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

Plantinga, Anna; Witte, Amanda; Li, Ming Hsin; Harmon, A.; Choi, Seok Ki; Holl, Mark M. Banaszak; Orr, Bradford G.; Baker, James R.; Sinniah, Kumar

doi:10.1021/ml100296z

Cited by 28 publications

(47 citation statements)

References 25 publications

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“…Such association must affect the overall functioning of the systems with which the redoxactive molecules are intimately associated. [50] We hope the results of the current studies will pave the way for further work aimed at enhancing the understanding of drug mechanisms intimately associated with each of the drug partners in artemisinin combination therapies.…”

Section: Wwwchemmedchemorgmentioning

confidence: 88%

“…[18] For the combination of MB screened in vitro with artemisinin 1 against the chloroquine (CQ)-resistant K1 strain, mean fractional inhibitory concentrations measured at the IC 50 value for each drug (FIC 50 ) are 0.67 at an artemisinin/MB ratio of 1:1, 0.73 (at 1:3), and 0.73 (at 3:1), indicative of synergism. [17] For the CQ-sensitive 3D7 strain, mean FIC 50 values for the MB-artemisinin combination are 0.60 (1:1), 0.85 (1:3), and 0.57 (3:1), again indicative of synergism. Artemether 3 is similarly synergistic with MB, whereas artesunate 4 is weakly synergistic, with the combination tending toward additivity.…”

Section: Introductionmentioning

confidence: 99%

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A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

Haynes

Cheu

et al. 2011

ChemMedChem

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Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH₂ of riboflavin (RF), and FADH₂ of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH₂, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin-mediated oxidation of RFH₂ generated from N-benzyl-1,4-dihydronicotinamide (BNAH)-RF, or FADH₂ generated from NADPH or NADPH-Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor-acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ-MB and CQ-artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP-CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ-resistance transporter (PfCRT).

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Section: Wwwchemmedchemorgmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

Haynes

Cheu

et al. 2011

ChemMedChem

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“…Applications of multifunctional NPs in anticancer therapeutic delivery have been well demonstrated by use of targeting ligands specific for a cell surface molecule overexpressed in cancer cells, such as folic acid receptor (FAR),[7–9] riboflavin receptor,[10,11] α v β 3 integrin,[12–14] prostate-specific membrane antigen,[15] Her2,[16] transferrin receptor,[17] and epidermal growth factor receptor. [16,18,19] The biological process for the effective uptake of such NPs requires multiple-ligand molecules attached to the NP surface.…”

Section: Introductionmentioning

confidence: 99%

Dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting

Choi

Thomas

et al. 2012

European Journal of Medicinal Chemistry

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Cancer-targeting drug delivery can be based on the rational design of a therapeutic platform. This approach is typically achieved by the functionalization of a nanoparticle with two distinct types of molecules, a targeting ligand specific for a cancer cell, and a cytotoxic molecule to kill the cell. The present study aims to evaluate the validity of an alternative simplified approach in the design of cancer-targeting nanotherapeutics: conjugating a single type of molecule with dual activities to nanoparticles, instead of coupling a pair of orthogonal molecules. Herein we investigate whether this strategy can be validated by its application to methotrexate, a dual-acting small molecule that shows cytotoxicity because of its potent inhibitory activity against dihydrofolate reductase and that binds folic acid receptor, a tumor biomarker frequently upregulated on the cancer cell surface. This article describes a series of dendrimer conjugates derived from a generation 5 polyamidoamine (G5 PAMAM) presenting a multivalent array of methotrexate and also demonstrates their dual biological activities by surface plasmon resonance spectroscopy, a cell-free enzyme assay, and cell-based experiments with KB cancer cells.

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“…ITC studies further demonstrate that quinacrine can serve as a targeting ligand for specific delivery of additional therapeutic molecules or imaging agents to the receptoroverexpressing cancer cells implicated in breast and prostate cancers. Pertinent to this targeting utility, it would be possible to apply the concept of multivalent ligand design, in which even suboptimal targeting capability can be enhanced through multivalent tight binding [108].…”

Section: Complexation With Proteinsmentioning

confidence: 99%

Self-Assembly Drugs: From Micelles to Nanomedicine

Messina¹,

Besada-Porto²,

Ruso

2014

CTMC

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Self-assembly has fascinated many scientists over the past few decades. Rapid advances and widespread interest in the study of this subject has led to the synthesis of an ever-increasing number of elegant and intricate functional structures with sizes that approach nano-and mesoscopic dimensions. Today, it has grown into a mature field of modern science whose interfaces with many disciplines have provided invaluable opportunities for crossing boundaries for scientists seeking to design novel molecular materials exhibiting unusual properties, and for researchers investigating the structure and function of biomolecules. Consequently, self-assembly transcends the traditional divisional boundaries of science and represents a highly interdisciplinary field including nanotechnology and nanomedicine. Basically, self-assembly focuses on a wide range of discrete molecules or molecular assemblies and uses physical transformations to achieve its goals. In this Review, we present a comprehensive overview of the advances in the field of drug self-assembly and discuss in detail the synthesis, self-assembly behavior, and physical properties as well as applications. We refer the reader to past reviews dealing with colloidal molecules and colloidal self-assembly. In the first part, we will discuss, compare, and link the various bioinformatic procedures: Molecular Dynamics and Quantitative Structure Activity Relationship. The second section deals with the self-assembly behavior in more detail, in which we focus on several experimental techniques, selected according to the depth of knowledge obtained. The last part will review the advances in drug-protein assembly. Nature provides many examples of proteins that form their substrate binding sites by bringing together the component pieces in a process of self-assembly. We will focus in the understanding of physical properties and applications developing thereof.

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

Cited by 28 publications

References 25 publications

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

Dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting

Self-Assembly Drugs: From Micelles to Nanomedicine

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