Influence of Riboflavin Targeting on Tumor Accumulation and Internalization of Peptostar Based Drug Delivery Systems

Abstract

Riboflavin carrier protein (RCP) and riboflavin transporters (RFVTs) have been reported to be highly overexpressed in various cancer cells. Hence, targeting RCP and RFVTs using riboflavin may enhance tumor accumulation and internalization of drug delivery systems. To test this hypothesis, butyl-based 3-arm peptostar polymers were synthesized consisting of a lysine core (10 units per arm) and a sarcosine shell (100 units per arm). The end groups of the arms and the core were successfully modified with riboflavin and the Cy5.5 fluorescent dye, respectively. While in phosphate buffered saline the functionalized peptostars showed a bimodal behavior and formed supramolecular structures over time, they were stable in the serum maintaining their hydrodynamic diameter of 12 nm. Moreover, the polymers were biocompatible and the uptake of riboflavin targeted peptostars in A431 and PC3 cells was higher than in nontargeted controls and could be blocked competitively. In vivo, the polymers showed a moderate passive tumor accumulation, which was not significantly different between targeted and nontargeted peptostars. Nonetheless, at the histological level, internalization into tumor cells was strongly enhanced for the riboflavin-targeted peptostars. Based on these results, we conclude that passive accumulation is dominating the accumulation of peptostars, while tumor cell internalization is strongly promoted by riboflavin targeting.

Nanomedicine Tumor Targeting

“…To this end, in the first exemplary study, we generated polymeric nanocarrier materials that are within the ideal size range for active targeting (i.e., above 5–10 nm and below 35 nm), and we modified them either with RGD and NGR peptides (for integrin and aminopeptidase targeting on endothelial, tumor cells and in the microenvironment) or with vitamin B2 (i.e., riboflavin; for targeting tumor cells, cancer stem cells and endothelial cells). [ 56–59 ] For RGD and NGR peptide‐mediated active targeting of 67 kDa (10–20 nm) pHPMA‐based polymeric nanocarriers, we observed rapid and efficient binding to angiogenic blood vessels in two different tumor models. However, due to presence of peptides, the polymeric nanocarriers were excreted more rapidly from the systemic circulation, and their long‐term levels of tumor targeting (i.e., AUC) were lower than those of non‐peptide‐modified control polymers.…”

Shining Light on Polymeric Drug Nanocarriers with Fluorescence Correlation Spectroscopy

“…If these experimental procedures are rigorously applied, FCS can accurately measure even the hydrodynamic radius of individual dye molecules [56,115] in undiluted blood plasma. Consequently, the method was applied to study the blood plasma (serum) stability of various nanocarrier systems including polyplexes, [79] branched polymers, [115][116][117] lipid nanoparticles, [118][119][120] nanogels, [90] etc.…”

Nanobiomimetic Medicine

“…As a class of typical biomimetic raw materials belonging to the bottom‐up preparation process, targeting ligand is prevalent for decorating the surface of nanomaterials to achieve the purpose of the improvement of material performance. The ligands have been characterized into a few categories, including small molecules (e.g., folate and riboflavin), [ 42 ] peptide (e.g., arginine‐glycine‐aspartic acid (RGD), [ 43 ] transactivator of transcription peptide (TAT) [ 44 ] ), proteins (e.g., transferrin family proteins, adhesion proteins, and lipoproteins), [ 45 ] carbohydrates, [ 46 ] lipid bilayers, [ 47 ] nucleic acid (DNA), [ 48 ] etc. For instance, the amide bonding reaction as a typical bottom‐up approach has been applied into the synthesis of doxorubicin (DOX)‐loaded heparin‐folate‐paclitaxel nanoparticles through the conjugation of ethylene diamine‐modified folate with heparin, achieving the purpose of sustained drug release and tumor localization.…”