Advertisement

Folate Receptor and Targeting Strategies

  • Bhagyashri Joshi
  • Sukhada S. Shevade
  • Prajakta Dandekar
  • Padma V. DevarajanEmail author
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 39)

Abstract

The folate receptor (FR) is essential for intracellular transport of folic acid, a vital enzymatic cofactor required for cell survival and growth. FR exists in four isoforms termed as α, β, γ, and δ having variable affinity for folate ligand and exhibit differential expression in normal tissues. The receptors are known to amplify in a broad spectrum of cancers and therefore have been extensively explored to treat as well as to diagnose various cancers. This chapter presents an overview of the receptor family, ligands explored, pathophysiological features, importance of FR in therapeutics and diagnostics, different FR-mediated delivery systems, and clinical studies relying on FR targeting.

Keywords

Folate Cancer Infectious disease Macrophage Targeting Photodynamic therapy Theranostics 

Abbreviations

5-CH3-THF

5 Methyl tetrahydrofolate

5-CHO-THF

5-Formyltetrahydrofolate

A549

human lung adenocarcinoma cell line

Ala

Alanine

ALL

Acute lymbhoblastic leukemia

AML

Acute myelogenous leukemias

Arg

Arginine

CD

Clusters of differentiation

CDDP

Cis-diamminedichloroplatinum

CLL

Chronic lymphocytic leukemia

CML

Chronic myelogenous leukemias

CT

Computed tomography

DNA

Deoxyribonucleic acid

DPPE

Dipalmitoyl phosphatidylethanolamine

DSPC

1,2-Distearoyl-sn-glycero-3-phosphatidylcholine

DSPE

1,2-Distearoylphosphatidylethanolamine

EPR effect

Enhanced permeation and retention effect

FA

Folic acid

FA-PEG/PEO–PPO–PCL

Folic acid–polyethyleneglycol/polyethyleneoxide-poly(Ɛ-caprolactone)

FA-PEG-DOX

Folic acid–polyethylene glycol–doxorubicin

FA-PEG-PLA

Folic acid–polyethylene glycol–polylactic acid

FITC

Fluorescein isothiocyanate

FR

Folate receptor

Glu

Glutamic acid

Gly

Glycine

GPI

Glycosyl phosphatidylinositol

HDL

High density lipid

HeLa

Cervical cancer cell lines

HepG2

Hepatocellular carcinoma cell line

His

Histidine

HT 29

A human colorectal adenocarcinoma cell line

HT-1080

A human fibrosarcoma cell line

HuR

Human antigen R

IC50

Inhibitory concentration 50

IM

Intramuscular

JEG-3 and JAR

Placental choriocarcinoma cell lines

KB

Line KB is now known to be a subline of the ubiquitous KERATIN-forming tumor cell line HeLa

Leu

Leucine

mab 343

A monoclonal antibody to FR-α

mab 909

A monoclonal antibody to FR-β

met

Methionine

MKN28

Gastric cancer cell line

MRI

Magnetic resonance imaging

m-RNA

Messenger RNA

NIR

Near infra red

NLCs

nanostructured lipid carriers

PAMAM

Polyamidoamine

PE

Phosphatidylethanolamine

PEG

Polyethylene glycol

PEO–PPO–PCL

Polyethylene oxide-polypropylene oxide-poly(Ɛ-caprolactone)

