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Riboflavin-Conjugated Multivalent Dendrimer Platform for Cancer-Targeted Drug and Gene Delivery

  • Pamela T. WongEmail author
  • Kumar SinniahEmail author
  • Seok Ki ChoiEmail author
Chapter
Part of the Nanomedicine and Nanotoxicology book series (NANOMED)

Abstract

Riboflavin receptors (RFRs) are overexpressed in several malignant cells, and have been characterized as an emerging tumor surface biomarker. In this article, we discuss the design principles of a RFR-targeted nanoparticle system and illustrate its applications with studies performed in our laboratories. This system is based on a poly(amidoamine) (PAMAM) dendritic polymer which is modified on the surface by conjugation with riboflavin (RF) as the targeting ligand. First, we discuss the application of this system for targeted drug delivery by its conjugation with methotrexate as an antitumor payload. In cell-based experiments performed in vitro, this drug conjugate displayed RF-dependent, potent inhibition of cell growth in RFR(+) KB carcinoma cells. Second, the use of the RF-conjugated dendrimer for gene delivery applications through the formation of polyplexes with plasmid DNA is described. The ability of this targeted system to significantly enhance gene transfection in epithelial cells points to its potential as a promising new class of nonviral vectors. Third, the tunability of the functional properties of the dendrimer through modular integration is illustrated with an optically active gold nanoparticle (AuNP). The resultant dendrimer-coated AuNPs have a unique capability for tumor cell imaging via surface plasmon resonance scattering. Finally, we discuss the biophysical basis of the multivalent mechanism involved in the tight and specific binding of a RF-conjugated multivalent dendrimer to RFRs on the cell surface. The design principles and proof of concept studies presented here are strongly supportive of the promising potential of RF-conjugated nanoparticles for delivery and imaging applications in tumors.

Keywords

Riboflavin Tumor surface marker PAMAM dendrimer Targeted delivery Multivalent avidity Surface plasmon resonance Imaging cavity 

Abbreviations

AFM

Atomic force microscopy

BSA

Bovine serum albumin

DAPP

3,8-Diamino-6-phenylphenanthridinium

DLS

Dynamic light scattering

EPR

Enhanced permeation and retention

EGFR

Epidermal growth factor receptor

FGFR

Fibroblast growth factor receptor

FAD

Flavin adenine dinucleotide

FMN

Flavin mononucleotide

FITC

Fluorescein isothiocyanate

FAR

Folate receptor

G5

Generation 5

AuNP

Gold nanoparticle

HPMA

N-(2-hydroxypropyl)methacrylamide

ITC

Isothermal titration calorimetry

MTX

Methotrexate

NP

Nanoparticle

pDNA

Plasmid DNA

PAMAM

Poly(amidoamine)

PSMA

Prostate-specific membrane antigen

RF

Riboflavin

RFBP

Riboflavin binding protein

RFR

Riboflavin receptor

SPR

Surface plasmon resonance

Notes

Acknowledgements

The authors wish to acknowledge the support from the Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School. SKC acknowledges partial support from the British Council and Department for Business Innovation and Skills through Global Innovation Initiative. KS acknowledges partial support from a Calvin College Research Fellowship.

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© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of Chemistry and BiochemistryCalvin CollegeGrand RapidsUSA

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