidine)-tagged 5-aminolevulinic acid prodrugs: new photosensitizing precursors of protoporphyrin IX for photodynamic colon cancer therapy.

Johnson RP, Chung CW, Jeong YI, Kang DH, Suh H, Kim I - Int J Nanomedicine (2012)

Bottom Line: ALA-p(L-His)(n) showed high phototoxicity and selectivity in different pH conditions compared with ALA alone.Because the length of the histidine chain increases in the ALA-p(L-His)(n) prodrugs, the PDT effect was found to be more powerful.In particular, high phototoxicity was observed when the cells were treated with ALA-p(L-His)(15), compared with treatment using ALA alone.

View Article: PubMed Central - PubMed

Affiliation: WCU Centre for Synthetic Polymer Bioconjugate Hybrid Materials, Department of Polymer Science and Engineering, Pusan National University, Pusan, Korea.

ABSTRACT

Background: 5-Aminolevulinic acid (ALA) and its derivatives have been widely used in photodynamic therapy. The main drawback associated with ALA-based photodynamic therapy (ALA-PDT) and ALA fluorescence diagnosis results from the hydrophilic nature of ALA and lack of selectivity for tumor versus nontumor cells. The application of certain triggers, such as pH, into conventional sensitizers for controllable (1)O(2) release is a promising strategy for tumor-targeted treatment.

Methods: A series of pH-sensitive ALA-poly(L-histidine) [p(L-His)(n)] prodrugs were synthesized via ring opening polymerization of 1-benzyl-N-carboxy-L-histidine anhydride initiated by the amine hydrochloride group of ALA itself. As an alternative to ALA for PDT, the synthesized prodrugs were used to treat a cultured human colon cancer HCT116 cell line under different pH conditions. The effect of ALA-p(L-His)(n) derivatives was evaluated by monitoring the fluorescence intensity of protoporphyrin IX, and measuring the cell survival rate after suitable light irradiation.

Results: The cytotoxicity and dark toxicity of ALA and synthesized ALA-p(L-His) derivatives in HEK293T and HCT116 cells in the absence of light at pH 7.4 and 6.8 shows that the cell viability was relatively higher than 100%. ALA-p(L-His)(n) showed high phototoxicity and selectivity in different pH conditions compared with ALA alone. Because the length of the histidine chain increases in the ALA-p(L-His)(n) prodrugs, the PDT effect was found to be more powerful. In particular, high phototoxicity was observed when the cells were treated with ALA-p(L-His)(15), compared with treatment using ALA alone.

Conclusion: The newly synthesized ALA-p(L-His)(n) derivatives are an effective alternative to ALA for enhancing protoporphyrin IX production and the selectivity of the phototoxic effect in tumor cells.

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Related in: MedlinePlus

1H nuclear magnetic resonance spectra of ALA-p(His)15 in dimethyl-d6 sulfoxide at 25°C.Abbreviation: ALA, 5-aminolevulinic acid.
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f2-ijn-7-2497: 1H nuclear magnetic resonance spectra of ALA-p(His)15 in dimethyl-d6 sulfoxide at 25°C.Abbreviation: ALA, 5-aminolevulinic acid.

Mentions: The protective benzyl side chains were removed by treating ALA-p(Bn-His)n with HBr/AcOH in trifluoroacetic acid, and the resulting product was characterized by gel permeation chromatography and various spectroscopic techniques. The 1H NMR spectra of ALA-p(L-His) are shown in Figure 2.


Poly(L-histidine)-tagged 5-aminolevulinic acid prodrugs: new photosensitizing precursors of protoporphyrin IX for photodynamic colon cancer therapy.

Johnson RP, Chung CW, Jeong YI, Kang DH, Suh H, Kim I - Int J Nanomedicine (2012)

1H nuclear magnetic resonance spectra of ALA-p(His)15 in dimethyl-d6 sulfoxide at 25°C.Abbreviation: ALA, 5-aminolevulinic acid.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3367496&req=5

f2-ijn-7-2497: 1H nuclear magnetic resonance spectra of ALA-p(His)15 in dimethyl-d6 sulfoxide at 25°C.Abbreviation: ALA, 5-aminolevulinic acid.
Mentions: The protective benzyl side chains were removed by treating ALA-p(Bn-His)n with HBr/AcOH in trifluoroacetic acid, and the resulting product was characterized by gel permeation chromatography and various spectroscopic techniques. The 1H NMR spectra of ALA-p(L-His) are shown in Figure 2.

Bottom Line: ALA-p(L-His)(n) showed high phototoxicity and selectivity in different pH conditions compared with ALA alone.Because the length of the histidine chain increases in the ALA-p(L-His)(n) prodrugs, the PDT effect was found to be more powerful.In particular, high phototoxicity was observed when the cells were treated with ALA-p(L-His)(15), compared with treatment using ALA alone.

View Article: PubMed Central - PubMed

Affiliation: WCU Centre for Synthetic Polymer Bioconjugate Hybrid Materials, Department of Polymer Science and Engineering, Pusan National University, Pusan, Korea.

ABSTRACT

Background: 5-Aminolevulinic acid (ALA) and its derivatives have been widely used in photodynamic therapy. The main drawback associated with ALA-based photodynamic therapy (ALA-PDT) and ALA fluorescence diagnosis results from the hydrophilic nature of ALA and lack of selectivity for tumor versus nontumor cells. The application of certain triggers, such as pH, into conventional sensitizers for controllable (1)O(2) release is a promising strategy for tumor-targeted treatment.

Methods: A series of pH-sensitive ALA-poly(L-histidine) [p(L-His)(n)] prodrugs were synthesized via ring opening polymerization of 1-benzyl-N-carboxy-L-histidine anhydride initiated by the amine hydrochloride group of ALA itself. As an alternative to ALA for PDT, the synthesized prodrugs were used to treat a cultured human colon cancer HCT116 cell line under different pH conditions. The effect of ALA-p(L-His)(n) derivatives was evaluated by monitoring the fluorescence intensity of protoporphyrin IX, and measuring the cell survival rate after suitable light irradiation.

Results: The cytotoxicity and dark toxicity of ALA and synthesized ALA-p(L-His) derivatives in HEK293T and HCT116 cells in the absence of light at pH 7.4 and 6.8 shows that the cell viability was relatively higher than 100%. ALA-p(L-His)(n) showed high phototoxicity and selectivity in different pH conditions compared with ALA alone. Because the length of the histidine chain increases in the ALA-p(L-His)(n) prodrugs, the PDT effect was found to be more powerful. In particular, high phototoxicity was observed when the cells were treated with ALA-p(L-His)(15), compared with treatment using ALA alone.

Conclusion: The newly synthesized ALA-p(L-His)(n) derivatives are an effective alternative to ALA for enhancing protoporphyrin IX production and the selectivity of the phototoxic effect in tumor cells.

Show MeSH
Related in: MedlinePlus