PET

Positron emission tomography

P-gp

P-glycoprotein

Phe

Phenylalanine

PLGA

Poly lactic-co-glycolic acid

Pro

Proline

PTX

Paclitaxel

RFC

Reduced folate carrier

RNA

Ribonucleic acid

Ser

Serine

siRNA

Small interfering RNA

SKOV3

Ovarian cancer cell line

SLN

Solid lipid nanoparticles

TAM

Tumor-associated macrophages

Thr

Threonine

Trp

Tryptophan

Tyr

Tyrosine

UVA

Ultraviolet A

Val

Valine

References

  1. 1.
    Kelemen LE. The role of folate receptor α in cancer development, progression and treatment: cause, consequence or innocent bystander? Int J Cancer. 2006;119(2):243–50.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Lucock M. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab. 2000;71(1–2):121–38.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Xia W, Hilgenbrink AR, Matteson EL, Lockwood MB, Cheng JX, Low PS. A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages. Blood. 2009;113(2):438–46.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Shen F, Wu M, Ross JF, Miller D, Ratnam M. Folate receptor type ϒ is primarily a secretory protein due to lack of an efficient signal for glycosylphosphatidylinositol modification: protein characterization and cell type specificity. Biochemistry. 1995;34(16):5660–5.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Antony AC. Folate receptors. Annu Rev Nutr. 1996;16(1):501–21.CrossRefGoogle Scholar
  6. 6.
    Matherly LH, Goldman D. Membrane transport of folates. Vitamins and hormones. 2003 Jan 1;66:405–57. Academic Press, USA.Google Scholar
  7. 7.
    Chen C, Ke J, Zhou XE, Yi W, Brunzelle JS, Li J, Yong E-L, Xu HE, Melcher K. Structural basis for molecular recognition of folic acid by folate receptors. Nature. 2013;500(7463):486–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Wibowo AS, Singh M, Reeder KM, Carter JJ, Kovach AR, Meng W. Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition. PNAS. 2013;110(38):15180–8.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Sabharanjak S, Mayor S. Folate receptor endocytosis and trafficking. Adv Drug Deliv Rev. 2004;56(8):1099–109.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Shannessy DJO, Somers EB, Albone E, Cheng X, Park C, Tomkowicz BE, et al. Characterization of the human folate receptor alpha via novel antibody-based probes. Oncotarget. 2011;2(12):1227–43.Google Scholar
  11. 11.
    Pissarek M. Activated microglia in the brain: mitochondrial and cell membrane-associated targets for positron emission tomography. World J Neurosci. 2019;8:50–81.CrossRefGoogle Scholar
  12. 12.
    Xing L, Xu Y, Sun K, Wang H, Zhang F, Zhou Z, et al. Identification of a peptide for folate receptor alpha by phage display and its tumor targeting activity in ovary cancer xenograft. Sci Rep. 2018;8(1):8426.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Walters CL, Arend RC, Armstrong DK, Naumann RW, Alvarez RD. Folate and folate receptor alpha antagonists mechanism of action in ovarian cancer. Gynecol Oncol. 2013;131(2):493–8.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Bueno R, Appasani K, Mercer H, Lester S, Sugarbaker D. The α folate receptor is highly activated in malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2001;121(2):225–33.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    O’Shannessy DJ, Somers EB, Wang LC, Wang H, Hsu R. Expression of folate receptors alpha and beta in normal and cancerous gynecologic tissues: correlation of expression of the beta isoform with macrophage markers. J Ovarian Res. 2015;8(1):1–9.CrossRefGoogle Scholar
  16. 16.
    Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski VR, et al. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res. 1992;52(12):3396–401.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Ross JF, Wang H, Behm FG, Mathew P, Wu M, Booth R, et al. Folate receptor type beta is a neutrophilic lineage marker and is differentially expressed in myeloid leukemia. Cancer. 1999;85(2):348–57.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Ross JF, Chaudhuri PK, Ratnam M. Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Cancer. 1994;73(9):2432–43.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Chancy CD, Kekuda R, Huang W, Prasad PD, Kuhnel JM, Sirotnak FM, et al. Expression and differential polarization of the reduced-folate transporter-1 and the folate receptor α in mammalian retinal pigment epithelium. J Biol Chem. 2000;275(27):20676–84.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Wu M, Gunning W, Ratnam M. Expression of folate receptor type α in relation to cell type, malignancy, and differentiation in ovary, uterus, and cervix. Cancer Epidemiol Biomark Prev. 1999;8(9):775–82.Google Scholar
  21. 21.
    Sun X, Antony AC. Evidence that a specific interaction between an 18-base cis-element in the human folate receptor-alpha mRNA and a 46-kDa cystolic trans-factor is critical for translation. J Biol Chem. 1996;271(41):25539–47.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Xiao X, Tang YS, Mackins JY, Sun XL, Jayaram HN, Hansen DK, et al. Isolation and characterization of a folate receptor mRNA-binding trans-factor from human placenta. Evidence favoring identity with heterogeneous nuclear ribonucleoprotein E1. J Biol Chem. 2001;276(44):41510–7.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Chung-Tsen HDB. Altered folate-binding protein mRNA stability in KB cells grown infolate-deficient medium. Biochem Pharmacol. 1993;45(12):2537–45.CrossRefGoogle Scholar
