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Combined hyperthermia and chlorophyll-based photodynamic therapy: tumour growth and metabolic microenvironment.

ABSTRACT: The effects of combined and simultaneously applied localised 43 degrees C hyperthermia (HT) and an antivascular bacteriochlorophyll-serine-based photodynamic therapy (Bchl-ser-PDT) on tumour growth and several microenvironmental parameters were examined. Rats bearing DS-sarcomas were allocated to treatment groups: (i) sham-treatment (control), (ii) Bchl-ser-PDT (20 mg kg(-1) i.v.), (iii) localised HT, (iv) Bchl-ser-PDT+HT. The light source used was an infrared-A irradiator, which, by use of appropriate filters, delivered the different ranges of wavelengths required. Following treatment, tumour volume was monitored. The greatest tumour growth inhibition was seen with Bchl-ser-PDT+HT, and subsequent experiments identified the pathophysiological basis for this effect. Red blood cell flux in tumour microvessels declined rapidly upon Bchl-ser-PDT+HT, reaching approximately 10% of initial values by the end of treatment. Similarly, tumour oxygenation worsened, reaching almost anoxic levels by the end of the treatment period. Assessment of metabolic parameters showed a pronounced increase in lactate levels and a decrease in ATP concentrations after combined treatment. The results presented suggest that vascular collapse and flow stasis resulting in a deterioration of tumour oxygenation and a switch from oxidative to glycolytic glucose turnover are key elements in the tumour eradication seen with this novel approach in which an antivascular PDT and HT are combined and simultaneously applied.

SUBMITTER: Kelleher DK

PROVIDER: S-EPMC2395271 | biostudies-other | 2003 Dec

REPOSITORIES: biostudies-other

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Project description:Innovative synthesis routes revolutionized nanomaterial combination and design possibilities resulting in a new generation of fine-tuned nanoparticles featuring exquisite shape and constitution control. However, there is still room for improvement when it comes to the development of multi-functional nanoparticle agents merging a plurality of therapeutic functions to tackle tumors simultaneously by synergic mechanisms. Herein, we report the design of an optimized nanohybrid for cancer tri-therapy featuring a maghemite (γ-Fe2O3) nanoflower-like multicore nanoparticle conceived for efficient magnetic hyperthermia (MHT) and a spiky copper sulfide shell (IONF@CuS) with a high near-infrared (NIR) absorption coefficient suitable for photothermal (PTT) and photodynamic therapy (PDT). Methods: Spiky-like IONF@CuS nanohybrids were obtained through a straightforward and scalable water-based template sacrificial synthesis, which allows the shell shape control by tuning polyvinylpyrrolidone (PVP) concentration. A comprehensive characterization of nanohybrid size, shape and structural properties was carried out by combining complementary TEM, SEM, HR-TEM, EELS, XRD and NTA. The all-in-one therapeutic multi-functionality was assessed on cancer cells and on tumor-bearing nude mice. Results: Tests carried out on IONF@CuS nanohybrid aqueous dispersion demonstrated their impressive efficiency to convert light (conversion coefficient = 42 ± 6 %) and magnetic stimulation (SAR ~ 350 W g-1) into heat as well as to induce concurrent reactive oxygen species (ROS) formation upon laser irradiation. Such capabilities were further confirmed in cellular environment by in vitro tests and at the organism level by in vivo tests in a murine tumor model. Notably, complete tumor regression was obtained for the PTT mode at low Cu concentration. Overall, these results allowed determining windows of applicability for each therapy individually or in combination. Conclusions: Altogether, the obtained data evidence the successful synthesis of a unique tri-therapeutic nanoparticle featuring highly relevant assets for clinical translation such as reduced nanoparticle administered dose, reduced laser power exposure, reduced magnetic field frequency, and the possibility of serial heating cycles and therapy monitoring by photoacoustic (PA) and magnetic resonance imaging (MRI). Furthermore, the integration of the dual heating capability (MHT + PTT) with the PDT insult offers a unique asset to tackle tumors by multiple cytotoxic strategies in order to improve the therapeutic outcome in a broader spectrum of clinical conditions.

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Combined hyperthermia and chlorophyll-based photodynamic therapy: tumour growth and metabolic microenvironment.

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