Abstract
Active targeting can improve the retention of drugs and drug delivery systems in tumors, thereby enhancing their therapeutic efficacy. In this context, vitamin receptors that are overexpressed in many cancers are promising targets. In the last decade, attention and research were mainly centered on vitamin B9 (folate) targeting; however, the focus is slowly shifting towards vitamin B2 (riboflavin). Interestingly, while the riboflavin carrier protein was discovered in the 1960s, the three riboflavin transporters (RFVT 1-3) were only identified recently. It has been shown that riboflavin transporters and the riboflavin carrier protein are overexpressed in many tumor types, tumor stem cells, and the tumor neovasculature. Furthermore, a clinical study has demonstrated that tumor cells exhibit increased riboflavin metabolism as compared to normal cells. Moreover, riboflavin and its derivatives have been conjugated to ultrasmall iron oxide nanoparticles, polyethylene glycol polymers, dendrimers, and liposomes. These conjugates have shown a high affinity towards tumors in preclinical studies. This review article summarizes knowledge on RFVT expression in healthy and pathological tissues, discusses riboflavin internalization pathways, and provides an overview of RF-targeted diagnostics and therapeutics.
Highlights
Nanomedicines are nano-sized systems conjugated to anti-cancer drugs
flavin mononucleotide (FMN) Ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) showed tumor specific accumulation in cancer cells and the tumor stroma, i.e., the tumor associated endothelial cells and macrophages. These results suggest that FMN is a promising diagnostic tag for diagnostic probes to simultaneously target different tumor compartments, including the cancer cells and its stroma
The ideal targeted system should be large enough to benefit from enhanced permeability and retention (EPR) but small enough to transit to the tumor cells, which might ideally be given for systems of antibody sizes
Summary
Nanomedicines are nano-sized systems conjugated to anti-cancer drugs. Owing to their size, the nanoparticles accumulate more at the tumor site based on the enhanced permeability and retention (EPR). The most common targeting moieties are antibodies as well as peptides, aptamers, and small molecules. Due to their considerably large size, antibodies can significantly alter drug pharmacokinetics and are relatively expensive to produce [3]. The coupling of antibodies to drug delivery systems is difficult to control, and their receptor affinities tend to decrease upon conjugation [4,5,6]. This review article will summarize the current knowledge of the mechanisms of RF internalization and report on studies using this pathway for targeted cancer diagnostics and nanomedicines
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