Cyclic hexapeptide-conjugated nanoparticles enhance curcumin delivery to glioma tumor cells and tissue

Abstract

Glioma has one of the highest mortality rates among primary brain tumors. The clinical treatment for glioma is very difficult due to its infiltration and specific growth locations. To achieve improved drug delivery to a brain tumor, we report the preparation and in vitro and in vivo evaluation of curcumin nanoparticles (Cur-NPs). The cyclic hexapeptide c(RGDf(N-me) VK)-C (cHP) has increased affinity for cells that overexpress integrins and was designed to target Cur-NPs to tumors. Functional polyethyleneglycol-modified poly( d , l -lactide-co-glycolide) (PEG-PLGA) conjugated to cHP was synthesized, and targeted Cur-NPs were prepared using a self-assembly nanoprecipitation process. The physicochemical properties and the in vitro cytotoxicity, accuracy, and penetration capabilities of Cur-NPs targeting cells with high levels of integrin expression were investigated. The in vivo targeting and penetration capabilities of the NPs were also evaluated against glioma in rats using in vivo imaging equipment. The results showed that the in vitro cytotoxicity of the targeted cHP-modified curcumin nanoparticles (cHP/Cur-NPs) was higher than that of either free curcumin or non-targeted Cur-NPs due to the superior ability of the cHP/Cur-NPs to target tumor cells. The targeted cHP/Cur-NPs, c(RGDf(N-me)VK)-C-modified Cur-NPs, exhibited improved binding, uptake, and penetration abilities than non-targeting NPs for glioma cells, cell spheres, and glioma tissue. In conclusion, c(RGDf(N-me)VK)-C can serve as an effective targeting ligand, and cHP/Cur-NPs can be exploited as a potential drug delivery system for targeting gliomas.

PLGA Nanoparticle-Based Formulations to Cross the Blood–Brain Barrier for Drug Delivery: From R&D to cGMP

“…Another strategy to treat glioma is to target the genes overexpressed in malignant glioma cells. Cyclic hexapeptide-conjugated PLGA-PEG NPs were able to deliver curcumin to the glioma by binding to integrins that are upregulated on the glial cell surface [94]. A nine amino acid linear peptide (Pep-1) targeting the interleukin 13 receptor α2 overexpressed on the surface of gliomas was conjugated to PLGA-PEG NPs [95].…”

Recent Progress in the Development of Poly(lactic-co-glycolic acid)-Based Nanostructures for Cancer Imaging and Therapy

“…In general, gadolinium (Gd) derivatives or iron oxide (Fe 3 O 4 ) NPs have been loaded to NPs to enhance the contrast in MR imaging [120,121,122]. 1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanineiodide (DIR) has been widely used for in vivo fluorescence imaging [123,124]. Recently, many attempts have been made using near-infrared fluorescence (NIRF) imaging during the development of nanoformulations due to its deeper tissue penetration and lower tissue scattering property than fluorescence imaging [125].…”

Targeted Theranostic Nanoparticles for Brain Tumor Treatment

“…Integrins are extracellular matrix transmembrane receptors, including α6β4, α5β1, αvβ6, and αvβ3, that are overexpressed on GB, but not on normal brain tissues, and this represents a typical targeted treatment strategy directed to angiogenesis, tumor cell proliferation, inflammation and survival [144]. αvβ3- and αvβ5-associated angiogenesis are respectively dependent on tumor cell-secreted fibroblast growth factor (bFGF)/tumor necrosis factor (TNF)α and VEGF through an amplification loop leading to αvβ3/αvβ5 overexpression on EC [145,146,147,148,149,150]. Integrin-mediated signaling pathways have been found to promote the invasiveness and survival of glioma cells in brain microenvironment, more concretely they support the formation of the tumoral niche [151].…”