  24. 24.
    Parker N, Turk MJ, Westrick E, Lewis JD, Low PS, Leamon CP. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem. 2005;338(2):284–93.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Li PY, Del Vecchio S, Fonti R, Carriero MV, Potena MI, Botti G, Miotti S, Lastoria S, Menard S, Colnaghi MISM. Local concentration of folate binding protein GP38 in sections of human ovarian carcinoma by in vitro quantitative autoradiography. J Nucl Med. 1996;37(4):665–72.PubMedPubMedCentralGoogle Scholar
  26. 26.
    O’Shannessy DJ, Somers EB, Maltzman J, Smale R, Fu YS. Folate receptor alpha (FRA) expression in breast cancer: identification of a new molecular subtype and association with triple negative disease. Springerplus. 2012 Dec 1;1(1):22.Google Scholar
  27. 27.
    Zhang Z, Wang J, Tacha DE, Li P, Bremer RE, Chen H, et al. Folate receptor α associated with triple-negative breast cancer and poor prognosis. Arch Pathol Lab Med. 2014;138(7):890–5.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Necela BM, Crozier JA, Andorfer CA, Lewis-Tuffin L, Kachergus JM, Geiger XJ, et al. Folate receptor-α (FOLR1) expression and function in triple negative tumors. PLoS One. 2015;10(3):e0122209.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Aboulhagag NAER, Torky RF, Fadel SA. Folate receptor α is associated with poor clinicopathological perspectives in breast carcinoma. Pathophysiology. 2018;25(1):71–6.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Weitman SD, Frazier KM, Kamen BA. The folate receptor in central nervous system malignancies of childhood. J Neuro-Oncol. 1994;21(2):107–12.CrossRefGoogle Scholar
  31. 31.
    Shen F, Ross JF, Wang X, Ratnam M. Identification of a novel folate receptor, a truncated receptor, and receptor type beta in hematopoietic cells: cDNA cloning, expression, immunoreactivity, and tissue specificity. Biochemistry. 1994;33(5):1209–15.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Dhawan D, Ramos-Vara JA, Naughton JF, Cheng L, Low PS, Rothenbuhler R, et al. Targeting folate receptors to treat invasive urinary bladder cancer. Cancer Res. 2013;73(2):875–84.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    D’Angelica M, Ammori J, Gonen M, Klimstra DS, Low PS, Murphy L, et al. Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance. Mod Pathol. 2011;24(9):1221–8.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Shia J, Klimstra DS, Nitzkorski JR, Low PS, Gonen M, Landmann R, et al. Immunohistochemical expression of folate receptor α in colorectal carcinoma: patterns and biological significance. Hum Pathol. 2008;39(4):498–505.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Chan SY, Empig CJ, Welte FJ, Speck RF, Schmaljohn A, Kreisberg JF, et al. Folate receptor-α is a cofactor for cellular entry by Marburg and Ebola viruses. Cell. 2001;106(1):117–26.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Simmons G, Rennekamp AJ, Chai N, Vandenberghe LH, Riley JL, Bates P. Folate receptor alpha and caveolae are not required for Ebola virus glycoprotein-mediated viral infection. J Virol. 2003;77(24):13433–8.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Zhao X, Li H, Lee RJ. Targeted drug delivery via folate receptors. Expert Opin Drug Deliv. 2008;5(3):309–19.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Zwicke GL, Mansoori GA, Jeffery CJ. Utilizing the folate receptor for active targeting of cancer nanotherapeutics. Nano Rev. 2012;3(1):18496.CrossRefGoogle Scholar
  39. 39.
    Reddy J, Allagadda VM, Leamon CP. Targeting therapeutic and imaging agents to folate receptor positive tumors. Curr Pharm Biotechnol. 2005;6(2):131–50.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Yoo HS, Park TG. Folate-receptor-targeted delivery of doxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugate. J Control Release. 2004;100(2):247–56.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Qiu J, Zhang H, Wang Z, Liu D, Liu S, Han W, et al. The antitumor effect of folic acid conjugated-Auricularia auricular polysaccharide-cisplatin complex on cervical carcinoma cells in nude mice. Int J Biol Macromol. 2018;107:2180–9.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Li H, Li Y, Ao H, Bi D, Han M, Guo Y. Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice. Drug Deliv. 2018;25(1):880–7.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Ahn GY, Kang R, Lee ES, Choi S. Electrosprayed folic acid-conjugated ursolic acid nanoparticles for tumor therapy. Macromol Res. 2018;26(7):573–6.CrossRefGoogle Scholar
  44. 44.
