Cyclic RGD-Linked Polymeric Micelles for Targeted Delivery of Platinum Anticancer Drugs to Glioblastoma through the Blood–Brain Tumor Barrier

Abstract

Ligand-mediated drug delivery systems have enormous potential for improving the efficacy of cancer treatment. In particular, Arg-Gly-Asp peptides are promising ligand molecules for targeting αvβ3/αvβ5 integrins, which are overexpressed in angiogenic sites and tumors, such as intractable human glioblastoma (U87MG). We here achieved highly efficient drug delivery to U87MG tumors by using a platinum anticancer drug-incorporating polymeric micelle (PM) with cyclic Arg-Gly-Asp (cRGD) ligand molecules. Intravital confocal laser scanning microscopy revealed that the cRGD-linked polymeric micelles (cRGD/m) accumulated rapidly and had high permeability from vessels into the tumor parenchyma compared with the PM having nontargeted ligand, "cyclic-Arg-Ala-Asp" (cRAD). As both cRGD/m- and cRAD-linked polymeric micelles have similar characteristics, including their size, surface charge, and the amount of incorporated drugs, it is likely that the selective and accelerated accumulation of cRGD/m into tumors occurred via an active internalization pathway, possibly transcytosis, thereby producing significant antitumor effects in an orthotopic mouse model of U87MG human glioblastoma.

Dual temperature- and pH-responsive polymeric micelle for selective and efficient two-step doxorubicin delivery

“…5,6 A variety of strategies were studied to overcome these drawbacks. One of these strategies is the modication of the end-group of the PEG segment with ligands such as folate, 7 cyclic Arg-Gly-Asp (cRGD) peptide, 8 and antibody fragments 9 that recognize cell-specic surface receptors, leading to the improvement of cellular selectivity and increased intracellular delivery of nanomedicines. Stimuli-responsive polymers or "smart materials", 10 whose characteristics undergo appropriate changes in response to surrounding environmental conditions, [11][12][13][14] were also studied for tumor targeting and effective release of anti-tumor agents.…”

c(RGDyK)-decorated Pluronic micelles for enhanced doxorubicin and paclitaxel delivery to brain glioma

“…We selected cyclic Arg-Gly-Asp cyclic arginineglycine-aspartic acid peptide (c(RGDyK)) as a candidate ligand because of its selective affinity for the α v β 3 integrin, which is overexpressed in glioblastoma multiforme cells (eg, the U87 malignant glioblastoma [U87MG] cell line) and BBB cells (eg, the brain capillary endothelial cells [BCEC] cell line). 16 We hypothesized that c(RGDyK)-decorated Pluronic micelles would be capable of overcoming the BBB, thus effectively accomplishing brain glioma targeting.…”

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

“…the U87MG cell line) (Miura et al, 2013). Current standard of care for patients diagnosed with high-grade malignant glioma includes post-operative temozolomide (TMZ) adjuvant to radiation (Buie & Valgus, 2012).…”