ABSTRACT
Combining targeting to therapy remains a major challenge in cancer treatment. To address this subject, the surface of lipid nanocapsules (LNC) was modified by grafting cRGD peptides, which are known to be recognised by αvß3 integrins expressed by tumour endothelium and cancer cells. Applicability of this LNC-cRGD in tumour targeting was first assessed in vitro by the use of U87MG glioma cells. Biodistribution and tumour accumulation of radiolabelled LNC-cRGD in vivo were then evaluated in mice bearing the same subcutaneous xenograft. Flow cytometry and confocal microscopy results revealed that the cRGD grafting improved binding and internalisation compared to negative control LNC-cRAD and blank LNC. The peptide-grafted LNC remained in the blood circulation up to 3h with reduced capture by the RES organs. Tumour accumulation of LNC-cRGD with respect to LNC-cRAD was significantly higher at 1-3h. These results show that cRGD grafted to LNC has created a promising tumour-targetable nanocarrier that could be used in cancer treatment.
Subject(s)
Antineoplastic Agents/administration & dosage , Drug Carriers/chemistry , Lipids/chemistry , Nanocapsules/chemistry , Peptides, Cyclic/chemistry , Animals , Drug Carriers/pharmacokinetics , Female , Humans , Lipids/pharmacokinetics , Mice, Nude , Molecular Targeted Therapy , Peptides, Cyclic/pharmacokinetics , Tissue Distribution , Xenograft Model Antitumor AssaysABSTRACT
In vivo biodistribution of nanoparticles depends on several physicochemical parameters such as size. After intravenous injection of 25, 50 and 100 nm lipid nanocapsules (LNC) in nude mice bearing HEK293(ß3) tumour xenografts, biodistribution was evaluated by γ-scintigraphy and by γ-counting. The small LNC 25 nm disappeared faster than the larger LNC 50 and 100 nm from the blood circulation due to faster elimination and wider tissue distribution. At 24h, biodistribution profiles of all these LNC were similar. Low LNC quantities were found in this weak EPR (enhanced permeability and retention) tumour regardless the particle size. Co-injected 50 nm fluorescent DiD-LNC and (99m)Tc-LNC allowed direct comparison of biodistribution as evaluated by the two methods. Optical imaging underestimated LNC quantity especially in dark-colored organs that were observed to capture extensive quantities of the particles by γ-counting (i.e. liver, spleen, and kidney).
Subject(s)
Lipids/pharmacokinetics , Nanocapsules , Animals , Female , HEK293 Cells , Humans , Lipids/administration & dosage , Lipids/chemistry , Mice , Mice, Nude , Nanocapsules/administration & dosage , Nanocapsules/chemistry , Optical Imaging/methods , Particle Size , Radionuclide Imaging , Scintillation Counting , Technetium , Tissue DistributionABSTRACT
To date, glioblastoma treatments have only been palliative. In this context, locoregional drug delivery strategies, which allow for blood--brain barrier bypass and reduced systemic toxicity, are of major significance. Recent progress in nanotechnology has led to the development of colloidal carriers of radiopharmaceutics, such as lipid nanocapsules loaded with rhenium-188 (LNC(188)Re-SSS) that are implanted in the brain. In our study, we demonstrated that fractionated internal radiation using LNC(188)Re-SSS triggered remarkable survival responses in a rat orthotopic glioma model (cure rates of 83%). We also highlighted the importance of the radioactivity activity gradient obtained by combining a simple stereotactic injection (SI) with convection-enhanced delivery (CED).We assumed that the immune system played a role in the treatment's efficacy on account of the overproduction of peripheral cytokines, recruitment of immune cells to the tumor site, and memory response in long-term survivor animals. Hence, nanovectorized internal radiation therapy with activity gradients stimulating immune responses may represent a new and interesting alternative for the treatment of solid tumors such as glioblastomas.