    Lu Y, Low PS. Folate targeting of haptens to cancer cell surfaces mediates immunotherapy of syngeneic murine tumors. Cancer Immunol Immunother. 2002;51(3):153–62.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Leamon CP, Low PS. Cytotoxicity of momordin-folate conjugates in cultured human cells. J Biol Chem. 1992;267(35):24966–71.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Atkinson SF, Bettinger T, Seymour LW, Behr J, Ward CM. Conjugation of folate via gelonin carbohydrate residues retains ribosomal-inactivating properties of the toxin and permits targeting to folate receptor positive cells ∗. J Biol Chem. 2001;276(30):27930–5.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Gabizon A, Shmeeda H, Horowitz AT, Zalipsky S. Tumor cell targeting of liposome-entrapped drugs with phospholipid-anchored folic acid-PEG conjugates. Adv Drug Deliv Rev. 2004;56(8):1177–92.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Goren D, Horowitz A, Tzemach D. Nuclear delivery of doxorubicin via folate targeted liposomes with bypass of multidrug resistance efflux pump 1. Clin Cancer Res. 2000;6(5):1949–57.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Guo W, Lee T, Sudimack J, Lee RJ. Receptor-specific delivery of liposomes via folate-Peg-Chol. J Liposome Res. 2000;10(2&3):179–95.CrossRefGoogle Scholar
  50. 50.
    Saul JM, Annapragada A, Natarajan JV, Bellamkonda RV. Controlled targeting of liposomal doxorubicin via the folate receptor in vitro. J Control Release. 2003;92(1–2):49–67.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Shmeeda H, Mak L, Tzemach D, Astrahan P, Tarshish M, AG, Experimental. Intracellular uptake and intracavitary targeting of folate-conjugated liposomes in a mouse lymphoma model with up-regulated folate receptors. Mol Cancer Ther. 2006;5(4):818–24.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Pan XQ, Zheng X, Shi G, Wang H, Ratnam M, Lee RJ. Strategy for the treatment of acute myelogenous leukemia based on folate receptor β-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. Blood. 2002;100(2):594–602.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Li M, Shi K, Tang X, Wei J, Cun X, Long Y, et al. Synergistic tumor microenvironment targeting and blood-brain barrier penetration via a pH-responsive dual-ligand strategy for enhanced breast cancer and brain metastasis therapy. Nanomedicine. 2018;14(6):1833–43.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Chen Y, Cheng Y, Zhao P, Zhang S, Li M, He C, et al. Co-delivery of doxorubicin and imatinib by pH sensitive cleavable PEGylated nanoliposomes with folate-mediated targeting to overcome multidrug resistance. Int J Pharm. 2018;542(1–2):266–79.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Zhou W, Yuan X, Wilson A, Yang L, Mokotoff M, Pitt B, et al. Efficient intracellular delivery of oligonucleotides formulated in folate receptor-targeted lipid vesicles. Bioconjug Chem. 2002;13(6):1220–5.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Michael P, Kern S, Lee D, Schmaus J. Folate receptor-directed orthogonal click-functionalization of siRNA lipopolyplexes for tumor cell killing in vivo. Biomaterials. 2018;178:630–42.CrossRefGoogle Scholar
  57. 57.
    Urbiola K, García L, Zalba S, Garrido MJ, Tros De Ilarduya C. Efficient serum-resistant lipopolyplexes targeted to the folate receptor. Eur J Pharm Biopharm. 2013;83(3):358–63.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Pan XQ, Wang H, Shukla S, Sekido M, Adams DM, Tjarks W, et al. Boron-containing folate receptor-targeted liposomes as potential delivery agents for neutron capture therapy. Bioconjug Chem. 2002;13(3):435–42.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Öztürk AB, Cevher E, Pabuccuoğlu S, Özgümüş S. pH sensitive functionalized hyperbranched polyester based nanoparticulate system for the receptor-mediated targeted cancer therapy. Int J Polym Mater Polym Biomater. 2018;68(8):417–32.CrossRefGoogle Scholar
  60. 60.
    Ma H, Deng C, Zong X, He Y, Cheng L, Fan Q, et al. Reversal of doxorubicin-resistance by delivering tetramethylprazine via folate-chitosan nanoparticles in MCF-7 / ADM cells. Int J Clin Exp Med. 2016;9(3):5439–48.Google Scholar
  61. 61.
    Thu HP, Nam NH, Duong LQ, Tham NT, Quang BT, Thi HTM, et al. Targeting effect of folate on cancer cell through curcumin carrier nano-system. Int J Drug Deliv. 2014;6(4):351–8.Google Scholar
  62. 62.
    Cheng L, Ma H, Shao M, Fan Q, Lv H, Peng J, et al. Synthesis of folate-chitosan nanoparticles loaded with ligustrazine to target folate receptor positive cancer cells. Mol Med Rep. 2017;16(2):1101–8.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Cao Y, He J, Liu J, Zhang M, Ni P, Cao Y, et al. Folate-conjugated polyphosphoester with reversible cross-linkage and reduction-sensitivity for drug delivery folate-conjugated polyphosphoester with reversible cross- linkage and reduction-sensitivity for drug delivery. ACS Appl Mater Interfaces. 2018;10(9):7811–20.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Fasehee H, Dinarvand R, Ghavamzadeh A, Esfandyari-Manesh M, Moradian H, Faghihi S, et al. Delivery of disulfiram into breast cancer cells using folate-receptor-targeted PLGA-PEG nanoparticles: in vitro and in vivo investigations. J Nanobiotechnol. 2016;14(1):1–18.CrossRefGoogle Scholar
  65. 65.
    Xu X, Wu C, Bai A, Liu X, Lv H, Liu Y. Folate-functionalized mesoporous silica nanoparticles as a liver tumor-targeted drug delivery system to improve the antitumor effect of paclitaxel. J Nanomater. 2017;2017:1–13.Google Scholar
