Folate receptor-mediated endocytosis

Lee, R. J. Wang, S. Low, R S., Measurement of endosome pH following folate receptor-mediated endocytosis, Biochim. Biophys. Acta 1312, 237-242 (1996). 

It has been hypothesized that folate receptor-mediated endocytosis can be exploited for the selective delivery of drugs by covalent attachment to folate via its y-carboxyl group. This concept was primarily designed for the targeting of various biomolecules to solid tumours. For a... 

Lee, R.J., and PS. Low, Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis. J Biol Chem, 1994. 269(5) 3198-204. 

Lu T, Sun J, Chen X, Zhang P, Jing X (2009) Folate-conjugated micelles and their folate-receptor-mediated endocytosis. Macromol Biosci 9 1059-1068... 

Folate as a Targeting Device for Proteins Utilizing Folate Receptor-Mediated Endocytosis... 

Fig. 6 The chemical structure of folic acid and the series of distinct steps of the folate receptor-mediated endocytosis (adapted from Ref. [187] with permission)...

On the other hand, the cellular uptake of probe 37 (Fig. 28.8) occurred via folate receptor-mediated endocytosis due to cancer targeting units, folic acids. It is well-known that cancer cells express more receptors for folic acid as compared with normal cells. HeLa cells, expressing more folate receptors as compared with fibroblast N1H3T3 cells, showed better internalization of probe 37. Co-localization studies revealed endo-lysosomal accumulation of probe 37. This suggests that cellular uptake and visualization of calix[4]arene can be enhanced using a cancer targeting unit. 

Boronated PAMAM dendrimers can be targeted to tumor using epidermal growth factors [67,68], vascular endothelial growth factor [69], and folic acid, a vitamin that is transported into cells through folate receptor-mediated endocytosis [70]. 

Fig. 11 Above Folate receptor-mediated targeting and SWNT-mediated delivery of structure 1 by endocytosis. Below. Structure 1. (Adapted from [60]).

Folic acid, shown in Fig. 12.3, is a common component of food and vitamins.36 The receptor for the vitamin folic acid is known as the folate receptor or the high-affinity membrane folate-binding protein.37 These folate receptors typically are not present in normal cells, but in a variety of human tumors they are greatly overexpressed.36-38 In addition, folate receptors mediate internalization by endocytosis. For these reasons, folic acid has been examined as a homing device. In general, studies have shown that by simple conjugation of folic acid to macromolecules, internalization into cells can occur similarly to that of free folic acid.39... 

The folate receptor is a glycophosphatidyl inositol anchored cell surface protein with a broader specificity that permits uptake of folate hy receptor-mediated endocytosis. At times of low folate requirement, the receptor is in intracellular vesicles, which migrate to the cell surface when the requirement for folate increases (Doucette and Stevens, 2001). 

The folate receptor facilitates the cellular uptake of folate and 5-methyltetrahydrofolate via receptor-mediated endocytosis at caveolae (caveolae are plasma membrane invaginations distinct from the classical clathrin-coated pits) (6). It has been hypothesized that the folate receptor is functionally coupled to an anion transporter to mediate cytosolic folate delivery by a process defined as potocytosis (6). More recent studies suggest that folate receptor endocytosis also occurs at clathrin-coated pits (7). Studies by Low and coworkers at Purdue University have shown that folate conjugates are also taken up by the folate receptor (8-10), but not by the reduced folate carrier. Figure 2 illustrates an endocytic pathway of the type envisioned for folate conjugates. Unfortunately, the subcellular transport pathway of the folate conjugates has been only partially characterized and may well be affected by the properties of the molecule attached to folate. 

Several small molecules, Including folate, galactose, lactose, and N-acetyl galactosamlne, also have been used to prepare polylysIne/DNA complexes for delivery of DNA by receptor-mediated endocytosis. 

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