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Bioanalytical Screening of Riboflavin Antagonists for Targeted Drug Delivery - A Thermodynamic and Kinetic Study.

ABSTRACT: The present study screened riboflavin mimicking small molecules to determine their binding activity for the riboflavin binding protein. We performed thermodynamic and kinetic binding studies of these molecules using a combination of two analytical approaches; isothermal titration calorimetry and surface plasmon resonance spectroscopy. Screening of a biased set of non-riboflavin based small molecules by microcalorimetry led to the discovery of two known drug molecules, quinacrine and chloroquine, as favorable ligands for the riboflavin receptor with K(D) value of 264, and 2100 nM, respectively. We further demonstrated that quinacrine is a competitive ligand for the receptor as measured by surface plasmon resonance. Thus this study describes the identification of a novel class of dual acting riboflavin antagonists that target riboflavin receptor for cellular uptake and display multifunctional activities upon cellular entry.

SUBMITTER: Plantinga A

PROVIDER: S-EPMC3114641 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Bioanalytical Screening of Riboflavin Antagonists for Targeted Drug Delivery - A Thermodynamic and Kinetic Study.

Plantinga Anna A Witte Amanda A Li Ming-Hsin MH Harmon Andrew A Choi Seok Ki SK Banaszak Holl Mark M MM Orr Bradford G BG Baker James R JR Sinniah Kumar K

ACS medicinal chemistry letters 20110501 5

The present study screened riboflavin mimicking small molecules to determine their binding activity for the riboflavin binding protein. We performed thermodynamic and kinetic binding studies of these molecules using a combination of two analytical approaches; isothermal titration calorimetry and surface plasmon resonance spectroscopy. Screening of a biased set of non-riboflavin based small molecules by microcalorimetry led to the discovery of two known drug molecules, quinacrine and chloroquine, ...[more]

PMID: 21686082

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Project description:The retention and cellular internalization of drug delivery systems and theranostics for cancer therapy can be improved by targeting molecules. Since an increased uptake of riboflavin was reported for various cancers, riboflavin and its derivatives may be promising binding moieties to trigger internalization via the riboflavin transporters (RFVT) 1, 2, and 3. Riboflavin is a vitamin with pivotal role in energy metabolism and indispensable for cellular growth. In previous preclinical studies on mice, we showed the target-specific accumulation of riboflavin-functionalized nanocarriers in cancer cells. Although the uptake mechanism of riboflavin has been studied for over a decade, little is known about the riboflavin transporters and their expression on cancer cells, tumor stroma, and healthy tissues. Furthermore, evidence is lacking concerning the representativeness of the preclinical findings to the situation in humans. In this study, we investigated the expression pattern of riboflavin transporters in human squamous cell carcinoma (SCC), melanoma and luminal A breast cancer samples, as well as in healthy skin, breast, aorta, and kidney tissues. Low constitutive expression levels of RFVT1-3 were found on all healthy tissues, while RFVT2 and 3 were significantly overexpressed in melanoma, RFVT1 and 3 in luminal A breast cancer and RFVT1-3 in SCC. Correspondingly, the SCC cell line A431 was highly positive for all RFVTs, thus qualifying as suitable in vitro model. In contrast, activated endothelial cells (HUVEC) only presented with a strong expression of RFVT2, and HK2 kidney cells only with a low constitutive expression of RFVT1-3. Functional in vitro studies on A431 and HK2 cells using confocal microscopy showed that riboflavin uptake is mostly ATP dependent and primarily driven by endocytosis. Furthermore, riboflavin is partially trafficked to the mitochondria. Riboflavin uptake and trafficking was significantly higher in A431 than in healthy kidney cells. Thus, this manuscript supports the hypothesis that addressing the riboflavin internalization pathway may be highly valuable for tumor targeted drug delivery.

Dataset Information

Bioanalytical Screening of Riboflavin Antagonists for Targeted Drug Delivery - A Thermodynamic and Kinetic Study.

Publications

Bioanalytical Screening of Riboflavin Antagonists for Targeted Drug Delivery - A Thermodynamic and Kinetic Study.

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