A series of receptors expressed in the surface of tumor cells, which are able to mediate internalizing effect by specially connecting with corresponding ligands. These receptors are potential targets for drugs combined with conjugates. So the drug-conjugate compounds can be targeted delivery to tumor cells. The folate receptor is a promising target because of its marrow tissue specificity, its overexpression in malignant tissues, especially in myeloid leukemic cells, and its ability to bind and internalize folic acid conjugates. It is a promising potential method to apply folate receptor in the receptor-mediated targeting therapy of leukemic cells. In this review, the biological features of folate receptor, its chromosome location and its interaction with ligands, the distribution characteristics of folate receptor in normal and tumor tissues, especially in myeloid leukemic cells, and progress of research on folate receptor mediated targeting tumor cells, especially leukemic cells were summarized.
Antineoplastic Agents ; administration & dosage ; Carrier Proteins ; metabolism ; Drug Delivery Systems ; methods ; Folate Receptors, GPI-Anchored ; Folic Acid ; metabolism ; Humans ; Leukemia ; drug therapy ; metabolism ; pathology ; Receptors, Cell Surface ; metabolism ; Tretinoin ; administration & dosage ; Tumor Cells, Cultured

Folate receptor (FR) is over-expressed in a variety of human cancers and it is seldom expressed or found in normal tissues. Therefore, folate receptor-mediated antitumor drugs can be targeted specially to the FR-positive tumor cells. This strategy improves the selectivity of drugs which may destroy the normal tissues in traditional chemotherapeutics. This review provides the delivery mechanism of FR-mediated antitumor drugs and highlights the novel folate-drug conjugates and their activities.
Animals ; Antineoplastic Agents ; administration & dosage ; chemistry ; pharmacology ; Carrier Proteins ; metabolism ; Cell Line, Tumor ; Drug Carriers ; Drug Delivery Systems ; Folate Receptors, GPI-Anchored ; Folic Acid ; administration & dosage ; analogs & derivatives ; chemistry ; pharmacology ; Humans ; Neoplasms ; metabolism ; pathology ; Receptors, Cell Surface ; metabolism

5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase ; genetics ; Carrier Proteins ; genetics ; Congenital Abnormalities ; etiology ; Folate Receptors, GPI-Anchored ; Folic Acid Deficiency ; complications ; etiology ; Homocysteine ; blood ; Humans ; Membrane Transport Proteins ; genetics ; Methylenetetrahydrofolate Reductase (NADPH2) ; genetics ; Receptors, Cell Surface ; genetics

Bovine serum albumin nanoparticles(BSANP) were prepared by desolvation method. The activated folic acid (N-hydroxysuccinimide ester of folic acid) was conjuated to the surface of BSANP via the amino groups. Then the folate-conjugated BSANPs (folate-BSANP) were purified with Sephadex G-50 column and completely separated from unreacted folic acid. After chymotryptic hydrolysis, the extent of folate conjugation on the BSANP was determined by quantitative ultraviolet(UV) spectrophotometric analysis. It was found that the spectrum of trypsin digest of folate-conjugate BSANP is basically identical with that of folate, thus indicating folate is successfully expressed on the surface of BSANP. The folate-BSANP was averagely 66 nm in diameter and was spherical in shape. Folate-conjugated BSANP was achieved, which represents a potential new drug carrier for tumor cell-selective targeting.
Animals ; Antineoplastic Agents ; administration & dosage ; Carrier Proteins ; chemistry ; Cattle ; Drug Delivery Systems ; methods ; Folate Receptors, GPI-Anchored ; Folic Acid ; chemistry ; Immunotoxins ; Microspheres ; Nanotechnology ; Receptors, Cell Surface ; chemistry ; Serum Albumin, Bovine ; chemistry

AIMTo demonstrate the specific killing of folate receptor (FR)-positive tumor cells can be achieved by folate-targeted penicillin-G amidase (PGA) combined with its prodrug substrate N-(phenylacetyl) doxorubicin (DOXP).

