Sustained and efficient porphyrin generation in vivo using dendrimer conjugates of 5-ALA for photodynamic therapy

Casas, Adriana; Battah, Sinan; Venosa, Gabriela Di; Dobbin, Paul S.; Rodríguez, Lorena; Fukuda, Haydée; Batlle, Alcira; MacRobert, Alexander J.

doi:10.1016/j.jconrel.2009.01.002

Cited by 59 publications

(38 citation statements)

References 55 publications

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“…administration [ 12,13 ] . However, specifi city towards the tumour was essentially identical to that for ALA and never exceeded a factor of two [ 13 ] . Malik et al .…”

Section: Discussionmentioning

confidence: 99%

“…Dendrimers are hyperbranched polymers that have attracted considerable interest in oncology for drug delivery, owing to their ability to carry high drug-payloads and their well-defi ned macromolecular structure [ 11 ] . Recently, a dendrimer containing 18 ALA molecules coupled through biodegradable ester linkages was synthesised and tested in vitro and in vivo [ 12,13 ] . Those studies indicated a more effi cient and sustained PpIX production than ALA at drug equivalent doses after i.p.…”

Section: Introductionmentioning

confidence: 99%

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Fluorescence diagnosis of bladder cancer: a novel in vivo approach using 5‐aminolevulinic acid (ALA) dendrimers

et al. 2012

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E 11 5 5What ' s known on the subject? and What does the study add? Fluorescence cystoscopy with hexylaminolevulinate (h-ALA, Hexvix ® ) is known to improve tumour detection in non-muscle-invasive bladder cancer. However, specifi city is relatively low and the intensity of the observed fl uorescence signal decreases over time due to protoporphyrin IX (PpIX) effl ux.This study evaluates in an in vivo model the use of a dendritic 5-aminolevulinic acid compound for fl uorescence diagnosis. Fluorescence ratios between tumour and urothelium as well as muscle were signifi cantly better as compared with h-ALA. Sustained synthesis of PpIX accounts for preservation of fl uorescence for > 24 h. OBJECTIVE• To overcome the relative lack of tumour selectivity of fl uorescence-guided cystoscopy using 5-aminolevulinic acid (ALA) or its ester derivative (e.g. hexylaminolevulinate, h-ALA; Hexvix ® ), we evaluated the use of dendrimers bearing different ALA loads in rats bearing orthotopic bladder tumours. MATERIALS AND METHODS• Rat bladders were instilled with h-ALA or ALA dendrimers and fl uorescence ratio between tumour and normal urothelium, as well as tumour and muscle and depth of fl uorescence were determined with Image J software.• Quantifi cation of ALA and/or esters systemic reabsorption was evaluated by high-performance liquid chromatography. RESULTS• Slow hydrolysis of ALA from dendrimers as observed in vitro implies a higher initial ALA load and longer resting times in vivo . Sustained synthesis of protoporphyrin IX (PpIX) explains persistence of fl uorescence for > 24 h.• There were signifi cantly better fl uorescence ratios with dendrimers, as well as higher penetration depths and absence of systemic reabsorption. CONCLUSION• The prolonged and sustained PpIX synthesis, the improved tumour selectivity with a deeper penetration and the absence of systemic reabsorption are primary indicators that ALA dendrimers could be an alternative to h-ALA in fl uorescence-guided cystoscopy.

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“…administration [ 12,13 ] . However, specifi city towards the tumour was essentially identical to that for ALA and never exceeded a factor of two [ 13 ] . Malik et al .…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fluorescence diagnosis of bladder cancer: a novel in vivo approach using 5‐aminolevulinic acid (ALA) dendrimers

et al. 2012

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“…They have the ability to control and modify the size and lipophilicity of the dendrimer-conjugate for optimizing uptake by cells and possess a high drug payload [65]. Unlike conventional photosensitizers, dendrimer PS demonstrate effective ROS production even at extremely high concentrations.…”

Section: 'Nano' Strategies For Photosensitizermentioning

confidence: 99%

Nanodrug applications in photodynamic therapy

Paszko

Ehrhardt

Senge

et al. 2011

Photodiagnosis and Photodynamic Therapy

326

215

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SummaryPhotodynamic therapy (PDT) has developed over last century and is now becoming a more widely used medical tool having gained regulatory approval for the treatment of various diseases such as cancer and macular degeneration. It is a two-step technique in which delivery of a photosensitizing drug is followed by irradiation of light. Activated photosensitizers transfer energy to molecular oxygen which results in generation of reactive oxygen species which in turn cause cells apoptosis or necrosis. Although this modality has significantly improved quality of life and survival time for many cancer patients it still offers significant potential for further improvement. In addition to the development of new PDT drugs, the use of nanosized carriers for photosensitizers is a promising approach which might improve the efficiency of photodynamic activity and which can overcome many side effects associated with classic photodynamic therapy. This review aims at highlighting the different types of nanomedical approaches currently used in PDT and outlines future trends and limitations of nanodelivery of photosensitizers. PDT -photodynamic therapy; PGA -poly(glycolic acid); PGLA -poly(D,L-lactide-coglycolide); PLA -poly(lactic acid); PS -photosensitizer; PEG -polyethylene glycol; ALA  aminolevulinic acid; m-THPC  5,10,15,20-tetra-(m-hydroxyphenyl)chlorine; m-THPP  meso-tetra(p-hydroxyphenyl); PpIX  protoporphyrin; Hp  hematoporphyrin; Pc4  silicon phthalocyanine; Ig  immunoglobulin; Tf  transferrin; TfR  transferrin receptor; VEGF  vascular endothelial growth factor; EPR  enhanced permeability and retention effect; FRET  fluorescence resonance energy transfer; MRI  magnetic resonance imaging; RES  reticuloendothelial system; ROS  reactive oxygen species; NP  nanoparticle; ND -nanodiamonds; SNP  silica nanoparticle; AMD  age-related macular degeneration; CNV  choroidal neovascularization; PTT  photothermal therapy;

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“…In the latter case, various iron chelators (25)(26)(27)(28) and chemotherapeutic agents (29) have been shown to be effective in enhancing levels of PpIX production upon administration of ALA. The use of ALA conjugated to first-or second-generation dendrimers also results in enhanced porphyrin synthesis with such prodrugs at low concentrations compared with an equivalent dose of ALA itself (30)(31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

Venosa

Vallecorsa

Giuntini

et al. 2015

Molecular Cancer Therapeutics

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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. Mol Cancer Ther; 14(2); 440-51. Ó2014 AACR.

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Sustained and efficient porphyrin generation in vivo using dendrimer conjugates of 5-ALA for photodynamic therapy

Cited by 59 publications

References 55 publications

Fluorescence diagnosis of bladder cancer: a novel in vivo approach using 5‐aminolevulinic acid (ALA) dendrimers

Fluorescence diagnosis of bladder cancer: a novel in vivo approach using 5‐aminolevulinic acid (ALA) dendrimers

Nanodrug applications in photodynamic therapy

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

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