The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy
Gabriela Di VenosaPablo VallecorsaFrancesca GiuntiniLeandro MamoneAlcira BatlleSilvia VanzuliÁngeles JuarranzAlexander J. MacRobertIan M. EgglestonAdriana Casas
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The use of endogenous protoporphyrin IX generated after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). However, the bioavailability of ALA is limited by its hydrophilic properties and limited cell uptake. A promising approach to optimize the efficacy of ALA-PDT is to deliver ALA in the form of prodrugs to mask its hydrophilic nature. The aim of this work was to evaluate the potential of two ALA dipeptide derivatives, N-acetyl terminated leucinyl-ALA methyl ester (Ac-Leu-ALA-Me) and phenylalanyl-ALA methyl ester (Ac-Phe-ALA-Me), for their use in PDT of cancer, by investigating the generation of protoporphyrin IX in an oncogenic cell line (PAM212-Ras), and in a subcutaneous tumor model. In our in vitro studies, both derivatives were more effective than ALA in PDT treatment, at inducing the same protoporphyrin IX levels but at 50- to 100-fold lower concentrations, with the phenylalanyl derivative being the most effective. The efficient release of ALA from Ac-Phe-ALA-Me appears to be consistent with the reported substrate and inhibitor preferences of acylpeptide hydrolase. In vivo studies revealed that topical application of the peptide prodrug Ac-Phe-ALA-Me gave greater selectivity than with ALA itself, and induced tumor photodamage, whereas systemic administration improved ALA-induced porphyrin generation in terms of equivalent doses administered, without induction of toxic effects. Our data support the possibility of using particularly Ac-Phe-ALA-Me both for topical treatment of basal cell carcinomas and for systemic administration. Further chemical fine-tuning of this prodrug template should yield additional compounds for enhanced ALA-PDT with potential for translation to the clinic.Keywords:
Protoporphyrin IX
The oral bioavailability of genistein(GE) in its benzensulfonate prodrug was studied in search for new drug.The plasma were collected at different points of time after the intragastric or intravenous administration of genistein benzensulfonate(GB) 40 mg/kg to rats.The GB and GE contents in plasma were determined by high performance liquid chromatography(HPLC).The compartment model was fitted and pharma cokinetic parameters were calculated by DAS 2.1.1.The results indicated that the dynamic processes of GE was consistent with one compartment model after intragastric or intravenous administration of GB prodrug to rats.The relative oral bioavailability of GE in prodrug GB was 110.9%.In conclusion,the above results demonstrated that the oral bioavailability of GE in prodrug had been improved remarkably.
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The oral bioavailability of genistein(GE) in its benzensulfonate prodrug was studied in search for its novel prodrug.The plasmas were collected at different points of time after the intragastric or intravenous administration of genistein benzensulfonate(GBS) 40mg /kg to rats.The GBS and GE contents in plasma were determined by HPLC.The compartment model was fitted and pharma cokinetic parameters were calculated by DAS 2.1.1.The results indicated that the dynamic processes of GE were consistent with two compartment model after intragastric administration of GBS prodrug to rats.The relative oral bioavailability of GE in prodrug GBS was 198.6%.In conclusion,the above results demonstrated that the oral bioavailability of GE in prodrug had been improved remarkably.
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The quantification of the induced fluorescence in tumor tissue is important to design optical equipment for photodynamic diagnosis (PDD). The fluorescence intensities of Protoporphyrin IX (PpIX) solved in Dimethylsulfoxid and induced via application of Aminolevulinic Acid in cells, cultivated in the hen's eggs model, have been measured photometrically. With an optimized CCD-camera-systems fluorescent tumor areas were detected before and after photodynamic therapy (PDT). The ratio of dead cells was detected by staining with trypan blue after PDT. The measurements were carried out with various energy densities at the time of maximal PpIX-enrichement.
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Protoporphyrin IX
Sonodynamic therapy
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Abstract Photodynamic therapy using 5‐aminolevulinic acid is a treatment method in which the fluorescent substance of protoporphyrin IX excessively accumulated specifically in cancer cells is excited by visible red or green light irradiation, and reactive oxygen is produced and injures cancer cells. Photodynamic therapy using 5‐aminolevulinic acid less markedly influences the surrounding normal cells and tissue as a result of no accumulation of protoporphyrin IX , being a low‐invasive, less harmful treatment localized to cancer. Furthermore, photodynamic therapy using 5‐aminolevulinic acid is painless, requiring no anesthesia because localized lesions are treated at a low‐energy level, and repeatedly applicable, unlike radiotherapy, and so is expected to be a new low‐invasive treatment based on a concept completely different from existing treatments. In fact, photodynamic therapy using 5‐aminolevulinic acid for bladder cancer was clinically demonstrated mainly for treatment‐resistant bladder carcinoma in situ , and favorable outcomes have been obtained. Photodynamic therapy using 5‐aminolevulinic acid are photodynamic technologies based on the common biological characteristic of cancers, and are expected as novel therapeutic strategies for many types of cancer.
Protoporphyrin IX
Cancer Therapy
Cancer Treatment
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正確かつ安全に悪性神経膠腫を最大限に摘出することは容易ではなく，（5-aminolevulinic acid: 5-ALA）を用いた光線力学的診断（Photodynamic diagnosis: PDD）を始め多くのモダリティが応用される．5-ALAは腫瘍内に選択的に集積し，その代謝産物である（Protoporphyrin IX: PpIX）の蛍光によって，腫瘍の存在を非常に簡便かつリアルタイムに示すことができ，本手術の遂行に有用である．最近ではPpIXの集積メカニズムの解明も進み，その集積効率を高めることで，PDDのみならず光線力学的療法（Photodynamic therapy: PDT）の効果増強に関する研究も期待されている．一方，本方法論には低悪性度神経膠腫での有用性が低い点，偽陽性や偽陰性の問題などがあり，その遂行には十分な知識と経験を要する．これら諸問題の克服のため，スペクトル解析を用いたPpIX蛍光の定量化技術の開発が進んでいる．また最近，本邦において悪性脳腫瘍のPDT治療剤として承認されているtalaporfin sodiumが，PDDにも応用可能であることが示され，今後は本薬剤を用いたPDDとPDTの併用が実現することが期待される．
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