  66. 66.
    Alvarez-Berríos MP, Vivero-Escoto JL. In vitro evaluation of folic acid-conjugated redox-responsive mesoporous silica nanoparticles for the delivery of cisplatin. Int J Nanomedicine. 2016;11:6251–65.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Xiuling Xu, Fan Hu, Qi Shuai. Facile synthesis of highly biocompatible folic acid-functionalized SiO2 encapsulated rare-earth metal complexes nanoparticles and its application on targeted metal-based complex delivery. Dalton Trans. 2017;46(44):15424–33.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Gao B, Shen L, He KW, Xiao WH. GNRs@SiO2-FA in combination with radiotherapy induces the apoptosis of HepG2 cells by modulating the expression of apoptosis-related proteins. Int J Mol Med. 2015;36(5):1282–90.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Ramesh I, Meena KS. Folic acid gelatin coated HAp @ Al2O3 core-shell NPs for receptor mediated targeted drug delivery system. Int J Curr Res. 2016;8(03):28000–6.Google Scholar
  70. 70.
    Ak G, Yilmaz H, Güneş A, Sanlier SH. In vitro and in vivo evaluation of folate receptor- targeted a novel magnetic drug delivery system for ovarian cancer therapy. Artif Cells Nanomed Biotechnol. 2018;46(Suppl 1):926–37.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Ramasamy S, Jeya R, Sam R, Enoch IVMV, Ramasamy S, Jeya R, et al. Folate-molecular encapsulator-tethered biocompatible polymer grafted with magnetic nanoparticles for augmented drug delivery. Artif Cells Nanomed Biotechnol. 2018;46(Suppl 2):675–82.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Feng S, Zhang H, Yan T, Huang D, Zhi C, Nakanishi H, Gao X-D. Folate-conjugated boron nitride nanospheres for targeted delivery of anticancer drugs. Int J Nanomedicine. 2016;11:4573–82.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Li X, Sun Y, Hu Y, Peng Y, Li Y, Yin G, et al. Synthesis of size-tunable hollow polypyrrole nanostructures and their assembly into folate targeting and pH-responsive anti- cancer drug delivery. Chem Eur J. 2017;23(68):17279–89.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Jafaria M, Heidaria D, Ebrahimnejad P. Synthesizing and characterizing functionalized short multiwall carbon nanotubes with folate, magnetite and polyethylene glycol as multi- targeted nanocarrier of anti-cancer drugs. Iran J Pharm Res. 2016;15(2):449–56.Google Scholar
  75. 75.
    Yao Y, Lee RJ. Folic acid receptor-targeted human serum albumin nanoparticle formulation of cabazitaxel for tumor therapy. Int J Nanomedicine. 2019;14:135–48.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Press D. Preparation, characterization, and in vitro targeted delivery of folate-decorated paclitaxel-loaded bovine serum albumin nanoparticles. Int J Nanomedicine. 2010;5:669–77.Google Scholar
  77. 77.
    Li H, Liu Y, Chen L, Liu Q, Qi S, Cheng X, et al. Folate receptor-targeted lipid-albumin nanoparticles (F-LAN) for therapeutic delivery of an Akt1 antisense oligonucleotide. J Drug Target. 2018;26(5–6):466–73.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Yoo HS, Park TG. Folate receptor targeted biodegradable polymeric doxorubicin micelles. J Control Release. 2004;96(2):273–83.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Chen L, Qian M, Zhang L, Xia J, Bao Y. Co-delivery of doxorubicin and shRNA of Beclin1 by folate receptor targeted pullulan-based cancer therapy. RSC Adv. 2018;8(32):17710–22.CrossRefGoogle Scholar
  80. 80.
    Wang Y, Ren J, Liu Y, Liu R, Wang L, Yuan Q, et al. Preparation and evaluation of folic acid modified succinylated gelatin micelles for targeted delivery of doxorubicin. J Drug Deliv Sci Technol. 2018;46:400–7.CrossRefGoogle Scholar
  81. 81.
    Lv Y, Yang B, Li YM, He F, Zhuo RX. Folate-conjugated amphiphilic block copolymer micelle for targeted and redox-responsive delivery of doxorubicin. J Biomater Sci Polym Ed. 2018;29(1):92–106.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Shi C, Zhang Z, Wang F, Luan Y. Active-targeting docetaxel-loaded mixed micelles for enhancing antitumor ef fi cacy. J Mol Liq. 2018;264:172–8.CrossRefGoogle Scholar
  83. 83.
    Jones SK, Lizzio V, Merkel OM. Folate receptor targeted delivery of siRNA and paclitaxel to ovarian cancer cells via folate conjugated triblock copolymer to overcome TLR4 driven chemotherapy resistance. Biomacromolecules. 2016;17(1):76–87.PubMedCrossRefGoogle Scholar
  84. 84.
    Zamani M, Rostamizadeh K, Manjili HK, Danafar H. In vitro and in vivo biocompatibility study of folate-lysine- PEG-PCL as nanocarrier for targeted breast cancer drug delivery. Eur Polym J. 2018;103:260–70.CrossRefGoogle Scholar
  85. 85.
    Chen D, Song X, Wang K. Design and evaluation of dual CD44 receptor and folate nanocarrier double-smart pH-response multifunctional nanocarrier. J Nanopart Res. 2017;19(12):400.CrossRefGoogle Scholar
  86. 86.
