Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma

Abstract

Glioblastoma-targeted drug delivery systems facilitate efficient delivery of chemotherapeutic agents to malignant gliomas, while minimizing systemic toxicity and side effects. Taking advantage of the fibrin deposition that is characteristic of tumors, we constructed spherical, Cy7-labeled, targeting micelles to glioblastoma through the addition of the fibrin-binding pentapeptide, cysteine–arginine–glutamic acid–lysine–alanine, or CREKA. Conjugation of the CREKA peptide to Cy7-micelles increased the average particle size and zeta potential. Upon intravenous administration to GL261 glioma bearing mice, Cy7-micelles passively accumulated at the brain tumor site via the enhanced permeability and retention (EPR) effect, and Cy7-CREKA-micelles displayed enhanced tumor homing via active targeting as early as 1 h after administration, as confirmed via in vivo and ex vivo imaging and immunohistochemistry. Biodistribution of micelles showed an accumulation within the liver and kidneys, leading to micelle elimination via renal clearance and the reticuloendothelial system (RES). Histological evaluation showed no signs of cytotoxicity or tissue damage, confirming the safety and utility of this nanoparticle system for delivery to glioblastoma. Our findings offer strong evidence for the glioblastoma-targeting potential of CREKA-micelles and provide the foundation for CREKA-mediated, targeted therapy of glioma.

Targeted delivery of thymosin beta 4 to the injured myocardium using CREKA-conjugated nanoparticles

“…Both our and other studies had recently found that CREKA could specifically bind to fibrin in microthrombus and stroma of tumors. [34][35][36][37] It occurred to us that CREKA peptide could mediate nanoparticle (NP) drug delivery system to fibrin in infarcted myocardium, which may increase the retention of Tβ4, improve its efficacy, and reduce its dosing systematically.…”

Water-soluble l-cysteine-coated FePt nanoparticles as dual MRI/CT imaging contrast agent for glioma

“…1 In the past decade, numerous novel strategies based on various nanomaterials have been developed to conquer the highly mortal brain tumors. [2][3][4][5] Interesting topics in this field include the targeted and controlled delivery system of anticancer drugs; [6][7][8][9] photodynamic, photothermal, and magnetothermal therapy of tumors; [10][11][12][13][14][15][16] and MRI, CT, and fluorescent imaging of brain tumors. [17][18][19][20][21][22] Among various nanomaterials, magnetic nanoparticles (NPs) such as superparamagnetic iron oxide NPs (SPIONs) are the most extensively studied.…”

Polyethylene glycol–polylactic acid nanoparticles modified with cysteine–arginine–glutamic acid–lysine–alanine fibrin-homing peptide for glioblastoma therapy by enhanced retention effect

“…[22][23][24] In addition, fibrin is considered more abundant and possibly more stable than nonspecific and limited numbers of receptors, and thus to be a better target, and it has been used in the molecular imaging of cancer. 1,25 Then, a novel drug-delivery system can be developed based on abundant and specific fibrin deposits, which may prolong drug retention in tumors and improve the effectiveness of tumor treatment.…”

“…26 Taking advantage of its fibrin-binding capacity to thrombi and microthrombi, this pentapeptide has been utilized for the image diagnosis of myocardial ischemia and tumors, 1,25,26 but not for the targeted therapy of GMB.…”