Novel RGD containing, temozolomide-loading nanostructured lipid carriers for glioblastoma multiforme chemotherapy

Abstract

Context: Glioblastoma multiforme (GBM) is the most common malignant brain tumor originating in the central nervous system. Efficient delivery of therapeutic molecules to the cells and tissues is a difficult challenge. Objective: Arginine-glycine-aspartic acid peptide (RGD)-modified nanostructured lipid carriers (NLCs) were used for the delivery of temozolomide (TMZ) into the GBM to provide a new paradigm in gliomatosis cerebri treatment. Methods:RGD-conjugated polyethylene glycol-b-distearoylphosphatidylethanolamine (PEG-DSPE) was synthesized. RGD containing, TMZ-loaded NLCs (RGD-TMZ/NLCs) were prepared. Their particle size, zeta potential, drug encapsulation efficiency (EE) and drug release behavior were evaluated. In vitro cytotoxicity study of TMZ/NLCs was tested in U87 malignant glioma cells (U87MG cells). In vivo antitumor efficacy of the carriers was evaluated on mice bearing GBM model. Results: The U87MG cells were successfully inhibited by RGD-TMZ/NLCs in vitro. RGD-TMZ/NLCs also displayed the highest antitumor efficacy in vivo than all the other formulations used for comparison. Conclusion: RGD-TMZ/NLCs were efficient in selective delivery of TMZ into U87MG cells, and inhibition efficacy is high. These RGD-modified vectors could be a superior drug delivery nanosystem to achieve therapeutic efficacy, and this research could be a new promising strategy for treatment in malignant gliomatosis cerebri.

Nanostructured lipid carriers, solid lipid nanoparticles, and polymeric nanoparticles: which kind of drug delivery system is better for glioblastoma chemotherapy?

“…Drug delivery remains a critical barrier to the treatment of central nervous system (CNS) tumors such as GBM. Based on the nanotechnology such as liposome, polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), recent research efforts have been aimed to targeting drugs to the brain (Chekhonin et al, 2012;Zhang et al, 2013;Carbone et al, 2014;Gastaldi et al, 2014;Song et al, 2016). Compared with conventional drug formulations, carefully designed nano-formulations offer significant advantages such as improved drug solubility, facilitation of drug delivery across the BBB, selective targeting, and reduced side effects (Jain, 2010;Kim et al, 2015).…”

“…Recently, our group dedicated to designing NLCs as the carrier for drug delivery for the treatment of glioma. For instance, arginine-glycine-aspartic acid peptide (RGD) modified NLCs were used for the delivery of TMZ for gliomatosis cerebri treatment (Song et al, 2016). NLCs were constructed and used for the co-delivery of vincristine and TMZ to glioma (Wu et al, 2015).…”

“…On the basis of the previous studies of our group (Wu et al, 2015;Chen et al, 2016;Song et al, 2016), this work aimed to the preparation of different nanocarriers (PNPs, SLNs, and NLCs) to select the ideal carrier with the most adequate physic-chemical and technological properties for the delivery of TMZ for the treatment of GBM. For the purpose, it was studied the in vitro cytotoxicity on U87 malignant glioma cells (U87 MG cells), in vivo biodistribution behavior and in vivo anti-tumor efficiency on mice-bearing malignant glioma model.…”

Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting

“…Furthermore, prolonged systemic administration of TMZ is associated with some toxic side effects such as hematological toxicity, acute cardiomyopathy, oral ulceration, and myelosuppression (Trinh et al., 2009 ). To avoid these problems, at present, microsphere formulations, topical implants and nanoformulations of TMZ have been widely studied for the study and treatment of GBM (Zhang & Gao, 2007 ; Song et al., 2016 ). Among them, the nanoparticle (NP)-based drug delivery systems for research and treatment of GBM seems to be more favored by the majority of researchers (Ling et al., 2012 ; Ramalho et al., 2018 ).…”

Effects of Gas1 on gliomas: a review on current preclinical studies

“…[10][11][12] To enhance the effect of TMZ it has been proposed the use of lipid-based nanoparticles, which cross the blood brain barrier more efficiently causing an increment of brain levels of TMZ and reducing the adverse effects in other organs such as the heart and kidneys. [16][17][18] Despite the above GBMs that express high levels of O 6 -methylguanine DNA methyltransferase (MGMT) protein are resistant to TMZ chemotherapy. [19][20][21][22] Small molecule inhibitors of MGMT exist, but their use in combination with TMZ is limited due to toxicity to peripheral organs.…”