METHODSFolic acid was covalently linked to PGA and folate content value was determined by quantitative UV spectrophotometry. The ability of folate conjugated PGA to hydrolyze DOXP was measured by RP-HPLC. Visual demonstration of uptake by FR (+) HeLa and SKOV3 cells was detected by using FITC labeled folate-PGA and a fluorescence microscopy. The cytotoxicity of DOXP towards the cells in the presence or absence of folate-PGA was assayed by using MTT method.

RESULTSThe folate-PGA has a specific activity of 29. 8 U x mg(-1) (protein). FR selectivity was confirmed by fluorescence microscopy. The combination of DOXP prodrug with folate-PGA generated higher cytotoxicity towards the FR (+) cells than free doxorubicin. The IC50 was 0.72 micromol x L(-1) for HeLa cells and 0.75 micromol x L(-1) for SKOV3 cells, respectively. Further, the enhanced cytotoxicity reduced greatly with the addition of free folic acid.

CONCLUSIONFolate conjugated PGA did not significantly compromise PGA catalytic activity and enabled binding prodrug-activating enzyme PGA to folate receptor expressing cells, and increased the sensitivity of the cells to doxorubicin followed by administration of its prodrug substrate.

Antibiotics, Antineoplastic ; pharmacology ; Carrier Proteins ; metabolism ; Cell Line, Tumor ; Doxorubicin ; analogs & derivatives ; pharmacology ; Drug Delivery Systems ; Female ; Folate Receptors, GPI-Anchored ; Folic Acid ; chemistry ; pharmacology ; HeLa Cells ; Humans ; Inhibitory Concentration 50 ; Ovarian Neoplasms ; pathology ; Penicillin Amidase ; chemistry ; pharmacology ; Prodrugs ; pharmacology ; Receptors, Cell Surface ; metabolism

A cationic liposome was prepared with a ligand directed at folate receptor in cancer cells to improve selectivity and facilitate its access to the cancer cells. Folate-polyethyleneglycol-distearoylphosphatidylethanolamine (F-PEG-DSPE) was synthesized by reacting folic acid (F), polyoxyethylene-bis-amine (NH2-PEG-NH2), succinic anhydride (SUC) with distearoylphosphatidylethanolamine (DSPE). Folate receptor-targeted liposomes composed of DPPC/DC-Chol/F-PEG-DSPE (10:10:0.75, molar ratio) were prepared by film dispersion method. A negative charged dextran fluorescein anionic (DFA) was used as a model to explore the in vitro properties and cell uptake efficiencies of liposomal DFA on KB and HpeG2 cells. The formulations were investigated by orthogonal experiment using encapsulation efficiency as the optimized indexes. The size, 4 potential, entrapment efficiency and DFA release in vitro were investigated. The results showed that DFA loaded folate receptor-targeted liposomes had high encapsulation efficiency and the mean size approximately 144 nm. The cationic liposomes had some toxicity to HepG2 cells, and at low concentration (0.0125-0.1 micromol x L(-1)) , the toxicity was linear with the concentration of DC-chol. The folate receptor-targeted liposomes showed great effects on increasing liposome cellular uptake of DFA. In summary, the method of film dispersion method is suitable for producing DFA loaded lipsomes with high entrapment efficiency, small size and slow release. The folate receptor-targeted liposomes can efficiently deliver DFA into cells in vitro. This may represent a promising option for researches on cancer gene therapy.
Carrier Proteins ; metabolism ; Dextrans ; chemistry ; Drug Carriers ; Drug Delivery Systems ; Fluoresceins ; chemistry ; Folate Receptors, GPI-Anchored ; Folic Acid ; chemistry ; Genetic Therapy ; Hep G2 Cells ; Humans ; KB Cells ; Liposomes ; administration & dosage ; chemical synthesis ; metabolism ; Particle Size ; Phosphatidylethanolamines ; chemistry ; Polyethylene Glycols ; chemistry ; Receptors, Cell Surface ; metabolism ; Transfection