    Rosière R, Van Woensel M, Gelbcke M, Mathieu V, Hecq J, Mathivet T, et al. New folate-grafted chitosan derivative to improve delivery of paclitaxel-loaded solid lipid nanoparticles for lung tumor therapy by inhalation. Mol Pharm. 2018;15(3):899–910.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Liu Z, Zhong Z, Peng G, Wang S, Du X, Yan D, et al. Folate receptor mediated intracellular gene delivery using the charge changing solid lipid nanoparticles. Drug Deliv. 2009;16(6):341–7.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Rajpoot K, Jain SK. Colorectal cancer-targeted delivery of oxaliplatin via folic acid-grafted solid lipid nanoparticles: preparation, optimization, and in vitro evaluation. Artif Cells Nanomed Biotechnol. 2018;46(6):1236–47.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Venishetty VK, Komuravelli R, Kuncha M, Sistla R, Diwan PV. Increased brain uptake of docetaxel and ketoconazole loaded folate-grafted solid lipid nanoparticles. Nanomedicine. 2013;9(1):111–21.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Gao W, Xiang B, Meng T, Liu F, Qi X. Chemotherapeutic drug delivery to cancer cells using a combination of folate targeting and tumor microenvironment-sensitive polypeptides. Biomaterials. 2013;34(16):4137–49.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Amreddy N, Babu A, Panneerselvam J, Srivastava A, Ms RM, Ms AC, et al. Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment. Nanomedicine. 2017;14(2):373–84.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Raniolo S, Vindigni G, Ottaviani A, Unida V, Iacovelli F, Manetto A, et al. Selective targeting and degradation of doxorubicin-loaded folate- functionalized DNA nanocages. Nanomedicine. 2018;14(4):1181–90.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Fong Y, Chen C-H, Chen J. Intratumoral delivery of doxorubicin on folate-conjugated graphene oxide by in-situ forming thermo-sensitive hydrogel for breast cancer therapy. Nano. 2017;7(11):388.Google Scholar
  94. 94.
    Elamin KM, Motoyama K, Higashi T, Yamashita Y, Tokuda A, Arima H. Dual targeting system by supramolecular complex of folate-conjugated methyl-β-cyclodextrin with adamantane-grafted hyaluronic acid for the treatment of colorectal cancer. Int J Biol Macromol. 2018;113:386–94.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Son J, Yang SM, Yi G, Roh YJ, Park H, Park JM, et al. Folate-modified PLGA nanoparticles for tumor-targeted delivery of pheophorbide a in vivo. Biochem Biophys Res Commun. 2018;498(3):523–8.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Peng F, Qiu L, Chai R, Meng F, Yan C, Chen Y, et al. Conjugated polymer-based nanoparticles for cancer cell-targeted and image-guided photodynamic therapy. Macromol Chem Phys. 2018;219(4):1–6.Google Scholar
  97. 97.
    Keyvan Rad J, Mahdavian AR, Khoei S, Shirvalilou S. Enhanced photogeneration of reactive oxygen species and targeted photothermal therapy of C6 glioma brain cancer cells by folate-conjugated gold-photoactive polymer nanoparticles. ACS Appl Mater Interfaces. 2018;10(23):19483–93.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Li J, Yao S, Wang K, Lu Z, Su X, Li L, et al. Hypocrellin B-loaded, folate-conjugated polymeric micelle for intraperitoneal targeting of ovarian cancer in vitro and in vivo. Cancer Sci. 2018;109(6):1958–69.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Chien YY, Wang TY, Liao PW, Wu WC, Chen CY. Folate-conjugated and dual stimuli-responsive mixed micelles loading indocyanine green for photothermal and photodynamic therapy. Macromol Biosci. 2018;18(6):1–12.CrossRefGoogle Scholar
  100. 100.
    Yu S, Tian-yi S, Ling-yun Z, Yu-yan Z, Bai-wang S, Xiao-ping L. Folate-decorated and NIR-activated nanoparticles based on platinum(IV) prodrugs for targeted therapy of ovarian cancer. J Microencapsul. 2017;34(7):675–86.CrossRefGoogle Scholar
  101. 101.
    Wong PT, Tang S, Cannon J, Chen D, Sun R, Phan J, et al. Photocontrolled release of doxorubicin conjugated through a thioacetal photocage in folate-targeted nanodelivery systems. Bioconjug Chem. 2017;28(12):3016–28.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Malekmohammadi S, Hadadzadeh H, Hossein Farrokhpour ZA. Immobilization of gold nanoparticles on the folate-conjugated dendritic mesoporous silica-coated reduced graphene oxide nanosheets: a new nanoplatform for curcumin pH-controlled and targeted delivery. Soft Matter. 2018;14(12):2400–10.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Meier R, Henning TD, Boddington S, Piontek G, Rudelius M. Breast cancers: MR imaging of folate-receptor expression with the folate specific nanoparticle P1133. Radiology. 2010;255(2):527–35.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Soleymani J, Hasanzadeh M, Somi MH, Shadjou N, Jouyban A. Probing the specific binding of folic acid to folate receptor using amino-functionalized mesoporous silica nanoparticles for differentiation of MCF 7 tumoral cells from MCF 10A. Biosens Bioelectron. 2018;115:61–9.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Chávez-García D, Juárez-Moreno K, Campos CH, Alderete JB, Hirata GA. Upconversion rare earth nanoparticles functionalized with folic acid for bioimaging of MCF-7 breast cancer cells. J Mater Res. 2018;33(2):191–200.CrossRefGoogle Scholar
  106. 106.
