Folic acid receptor (FR) is a glycosylphosphatidylinositol-linked membrane glycoprotein that mediates the endocytosis of folic acid and its derivatives. Two membrane-bound FR isomers (FR-α and FR-β) have been identified in humans, both of which show extremely high binding affinity to folic acid and effectively promote intracellular transport of folic acid. Up-regulation of FR-α expression has been observed in many human cancers, and high FR-α expression levels are usually associated with advanced histological invasiveness. The high expression of FR-α in human cancer makes it an ideal candidate target for targeted delivery. In the past few decades, many efforts have been made for FR-α for therapeutic, diagnostic and surgical navigation purposes. Unfortunately, there is currently no drug approved for clinical use.

Investigate the reason, why the targeted molecule does not perform clinically?

Introduction
In view of this, Professor Zhan Changyou of Fudan University and others have re-studied the regulation effect of plasma protein on the fate of FA functionalized nano-drugs and re-explored the targeting ability of folic acid in the body. The results were published in ACS Nano magazine.

Deprived of targeting, but also captured
It is found that FA functionalization induces the adsorption of a large amount of natural IgM on the surface of liposomes, which deprives the ability of FA receptor recognition and accelerates complement activation in vivo. Compared with ordinary liposomes (without FA), FA functionalization will not enhance the distribution of liposomes in tumors with high FR-α expression, but will increase the effect of macrophages on lipids in tumors, liver and spleen. Body capture.

Caution in clinical application
In addition, FA functionalized polymer nanoparticles are also susceptible to natural IgM adsorption. This work emphasizes the key role of natural IgM in regulating the in vivo administration of FA functionalized nanomedicine. Due to the general connection between immune disorders and immunoglobulin levels and cancer patients, the clinical application of FA targeted drug delivery systems requires extra caution.

references:
Huan Wang, et al., Interrogation of Folic Acid-Functionalized Nanomedicines: The Regulatory Roles of Plasma Proteins Reexamined. ACS Nano 2020.
DOI: 10.1021/acsnano.0c02821
https://pubs.acs.org/doi/10.1021/acsnano.0c02821

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