Targeting Macrophage Folate Receptor for Drug Delivery

Folate receptor (FR) expression on activated macrophages represents an important biomarker in various autoimmune inflammatory diseases. FRβ serves as an excellent target for the delivery of therapeutics to macrophages. By leveraging the wealth of information that we have on macrophage-targeted drug delivery, Creative Biolabs is happy to help our clients with their study on the conjugation of folate to drugs, folate antagonists, nanoparticles for macrophage-targeted delivery.

Properties of FR

FR is a 38 kDa glycosylphosphatidylinositol (GPI)-anchored protein. It is anchored to the plasma membrane via a GPI anchor. FR binds to the vitamin folic acid with high affinity. Following binding, rapid endocytosis delivers a fraction of the receptors into a low pH compartment where dissociation of the vitamin from its receptor is promoted. At least 3 isoforms of FR exist, FRα, FRβ, and FRγ. The FRα has a relatively broad tissue distribution profile in the placenta, kidney, malignant tumors, and various cancer cell lines. Whereas FRβ expression is restricted to hematopoietic cells of the myeloid lineage. In fact, FRβ is expressed on monocytes, activated macrophages of rheumatoid arthritis (RA) patients, tumor-associated macrophages, and acute myeloid leukemia (AML) cells. A number of substances have been reported to upregulate FRβ expression, such as retinoic acid and curcumin, whereas a pluripotent growth factor-like activin A downregulates FRβ expression. In contrast, FRγ, which is primarily a secreted isoform of hematopoietic origin, is difficult to detect under normal conditions.

Fig.1 Formulations internalization targeting folic acid and FR. (Martín-Sabroso, et al., 2021)Fig.1 Scheme showing folic acid- and FR-targeted formulations internalization.1

Therapeutic Targeting of FR

FRs have been exploited for therapeutic targeting in cancer and inflammation. For targeting of FRα-expressing tumors, several methods have been employed, such as folate-conjugated radionuclides, folate-conjugated anti-cancer drugs, folate-conjugated nanoparticles containing siRNAs, miRNAs, genes or folate antagonists which FRα has a high affinity. For FRβ, the targeting approaches are similar. Many approaches have been reported for targeting FRβ-expressing macrophages in RA and FRβ-expressing tumor-associated macrophages. FRβ expression on activated macrophages may be exploited to guide targeted therapies and therapy response monitoring in RA.

FR-based Macrophage-targeted Drug Delivery System Development at Creative Biolabs

Studies have shown that FR constitutes a marker for macrophage activation and that FR+ macrophages can be targeted with folate-conjugated drugs without promoting drug uptake by nonactivated macrophages. Moreover, conjugation of folate to low molecular weight drugs, genes, liposomes, nanoparticles has minor effects on FR binding. Therefore, FR can be exploited to target therapeutic agents to activated macrophages. Equipped with a team of seasoned scientists with facilities designed specifically to meet very challenging requirements in Macrophage-targeted Drug Delivery System Development, Creative Biolabs offers reliable support for the conjugation of folate to drugs, folate antagonists, nanoparticles containing siRNAs, miRNAs, genes.

Scientists at Creative Biolabs lend their expertise and assist you in choosing a suitable strategy for the development of FR-based macrophage-targeted drug delivery systems. For more detailed information, please feel free to contact us or send us your inquiry or question.


  1. Martín-Sabroso, Cristina, et al. "Active targeted nanoformulations via folate receptors: State of the art and future perspectives." Pharmaceutics 14.1 (2021): 14.
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