Denise Bechet

Nanoparticles as vehicles for delivery of photodynamic therapy agents

Photodynamic therapy (PDT) in cancer treatment involves the uptake of a photosensitizer by cancer tissue followed by photoirradiation. The use of nanoparticles as carriers of photosensitizers is a very promising approach because these nanomaterials can satisfy all the requirements for an ideal PDT agent. This review describes and compares the different individual types of nanoparticles that are currently in use for PDT applications. Recent advances in the use of nanoparticles, including inorganic oxide-, metallic-, ceramic-, and biodegradable polymer-based nanomaterials as carriers of photosensitizing agents, are highlighted. We describe the nanoparticles in terms of stability, photocytotoxic efficiency, biodistribution and therapeutic efficiency. Finally, we summarize exciting new results concerning the improvement of the photophysical properties of nanoparticles by means of biphotonic absorption and upconversion.

Photodynamic therapy of malignant brain tumours: A complementary approach to conventional therapies

The poor outcome of primary malignant brain tumours is predominantly due to local invasion and local recurrence and their prognosis is highly dependent on the degree of resection. They have no border and, at best, a marginal zone that remains invisible to the surgeon. Photodynamic therapy (PDT) appears to be an interesting modality to fill the need for a targeted treatment that may reduce recurrence and extend survival with minimal side effects. In this review, we summarize the different technologies of brain tumour PDT employed such as interstitial PDT, and PDT-associated surgical resection, describing new light delivery devices. The role of dosimetry - one of the key factors behind successful brain tumour PDT - is discussed. This can be achieved by integrating results from in vivo studies. In this context, the development of new therapeutic photosensitizer delivery systems is also an area of significant research interest. Multifunctionality can be engineered into a single nanoplatform to provide tumour-specific detection, treatment, and follow-up. Such multitasking systems appear to be complementary to conventional technologies.

Functionalized silica-based nanoparticles for photodynamic therapy

AIM The strategy developed aims to favor the vascular effect of photodynamic therapy by targeting tumor-associated vascularization using peptide-functionalized nanoparticles. We previously described the conjugation of a photosensitizer to a peptide targeting neuropilin-1 overexpressed in tumor angiogenic vessels. MATERIALS & METHODS In this study, we have designed and photophysically characterized a multifunctional nanoparticle consisting of a surface-localized tumor vasculature targeting peptides and encapsulated photodynamic therapy and imaging agents. RESULTS & CONCLUSION The elaboration of these multifunctional silica-based nanoparticles is reported. Nanoparticles functionalized with approximately 4.2 peptides bound to recombinant neuropilin-1 protein. Nanoparticles conferred photosensitivity to cells overexpressing neuropilin-1, providing evidence that the chlorin grafted within the nanoparticle matrix can be photoactivated to yield photocytotoxic effects in vitro.

Response surface methodology: an extensive potential to optimize in vivo photodynamic therapy conditions.

PURPOSE Photodynamic therapy (PDT) is based on the interaction of a photosensitizing (PS) agent, light, and oxygen. Few new PS agents are being developed to the in vivo stage, partly because of the difficulty in finding the right treatment conditions. Response surface methodology, an empirical modeling approach based on data resulting from a set of designed experiments, was suggested as a rational solution with which to select in vivo PDT conditions by using a new peptide-conjugated PS targeting agent, neuropilin-1. METHODS AND MATERIALS A Doehlert experimental design was selected to model effects and interactions of the PS dose, fluence, and fluence rate on the growth of U87 human malignant glioma cell xenografts in nude mice, using a fixed drug-light interval. All experimental results were computed by Nemrod-W software and Matlab. RESULTS Intrinsic diameter growth rate, a tumor growth parameter independent of the initial volume of the tumor, was selected as the response variable and was compared to tumor growth delay and relative tumor volumes. With only 13 experimental conditions tested, an optimal PDT condition was selected (PS agent dose, 2.80 mg/kg; fluence, 120 J/cm(2); fluence rate, 85 mW/cm(2)). Treatment of glioma-bearing mice with the peptide-conjugated PS agent, followed by the optimized PDT condition showed a statistically significant improvement in delaying tumor growth compared with animals who received the PDT with the nonconjugated PS agent. CONCLUSIONS Response surface methodology appears to be a useful experimental approach for rapid testing of different treatment conditions and determination of optimal values of PDT factors for any PS agent.

Multifunctional ultrasmall nanoplatforms for vascular-targeted interstitial photodynamic therapy of brain tumors guided by real-time MRI

Photodynamic therapy (PDT) for brain tumors appears to be complementary to conventional treatments. A number of studies show the major role of the vascular effect in the tumor eradication by PDT. For interstitial PDT (iPDT) of brain tumors guided by real-time imaging, multifunctional nanoparticles consisting of a surface-localized tumor vasculature targeting neuropilin-1 (NRP-1) peptide and encapsulated photosensitizer and magnetic resonance imaging (MRI) contrast agents, have been designed. Nanoplatforms confer photosensitivity to cells and demonstrate a molecular affinity to NRP-1. Intravenous injection into rats bearing intracranial glioma exhibited a dynamic contrast-enhanced MRI for angiogenic endothelial cells lining the neovessels mainly located in the peripheral tumor. By using MRI completed by NRP-1 protein expression of the tumor and brain adjacent to tumor tissues, we checked the selectivity of the nanoparticles. This study represents the first in vivo proof of concept of closed-head iPDT guided by real-time MRI using targeted ultrasmall nanoplatforms. From the clinical editor: The authors constructed tumor vascular peptide targeting multifunctional silica-based nanoparticles, with encapsulated gadolinium oxide as MRI contrast agent and chlorin as a photosensitizer, as a proof of concept novel treatment for glioblastoma in an animal model.

