Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery
Department of Internal Medicine, Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI 48109, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Bing Yan
Int. J. Mol. Sci. 2015, 16(1), 1772-1790; https://doi.org/10.3390/ijms16011772
Received: 23 December 2014
/
Accepted: 5 January 2015
/
Published: 13 January 2015
(This article belongs to the Special Issue Bioactive Nanoparticles 2014)
The rational design of a nanoplatform in drug delivery plays a crucial role in determining its targeting specificity and efficacy in vivo. A conventional approach relies on the surface conjugation of a nanometer-sized particle with two functionally distinct types of molecules, one as a targeting ligand, and the other as a therapeutic agent to be delivered to the diseased cell. However, an alternative simplified approach can be used, in which a single type of molecule displaying dual function as both a targeting ligand and therapeutic agent is conjugated to the nanoparticle. In this review, we evaluate the validity of this new strategy by using methotrexate, which displays multifunctional mechanisms of action. Methotrexate binds to the folate receptor, a surface biomarker frequently overexpressed in tumor cells, and also inhibits dihydrofolate reductase, an enzyme critical for cell survival and division. Thus we describe a series of fifth generation poly(amido amine) dendrimers conjugated with methotrexate, and discuss several lines of evidence supporting the efficacy of this new platform strategy based on surface plasmon resonance spectroscopy, enzyme activity assays, and cell-based studies with folate receptor (+) KB cancer cells.
View Full-Text
Keywords:
folate; methotrexate; folate receptor; dihydrofolate reductase; PAMAM dendrimer; multivalent design; avidity; targeted delivery; nanotherapeutics
▼
Show Figures
Graphical abstract
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
MDPI and ACS Style
Wong, P.T.; Choi, S.K. Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery. Int. J. Mol. Sci. 2015, 16, 1772-1790. https://doi.org/10.3390/ijms16011772
AMA Style
Wong PT, Choi SK. Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery. International Journal of Molecular Sciences. 2015; 16(1):1772-1790. https://doi.org/10.3390/ijms16011772
Chicago/Turabian StyleWong, Pamela T., and Seok Ki Choi. 2015. "Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery" International Journal of Molecular Sciences 16, no. 1: 1772-1790. https://doi.org/10.3390/ijms16011772
Find Other Styles
