A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

Abstract

By focusing on rat glioma, we elucidated whether new lipid nanocapsules (LNC) were able to improve anticancer hydrophobic drug bioavailability while also overcoming multidrug resistance. Blank LNCs and LNCs loaded with the antineoplastic agent paclitaxel were formulated by an emulsion inversion phase process. Expression of efflux pumps by rat glioma cells was assessed by reverse transcription-PCR, Western blot, and immunohistochemistry, and their activity was followed using the tracer 99 Tc m -methoxyisobutylisonitrile. Modalities of LNC action were addressed by using confocal microscopy detection of fluorescently labeled LNCs, fluorescence-activated cell sorting, high-performance liquid chromatography measurement of paclitaxel release, and analysis of tumor cell growth. This revealed an interaction between LNCs and efflux pumps that resulted in an inhibition of multidrug resistance in glioma cells, both in culture and in cell implants in animals. LNCs were able to target the intracellular compartment of glioma cells, a mechanism that was abrogated by using intracellular cholesterol inhibitors but not by clathrin-coated pit or caveolae uptake inhibitors. This result can be correlated to the LNC inhibitory effects on efflux pump activity that is itself known to be stimulated by intracellular cholesterol. In parallel, we showed that paclitaxel-loaded LNCs were active reservoirs from which paclitaxel could be released. Finally, we established that paclitaxel-loaded LNCs were more efficient than the commercially available paclitaxel formulation (Taxol) for clinical use, thus reducing tumor expansion in vitro and in vivo. Considering the physiologically compatible nature of LNC excipients, these data may represent an important step towards the development of new clinical therapeutic strategies against cancers.

Long-circulating DNA lipid nanocapsules as new vector for passive tumor targeting

“…DNA LNCs were synthesized as already described [6]. Fluorescent lipid nanocapsules (DiI or DiD empty LNCs and DiI or DiD DNA LNCs) were obtained by a previouslydescribed method [13]. Briefly, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI, emission wavelength (em.)…”

Multidrug Resistance in Cancer Circumvented Using a Cytosolic Drug Reservoir

“…Recently, nanocarrier‐drugs have been proposed as promising candidates against the MDR effect, as being mainly ascribed to their easy cellular uptake, i.e., cellular entry of “disguised” drugs via nanoparticle (NP) endocytosis would lead to enhanced cellular uptake of drugs 8, 9, 10, 11, 12, 13, 14, 15, 16. Although enhanced drug efficacy was indeed observed in some cases, whether there is a MDR reversal effect remained unclear, because of the lack of comparisons of drug efficacy between drug sensitive cells and its corresponding resistant cells.…”

Tumour targeting of lipid nanocapsules grafted with cRGD peptides

“…Their size can be tuned within the range of 20-100 nm [9]. LNC have been used for the delivery of cancer therapeutics [10][11][12][13] and other drug molecules [14], macromolecules such as siRNA and DNA [15], and radiotherapeutics [16][17][18]. In the context of radiotherapy, 188 Re-LNC have been tested for locoregional treatment of glioma in rats by stereotactic administration [18].…”