Sugar-based peptidomimetics as potential inhibitors of the vascular endothelium growth factor binding to neuropilin-1.

Neuropilin-1 (NRP-1) is a co-receptor of VEGFR(165) and molecules interfering with VEGF(165) binding to NRP-1 seem to be promising candidates as new angiogenesis modulators. Based on the minimal four amino acid sequence of peptidic ligands known to bind NRP-1, we describe here the design, synthesis and biological evaluation of series of original sugar-based peptidomimetics using a C-glycosyl compound, derived from d-gulonolactone, as a scaffold, which was functionalized with side chains of the amino-acids arginine, and tryptophane or threonine. At 100 microM, all compounds exhibited a weak affinity for NRP-1, the most efficient being the bis-guanidinylated compound 32 (IC(50)=92 microM) which could be considered as a new NRP-1 non-peptidic ligand.

Peptide-conjugated chlorin-type photosensitizer binds neuropilin-1 in vitro and in vivo

The strategy developed aims to favor the vascular effect of photodynamic therapy (PDT) by targeting tumor vasculature. This approach is considered by coupling a photosensitizer (PS) to an heptapeptide targeting neuropilin-1 (NRP-1). We previously demonstrated that this new conjugated PS, which binds to recombinant NRP-1 protein, was a much more potent PS compared to the non-conjugated PS in human umbilical vein endothelial cells (HUVEC) expressing NRP-1, due to the coupling of the peptide moiety. To argue the involvement of NRP-1 in the conjugated PS cellular uptake, MDA-MB-231 breast cancer cells were used, strongly over-expressing NRP-1 receptor, and we evidenced a significant decrease of the conjugated PS uptake after RNA interference-mediated silencing of NRP-1. In mice xenografted ectopically with U87 human malignant glioma cells, we demonstrated that only the conjugated PS allowed a selective accumulation in endothelial cells lining tumor vessels. Vascular endothelial growth factor (VEGF) plasma and tumor levels could not prevent the recognition of the conjugate by NRP-1. The vascular effect induced by the conjugated PS, was characterized by a reduction in tumor blood flow around 50% during PDT. In vivo, the photodynamic efficiency with the conjugated PS induced a statistically significant tumor growth delay compared to the non-coupled PS. The peptide-conjugated chlorin-type PS uptake involves NRP-1 and this targeting strategy favors the vascular effect of PDT in vivo.

Neuropilin-1 Targeting Photosensitization-Induced Early Stages of Thrombosis via Tissue Factor Release

PurposeThis article characterizes the vascular effects following vascular-targeted photodynamic therapy with a photosensitizer which actively targets endothelial cells.MethodsThis strategy was considered by coupling a chlorin to a heptapeptide targeting neuropilin-1 in human malignant glioma-bearing nude mice. A laser Doppler microvascular perfusion monitor was used to monitor microvascular blood perfusion in tumor tissue. Endothelial cells’ ultra structural integrity was observed by transmission electron microscopy. The consequences of photosensitization on tumor vessels, tissue factor expression, fibrinogen consumption, and thrombogenic effects were studied by immunohistochemical staining.ResultsTreatment of glioma-bearing mice with the conjugate showed a statistically significant tumor growth delay. Vascular effect was characterized by a decrease in tumor tissue blood flow at about 50% baseline during treatment not related to variations in temperature. This vascular shutdown was mediated by tumor blood vessels’ congestion. A pro-thrombotic behavior of targeted endothelial cells in the absence of ultra structural changes led to the induction of tissue factor expression from the earliest times post-treatment. Expression of tissue factor-initiated thrombi formation was also related to an increase in fibrinogen consumption.ConclusionUsing a peptide-conjugated photosensitizer targeting neuropilin-1, induction of tissue factor expression immediately post-treatment, led to the establishment of thrombogenic effects within the vessel lumen.

Innovations of Photodynamic Therapy for Brain Tumors: Potential of Multifunctional Nanoparticles

The poor outcome of primary malignant brain tumors is predominantly due to local invasion and recurrence. Multifunctional nanoparticles harbouring various functions including targeting, imaging and treatment have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Multifunctionality can be engineered into a single nanoplatform to provide tumour-specific detection, treatment, and follow-up. This review summarizes different targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivo applications. Using nanoparticles as carriers of photoactivable compounds is a very promising approach as they can satisfy all the requirements for an ideal photodynamic therapy agent. Nanoparticles represent emerging photosensitizer carriers that show great promise for PDT.

System identification of the intracellular photoreaction process induced by photodynamic therapy

Photodynamic therapy (PDT) is an alternative treatment for cancer that involves the administration of a photosensitizing agent, which is activated by light at a specific wavelength. This illumination causes a sequence of photoreactions, which - in the presence of molecular oxygen - is supposed to be responsible for the death of the tumor cells. The PDT efficiency stems from the optimal interaction between these three factors (light, drug and oxygen). In this paper, a new approach is proposed to estimate photophysical parameters which characterize the ability of a photosensitizing drug to produce singlet oxygen. This approach is based on system identification techniques. This model-based method would allow biologists to estimate all the photophysical parameters from spectro-fluorescence data generated by only one experiment. Secondly, contrary to usual techniques which are restricted to in vitro studies, this approach can be directly applied to in vivo data.