The anti-tumor activity of folate receptor targeting docetaxel-loaded membrane-modified liposomes (FA-PDCT-L) was investigated in vitro and in vivo. FA-PDCT-L was prepared by organic solvent injection method. Transmission electron microscope, dynamic light scattering and electrophoretic light scattering were employed to study the physicochemical parameters of FA-PDCT-L. The inhibitory effects of docetaxel injection (DCT-I), non-modified DCT liposomes (DCT-L) and FA-PDCT-L on the growth of MCF-7 and A-549 cells at different incubation times were detected by CCK-8 assay; and the hemolytic test was employed in vitro. Tumor mice were randomized into 4 groups: DCT-I, DCT-L, FA-PDCT-L and control group (normal saline), and given drugs at 10 mg x kg(-1) x d(-1) through tail vein. The tumor volume, mice weight, inhibition rate of tumor and life span were measured at the end of experiments. The IC50 of the FA-PDCT-L for MCF-7 and A549 cell lines were significantly lower than that of DCT-I and DCT-L, without hemolysis reaction observed. Compared with control group, the weights of tumor in DCT-I, DCT-L and FA-PDCT-L were decreased, especially for FA-PDCT-L, with inhibitory rates at 79.03 % (P < 0.05). The life span and median survival time of FA-PDCT-L treated mice were significantly higher than that of DCT-I and DCT-L. In conclusion, FA-PDCT-L shows a good anti-tumor activity, indicating that it is potential carriers for DCT in the treatment of tumor.
Animals ; Antineoplastic Agents ; administration & dosage ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cyanoacrylates ; chemistry ; Drug Carriers ; Female ; Folate Receptors, GPI-Anchored ; chemistry ; Humans ; Inhibitory Concentration 50 ; Liposomes ; chemistry ; Lung Neoplasms ; pathology ; MCF-7 Cells ; Mice ; Neoplasm Transplantation ; Particle Size ; Polyethylene Glycols ; chemistry ; Rabbits ; Random Allocation ; Sarcoma 180 ; pathology ; Taxoids ; administration & dosage ; pharmacology ; Tumor Burden ; drug effects

A novel amphiphilic copolymer, folate-poly (PEG-cyanoacrylate-co-cholesteryl cyanoacrylate) (FA-PEG-PCHL) was synthesized as liposomal modifying material with folate receptor targeting and long circulating property. FA-PEG-PCHL-modified docetaxel-loaded liposomes (FA-PDCT-L) were prepared by organic solvent injection method, and the system was optimized using central composite design-response surface methodology. The structure of the FA-PEG-PCHL copolymer was confirmed by FT-IR and 1H NMR. Ultrafiltration technique, transmission electron microscope, dynamic light scattering and electrophoretic light scattering, and fluorescence polarization method were used to study the physicochemical parameters of FA-PDCT-L. FA-PDCT-L showed spherical or ellipsoid shape. The mean particle sizes were in the range of 111.6-126.9 nm, zeta potentials were from -6.54 mV to -14.13 mV and the drug encapsulation efficiency achieved 97.8%. The observed values agreed well with model predicted values. The membrane fluidity increased with the increment of the molecular weight of PEG and the decrement of the amount of FA-PEG-PCHL. The in vitro release test showed that the drug could be sustained-released from liposomes without a burst release and with stability for 6 months. After 24 h only 31.1%, 27.2% and 19.5% of encapsulated docetaxel were released for FA-PDCT10000-L, FA-PDCT4000-L and FA-PDCT2000-L, respectively. This work is useful for further research on the application of the synthesized copolymer-modified long circulating liposomes for cancer therapy.
Antineoplastic Agents ; administration & dosage ; Cholesterol Esters ; chemistry ; Cyanoacrylates ; chemistry ; Delayed-Action Preparations ; Drug Carriers ; chemical synthesis ; chemistry ; Drug Delivery Systems ; Folate Receptors, GPI-Anchored ; chemistry ; Liposomes ; administration & dosage ; chemistry ; Molecular Weight ; Particle Size ; Polyethylene Glycols ; chemistry ; Polymers ; chemical synthesis ; chemistry ; Taxoids ; administration & dosage