    Khademi S, Sarkar S, Shakeri-zadeh A, Attaran N. Folic acid-cysteamine modified gold nanoparticle as a nanoprobe for targeted computed tomography imaging of cancer cells. Mater Sci Eng C. 2018;89(2017):182–93.CrossRefGoogle Scholar
  107. 107.
    Xia J, Wei X, Chen X, Shu Y. Folic acid modified copper nanoclusters for fluorescent imaging of cancer cells with over-expressed folate receptor. Microchim Acta. 2018;185(3):205.CrossRefGoogle Scholar
  108. 108.
    Li R, Wang X, Li Z, Zhu H, Liu J. Folic acid-functionalized graphene quantum dots with tunable fluorescence emission for cancer cell imaging and optical detection of Hg2+. New J Chem. 2018;42(6):4352–60.CrossRefGoogle Scholar
  109. 109.
    Moon WK, Lin Y, O’Loughlin T, Tang Y, Kim DE, Weissleder R, et al. Enhanced tumor detection using a folate receptor-targeted near-infrared fluorochrome conjugate. Bioconjug Chem. 2003;14(3):539–45.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Predina JD, Newton AD, Connolly C, Ashley Dunbar MB, Deshpande C, Cantu E III, Stadanlick J, Kularatne SA, Low PS, Singhal S. Identification of a folate receptor-targeted near-infrared molecular contrast agent to localize pulmonary adenocarcinomas. Mol Ther. 2018;26(2):390–403.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Chen Q, Meng X, McQuade P, Rubins D, Lin SA, Zeng Z, et al. Folate-PEG-NOTA-Al18F: a new folate based radiotracer for PET imaging of folate receptor-positive tumors. Mol Pharm. 2017;14(12):4353–61.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Dong S, Teo JDW, Chan LY, Lee CK, Sou K. Far-red fluorescent liposomes for folate receptor-targeted bioimaging. ACS Appl Nano Mater. 2018;1(3):1009–13.CrossRefGoogle Scholar
  113. 113.
    Corbin IR, Ng KK, Ding L, Jurisicova AZG. Near-infrared fluorescent imaging of metastatic ovarian cancer using folate-receptor targeted high-density lipoprotein. Nanomedicine. 2013;8(6):875–90.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Konda SD, Aref M, Wang S, Brechbiel M, Wiener EC. Specific targeting of folate-dendrimer MRI contrast agents to the high affinity folate receptor expressed in ovarian tumor xenografts. MAGMA. 2001;12(01):104–13.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Liang L, Zhang X, Su X, Li J, Tian Y, Xue H, et al. 99m Tc-labeled oligomeric nanoparticles as potential agents for folate receptor-positive tumor targeting. J Label Compd Radiopharm. 2018;61(2):54–60.CrossRefGoogle Scholar
  116. 116.
    Rajkumar S, Prabaharan M. Multi-functional nanocarriers based on iron oxide nanoparticles conjugated with doxorubicin, poly(ethylene glycol) and folic acid as theranostics for cancer therapy. Colloids Surf B Biointerfaces. 2018;170:529–37.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Maeng JH, Lee DH, Jung KH, Bae YH, Park IS, Jeong S, et al. Multifunctional doxorubicin loaded superparamagnetic iron oxide nanoparticles for chemotherapy and magnetic resonance imaging in liver cancer. Biomaterials. 2010;31(18):4995–5006.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Wang H, Wang S, Liao Z, Zhao P, Su W, Niu R, et al. Folate-targeting magnetic core – shell nanocarriers for selective drug release and imaging. Int J Pharm. 2012;430(1–2):342–9.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Poshteh Shirani M, Rezaei B, Khayamian T, Dinari M, Karami K, Mehri-Lighvan Z, et al. Folate receptor-targeted multimodal fluorescence mesosilica nanoparticles for imaging, delivery palladium complex and in vitro G-quadruplex DNA interaction. J Biomol Struct Dyn. 2018;36:1456–69.CrossRefGoogle Scholar
  120. 120.
    Mendoza-nava H, Ferro-flores G, Ramírez FDM, Ocampo-garcía B, Santos-cuevas C, Aranda-lara L, et al. Lu-dendrimer conjugated to folate and bombesin with gold nanoparticles in the dendritic cavity: a potential theranostic radiopharmaceutical. J Nanomater. 2016;2016:1039258.CrossRefGoogle Scholar
  121. 121.
    Patel NR, Piroyan A, Ganta S, Morse AB, Candiloro KM, Solon AL, et al. In vitro and in vivo evaluation of a novel folate-targeted theranostic nanoemulsion of docetaxel for imaging and improved anticancer activity against ovarian cancers. Cancer Biol Ther. 2018;19(7):554–64.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Puligujja P, McMillan JE, Kendrick L, Li T, Balkundi S, Smith N, et al. Macrophage folate receptor-targeted antiretroviral therapy facilitates drug entry, retention, antiretroviral activities and biodistribution for reduction of human immunodeficiency virus infections. Nanomedicine. 2013;9(8):1263–73.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Date PV, Patel MD, Majee SB, Samad A, Devarajan PV. Ionic complexation as a non-covalent approach for the design of folate anchored rifampicin gantrez nanoparticles. J Biomed Nanotechnol. 2013;9(5):765–75.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Patel MD, Date PV, Gaikwad RV, Samad A, Malshe VC, Devarajan PV. Comparative evaluation of polymeric nanoparticles of rifampicin comprising Gantrez and poly(ethylene sebacate) on pharmacokinetics, biodistribution and lung uptake following oral administration. J Biomed Nanotechnol. 2014;10(4):687–94.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Teng L, Xie J, Teng L, Lee RJ. Clinical translation of folate receptor-targeted therapeutics. Expert Opin Drug Deliv. 2012;9(8):901–8.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Vergote I, Leamon CP. Vintafolide: a novel targeted therapy for the treatment of folate receptor expressing tumors. Ther Adv Med Oncol. 2015;7(4):206–18.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Study for women with platinum resistant ovarian cancer evaluating EC145 in combination with Doxil® (PROCEED) (PROCEED) [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT01170650?cond=NCT01170650&rank=1.
