Tumor cells receptor-mediated endocytosis

Although not yet proven, it is likely that receptor-mediated endocytosis occurs with a number of systems in which the imaging Gd-probes are linked either to peptides as targeting vectors that bind to specific receptors or to nutrient or pseudo-nutrient moieties that interact with the proper transporter up-regulated in tumor cells. 

If the same endocytic LCM-uptake mechanism(s) which has been observed and analyzed in detail with C6 and 9L tumor cells in culture (see Section 13.1) were also operative in vivo, it would indicate that a sizable portion of intravenously injected LCM that bypasses the reticuloendothelial system will then become endo-cytosed directly by tumor cells (ref. 531). The actual endocytic pathways that are likely to be involved in LCM uptake by tumors are not known, at the present time, due to the lack of any detailed receptor-binding studies with LCM to date. However, a few reasonable candidates for such endocytic pathways emerge upon reviewing parts of an extensive research literature describing significantly enhanced, receptor-mediated endocytosis in many different cancerous cells and solid tumors (see below). 

Numerous studies have pointed to an important role for cholesterol during proliferation and progression of cancer (e.g., ref. 612-615). Rapidly dividing cancer cells have two major routes to fulfill their need for cholesterol to form new cell membrane endogenous synthesis of cholesterol and/or receptor-mediated uptake of exogenous LDL particle-associated cholesterol and cholesterol esters (ref. 612,613,615). Each LDL particle contains a cholesterol ester core surrounded by a polar shell of phospholipids (primarily phosphoglycerides), free cholesterol, and apolipoprotein B (ref. 616-618). Once bound to its cell surface receptor, LDL is internalized by receptor-mediated endocytosis and degraded in lysosomes, and the subsequently released cholesterol may be used for membrane synthesis by the tumor (ref. 619). 

Many putative receptors for anti-dsDNA on the membrane of various cell types have been noted. Some workers found a 30-kDa protein involved in the binding and internalization of [3H]DNA via receptor-mediated endocytosis (B12, B13). Other possible receptors include nucleosomes on human leukocytes (R8), Fc receptors on human T cells (A6), DNA on mouse and human mononuclear cells (06), a 94-kDa protein on several cells lines (J2), DNase-resistant target on human fibroblasts and PK 15 cells (K9), membrane determinant precisely resembling DNA in murine renal tubular cells (Zl), Hp8 on human and murine tubular cells (Z2), ribosomal P protein on rat and human glomerular mesangial cells (S30, S31), brush border myosin 110 kDa on rat hepatoma cells, and a diverse set of membrane proteins on a series of human tumor cell lines (R3). 

Transferrin is a single-chain glycoprotein which has two similar binding sites for Fem ions situated in interdomain clefts in the N-terminal half (N-lobe) and C-terminal half of the molecule. Diferric transferrin is taken up by cells via receptor-mediated endocytosis. It is possible that transferrin delivers Pt to tumor cells which are known to overexpress such receptors. The combination of 1H-, 15N- and 13C-NMR spectroscopy (15N-cisplatin and 13C-Met-transferrin) has shown that one of the major cisplatin binding sites is Met-256 in the N-lobe which is solvent-accessible [51]. 

Tumor cellular uptake at the target site can be further enhanced by promoting receptor-mediated endocytosis (25). Polymeric-based delivery vehicles can be complexed with monoclonal antibodies for recognized cell surface markers as well as peptides, small molecule ligands, and aptamers directed to the target tumor cells. 

A common approach to increase the cellular uptake (internalization) is through receptor-mediated endocytosis by decorating nanoparticles with ligands that bind the receptors on tumor cells. The main challenge in this approach is to make these ligands selective for tumor cells and avoid healthy cells that may express the same... 

For an ideal photosensitizer, solubility in wato is a majca requirement, in addition to long-wavelength absorption. Therefore, in recent years, a number of carbohydrate derivatives of various photosensitizers have been synthesized. It was shown recendy that some carbohydrate-substituted porphyrins exhibit enhanced selectivity to cancer cells. Although the mechanism of sensitizer uptake is not clear, there is evidence that hydrophobic and amphiphilic porphyrins associate strongly to low-density lipoprotein (LDL) and are introduced into Ae tumor cells by receptor mediated endocytosis. Amphiphilic porphyrins may be incorporated into the plasma membranes of the tumor cells. Such incorporation of a photosensitizCT into a plasma membrane leads to a high quantum yield of cell deactivation. ... 

Synthesis, biophysical characterization, tumor cell-selective internalization, and anticancer dmg delivery of QD-ILs. QD-ILs prepared by insertion of anti-HER2 scFv exhibited efficient receptor-mediated endocytosis in HER2-overexpressing SK-BR-3 and MCF-7/HER2 cells but not in control MCF-7 cells, as analyzed by flow cytometry and confocal microscopy... 

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