Targeting B16 tumorsin vivowith peptide-conjugated gold nanoparticles

Abstract

This study examines the effects of polyethylene glycol (PEG) and peptide conjugation on the biodistribution of ultrasmall (2.7 nm) gold nanoparticles in mice bearing B16 melanoma allografts. Nanoparticles were delivered intravenously, and biodistribution was measured at specific timepoints by organ digestion and inductively coupled plasma mass spectrometry. All major organs were examined. Two peptides were tested: the cyclic RGD peptide (cRGD, which targets integrins); and a recently described peptide derived from the myxoma virus. We found the greatest specific tumor delivery using the myxoma peptide, with or without PEGylation. Un-PEGylated cRGD performed poorly, but PEGylated RGD showed a significant transient collection in the tumor. Liver and kidney were the primary targets of all constructs. None of the particles were able to cross the blood-brain barrier. Although it was able to deliver Au to B16 cells, the myxoma peptide did not show any cytotoxic activity against these cells, in contrast to previous reports. These results indicate that the effect of passive targeting by PEGylation and active targeting by peptides can be independent or combined, and that they should be evaluated on a case-by-case basis when designing new nanosystems for targeted therapies. Both myxoma peptide and cRGD should be considered for specific targeting to melanoma, but a thorough investigation of the cytotoxicity of the myxoma peptide to different cell lines remains to be performed.

RGDfK‐functionalized gold nanorods bind only to activated platelets

“…Thus, selectively targeting the α v β 3 integrin with anti‐tumor drugs or thermal stress is thought to provide an opportunity to deliver agents and destroy tumor vessels while leaving healthy tissue intact. However, previous efforts have had only moderate success in targeting such therapies using RGD ligands to these tumor‐specific receptors . More specifically, a prior report describing intravenous infusion of the same RGDfK‐labeled GNRs used here to ectopic solid murine tumor models showed that the majority of the GNRs were sequestered by the liver and spleen, with little targeting specificity seen toward the tumor …”

“…Platelet consumption and clearance occurs through hemostatic processes such as controlling bleeding and active, continual removal by the reticuloendothelial system in the liver and the spleen. Previous research shows that the spleen and liver play a significant role in the clearance of the majority of intravenously dosed RGD‐labeled targeted agents and specifically, GNRs . With platelet turnover close to a 100 billion platelets a day, many which are activated, and the ability of activated platelets to bind RGDfK‐labeled GNRs, the observed increase in liver and splenic clearance of targeted RGDfK GNRs could very be attributed to increased platelet uptake of these GNRs and clearance through these organs.…”

“…Diagnostic, biomedical, and clinical applications for gold nanoparticles are diverse and increasing, central to new optical imaging-based contrast agents, delivery vehicles for drugs and infused media for photothermal therapy. [43][44][45][46][47] Targeted approaches to elicit selective and specific binding and tissue biodistributions using specific ligands conjugated to gold nanoparticle surfaces are reported to increase their localization to specific tissues 13,48,49 although substantial off-target accumulation in filtration organs (that is, RES/ MPS system comprising liver, spleen, kidneys, lungs) is consistently reported. In targeting nanoparticles in vitro and in vivo, significant attention has been paid to the avb3 integrins, commonly targeted through the well-known cell adhesion peptide, Arg-Gly-Asp (RGD), and its increasingly diverse related peptide analogs.…”

“…[3][4][5][6] Despite integrin peptide targeting. 7,8 this approach often leads to dose deposition at nontarget sites for RGD-labeled soluble polymers, 9,10 particles, [11][12][13] and other bioactive compounds. [14][15][16][17] In vitro affinities for RGD and RGDfK peptide ligands in serum-free media with endothelial cell lines are 12.22 310 6 M 21 and 6.33 310 6 M 21 (K d 5 818 and 158 nM), respectively.…”

Nanomedicine in Melanoma: Current Trends and Future Perspectives

“…Nanoparticle quantum dots (QDs), fluorescent nanoparticles characterized by excellent brightness, narrow field of emissions, broad absorption spectrum, and excellent photostability, have been suggested as a useful technique for cancer detection (31)(32)(33)(34)(35). Those photophysical properties allowed researchers to conjugate QDs with variable cancer-specific molecules as folic acid or antibodies against specific cancer antigens (36-40).…”