  128. 128.
    Peethambaram PP, Hartmann LC, Jonker DJ, de Jonge M, Plummer ER, Martin L, Konner J, Marshall J, Goss GD, Teslenko V, Clemens PL, Cohen LJ, Ahlers CM, Alland L. A phase I pharmacokinetic and safety analysis of epothilone folate (BMS-753493), a folate receptor targeted chemotherapeutic agent in humans with advanced solid tumors. Invest New Drugs. 2015;33(2):321–31.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    A phase 1/2 study of epofolate (BMS-753493) in subjects with advanced cancer (Schedule 2) [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT00550017?cond=NCT00550017&rank=1.
  130. 130.
    Messmann R, Amato R, Hernandez-McClain J, Conley B, Rogers H, Lu Y, Low P, Bever S, Morgenstern D. A phase II study of FolateImmune (EC90 with GP1-0100 adjuvant followed by EC17) with low dose cytokines interleukin-2 (IL-2) and interferon-{alpha} (IFN-{alpha}) in patients with refractory or metastatic cancer. J Clin Oncol. 2007;25(18_suppl):13516.Google Scholar
  131. 131.
    A phase II study of EC17 (Folate-hapten Conjugate) in patients with progressive metastatic renal cell carcinoma [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT00485563?cond=NCT00485563&rank=1.
  132. 132.
    Maurer AH, Elsinga P, Fanti S, Nguyen B, Oyen WJG, Weber WA. Imaging the folate receptor on cancer cells with 99mTc-Etarfolatide: properties, clinical use, and future potential of folate receptor imaging. J Nucl Med. 2014;55(5):701–4.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Cheung A, Bax HJ, Josephs DH, Ilieva KM, Pellizzari G, Opzoomer J, et al. Targeting folate receptor alpha for cancer treatment. Oncotarget. 2016;7(32):52553–74.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Study of EC0489 for the treatment of refractory or metastatic tumors [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT00852189?cond=NCT00852189&rank=1.
  135. 135.
    Sharma S, Sausville EA, LoRusso P, Vogelzang NJ, Samlowski WE, Carter J, Forman K, Bever S, Messmann RA. A phase I study of EC0225 administered weeks 1 and 2 of a 4-week cycle. J Clin Oncol. 2010;28(15 Suppl):3082.CrossRefGoogle Scholar
  136. 136.
    Study of EC0225 for the treatment of refractory or metastatic tumors [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT00441870?cond=NCT00441870&rank=1.
  137. 137.
    Sachdev JC, Matei D, Harb WA, Clark R, Edelman MJ, Starodub A. A phase 1 dose-escalation study of the folic acid-tubulysin small molecule drug conjugate (SMDC) folate-tubulysin EC1456 in advanced cancer patients. J Oncol. 2016;34(15_suppl):2585.CrossRefGoogle Scholar
  138. 138.
    Folic acid-tubulysin conjugate EC1456 in patients with advanced solid tumors [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT01999738?cond=NCT01999738&rank=1.
  139. 139.
    OTL38 for intra-operative imaging of folate receptor positive ovarian cancer [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT03180307?cond=NCT03180307&rank=1.
  140. 140.
    Vergote I, Armstrong D, Scambia G, Teneriello M, Sehouli J, Schweizer C, et al. A randomized, double-blind, placebo-controlled, phase 3 study to assess efficacy and safety of weekly farletuzumab in combination with carboplatin and taxane in patients with ovarian cancer in first platinum-sensitive relapse. J Clin Oncol. 2016;34(19):2271–8.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Ab O, Whiteman KR, Bartle LM, Sun X, Singh R, Tavares D, et al. IMGN853, a folate receptor-α (FRα) – targeting antibody – drug conjugate, exhibits potent targeted antitumor activity against FR a – expressing tumors. Mol Cancer Ther. 2015;17:1605–14.CrossRefGoogle Scholar
  142. 142.
    Moore KN, Vergote I, Oaknin A, Colombo N, Oza A, Pautier P, et al. FORWARD I: a phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer. Future Oncol. 2018;14(17):1669–78.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    PH3 Study of Mirvetuximab Soravtansine vs Investigator’s Choice of Chemotherapy in Women With FRa+ Adv. EOC, Primary Peritoneal or Fallopian Tube Cancer (FORWARD I) [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT02631876?cond=NCT02631876&rank=1.

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Bhagyashri Joshi
    • 1
  • Sukhada S. Shevade
    • 1
  • Prajakta Dandekar
    • 2
  • Padma V. Devarajan
    • 2
    Email author
  1. 1.Department of Pharmaceutical Sciences & TechnologyInstitute of Chemical TechnologyMumbaiIndia
  2. 2.Department of Pharmaceutical SciencesInsitute of Chemical Technology, Deemed University, Elite Status and Centre of Excellence, Government of MaharashtraMumbaiIndia

Personalised recommendations