OBJECTIVES: Maternal periconceptional folic acid supplement is by far the most effective primary prevention strategy to reduce the incidence of congenital heart disease (CHD) in offspring. It was revealed that the underlying mechanisms are complex, including a combination of genetic and environmental factors. The purpose of this study is to investigate the association between periconceptional folic acid supplement, the genetic polymorphisms of maternal folic acid receptor 1 gene (FOLR1) and folic acid receptor 2 gene (FOLR2) and the impact of their interaction on the risk of CHD in offspring, and to provide epidemiological evidence for individualized folic acid dosing in hygienic counseling. METHODS: A case-control study on 569 mothers of CHD infants and 652 mothers of health controls was performed. The interesting points were periconceptional folate supplements, single nucleotide polymorphisms (SNPs) of maternal FOLR1 gene and FOLR2 gene. RESULTS: Mothers who took folate in the periconceptional period were observed a decreased risk of CHD [adjusted odds ratio (aOR)=0.58, 95% CI 0.35 to 0.95]. Our study also found that polymorphisms of maternal FOLR1 gene at rs2071010 (G/A vs G/G: aOR=0.67, 95% CI 0.47 to 0.96) and FOLR2 gene at rs514933 (T/C vs T/T: aOR=0.60, 95% CI 0.43 to 0.84; C/C vs T/T: aOR=0.55, 95% CI 0.33 to 0.90; the dominant model: T/C+ C/C vs T/T: aOR=0.59, 95% CI 0.43 to 0.81; and the addictive model: C/C vs T/C vs T/T: aOR=0.70, 95% CI 0.56 to 0.88) were significantly associated with lower risk of CHD [all P<0.05, false discovery rate P value (FDR_P)<0.1]. Besides, significant interaction between periconceptional folate supplements and rs2071010 G→A (aOR=0.59, 95% CI 0.41-0.86) and rs514933 T→C (aOR=0.52, 95% CI 0.37 to 0.74) on CHD risk were observed (all P<0.05, FDR_P<0.1). CONCLUSIONS Periconceptional folate supplements, polymorphisms of FOLR1 gene and FOLR2 gene and their interactions are significantly associated with risk of CHD. However, more studies in different ethnic populations with a larger sample and prospective designs are required to confirm our findings.
Case-Control Studies ; Dietary Supplements ; Female ; Folate Receptor 1/genetics* ; Folate Receptor 2/genetics* ; Folic Acid/administration & dosage* ; Heart Defects, Congenital/genetics* ; Hospitals ; Humans ; Infant ; Polymorphism, Single Nucleotide ; Prospective Studies ; Risk Factors

OBJECTIVETo establish the method of enzyme-linked immunosorbent assay (ELISA) for measuring human IgM autoantibody to folate receptor.

METHODSFolate receptor was extracted and purified from the healthy woman placenta. The protein was coated on 96-well plates with a concentration of 5 ng/Μl. Goat monoclonal antibody was used for detecting antibody. Pooled plasma from healthy donors was used to plot the standard curve and the IgM concentration of pooled plasma was defined as 1. We set up an ELISA procedure to measure human IgM autoantibody to folate receptor. The sensitivity, precision, and stability of the method were evaluated. Further, the folate receptor and bovine folate-binding protein were used as the antigen, respectively, to determine the autoantibody levels in 24 healthy individuals and 20 individuals once gave birth to baby with neural tube defects.

RESULTSThe measuring range of the method was from 6.25 × 10⁻⁴ to 8.00 × 10⁻&sup2;. The lowest IgM level that can be detected was 3.12 × 10⁻⁴. The inter-assay coefficients of variations for samples with high, medium, and low IgM levels were 6.61%,3.50%, and 5.12%, respectively. The intra-assay coefficients of variations were 4.54%, 5.49%, and 5.44%, respectively. The stability test results were considered within acceptable limits. The data from folate receptor-ELISA was significantly higher than that from bovine folate binding protein-ELISA, both in the healthy group (t=-11.9, P<0.001) and in the neural tube defect group (t = 7.35, P<0.001).

CONCLUSIONSThe folate receptor-ELISA method for measuring human IgM autoantibody to folate receptor was successfully established. The method is sensitive, repeatable, and stable.

Autoantibodies ; blood ; Enzyme-Linked Immunosorbent Assay ; methods ; Folate Receptor 2 ; immunology ; Humans ; Immunoglobulin M ; blood