A Novel Solid Lipid Nanoparticle Formulation for Active Targeting to Tumor α_vβ₃ Integrin Receptors Reveals Cyclic RGD as A Double‐Edged Sword

Abstract

The overexpression of α(v) β(3) integrin receptors on tumor cells and tumor vascular endothelium makes it a useful target for imaging, chemotherapy and anti-angiogenic therapy. However integrin-targeted delivery of therapeutics by nanoparticles have provided only marginal, if any, enhancement of therapeutic effect. This work was thus focused on the development of novel α(v) β(3) -targeted near infrared light-emitting solid lipid nanoparticles (SLN) through conjugation to the α(v) β(3) integrin-specific ligand cyclic Arg-Gly-Asp (cRGD), and the assessment of the effects of α(v) β(3) targeting on nanoparticle biodistribution. Since our previously developed non-targeted "stealth" SLN showed little hepatic accumulation, unlike most reported liposomes and micelles, they served as a reference for quantifying the effects of cRGD-conjugation on tumor uptake and whole animal biodistribution of SLN. Non-targeted SLN, actively targeted (RGD-SLN) and blocked RGD-SLN were prepared to contain near infrared quantum dots for live animal imaging. They were injected intravenously to nude mice bearing xenograft orthotopic human breast tumors or dorsal window chamber breast tumors. Tumor micropharmacokinetics of various SLN formulations were determined using intravital microscopy, and whole animal biodistribution was followed over time by optical imaging. The active tumor targeting with cRGD was found to be a "double-edged sword": while the specificity of RGD-SLN accumulation in tumor blood vessels and their tumor residence time increased, their distribution in the liver, spleen, and kidneys was significantly greater than the non-targeted SLN, leaving a smaller amount of nanoparticles in the tumor tissue. Nevertheless the enhanced specificity and retention of RGD-SLN in tumor neovasculature could make this novel formulation useful for tumor neovascular-specific therapies and imaging applications.

The Impact of Aspect Ratio on the Biodistribution and Tumor Homing of Rigid Soft‐Matter Nanorods

“…[56] In contrast, the RGD-TM and RGD-TL particles would be expected to bind two or more integrins simultaneously. Furthermore, recent studies have suggested that RGD ligands are useful for the imaging of tumor neovasculature but that the targeting ligand may not increase tumor homing [53] but instead may increase overall tissue distribution, [57] which is also consistent with our findings (Figure 2C). Effective integrin targeting is highly dependent on the ligand density.…”

“…Nanoparticles decorated with RGD ligands have previously been shown to accumulate in the organs of the macrophagocytic system, reflecting structural differences in the protein corona compared to stealth nanoparticles. [57] Rapid tissue clearance is consistent with our previous TMV biodistribution studies, [62] and makes TMV particularly attractive for molecular imaging and drug delivery approaches where rapid tissue clearance is necessary.…”

Polydopamine-Based Simple and Versatile Surface Modification of Polymeric Nano Drug Carriers

“…Folate and cRGD are frequently used as ligands to target cancer cells overexpressing folate receptors 33 and neovasculature of tumors, 34 respectively. Amine-terminated betaine polymer (pCB) was synthesized as a new stealth coating with a potent anti-fouling effect.…”

Nanomedicine of synergistic drug combinations for cancer therapy – Strategies and perspectives

“…Surface conjugation of antibodies or proteins on the nanoparticles may enhance tumor recognition and binding, but it may increase chances of being removed from the circulation by the RES. For example, nanoparticles (liposome, SLN or nanoparticle coated with chitosan) conjugated with integrin ( α v β 3 ) specific ligand cyclic Arg-Gly-Asp Peptide ( c RGD) showed much greater hepatic uptake than non-targeted nanoparticles, resulting in lower tumor accumulation [154-156]. In addition to higher liver uptake of nanoparticles observed with targeting moieties than non-targeted nanoparticles, the difference in targeting receptor expressions between rodents for preclinical studies and humans.…”