A review of therapeutic challenges and achievements of methotrexate delivery systems for treatment of cancer and rheumatoid arthritis

Abstract

Purpose

Methotrexate (MTX) is one of the most widely studied and effective therapeutics agents available to treat many solid tumors, hematologic malignancies, and autoimmune diseases such as rheumatoid arthritis; however, the poor pharmacokinetic and narrow safety margin of the drug limits the therapeutic outcomes of conventional drug delivery systems. For an improved delivery of MTX, several pathophysiological features such as angiogenesis, enhanced permeability and retention effects, acidosis, and expression of specific antigens and receptors can be used either as targets or as tools for drug delivery.

Methods

There are many novel delivery systems developed to improve the pitfalls of MTX therapy ranged from polymeric conjugates such as human serum albumin, liposomes, microspheres, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, polymeric micelles, in situ forming hydrogels, carrier erythrocyte, and nanotechnology-based vehicles such as carbon nanotubes, magnetic nanoparticles, and gold nanoparticles. Some are further modified with targeting ligands for active targeting purposes.

Results

Such delivery systems provide prolonged plasma profile, enhanced and specific activity in vitro and in vivo in animal models. Nevertheless, more complementary studies are needed before they can be applied in human.

Conclusion

This review deals with the challenges of conventional systems and achievements of each pharmaceutical class of novel drug delivery vehicle.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    Purcell WT, Ettinger DS (2003) Novel antifolate drugs. Curr Oncol Rep 5(2):114–125

    PubMed  Article  Google Scholar 

  2. 2.

    Bleyer WA (1978) The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 41(1):36–51

    PubMed  CAS  Article  Google Scholar 

  3. 3.

    Grim J, Chladek J, Martinkova J (2003) Pharmacokinetics and pharmacodynamics of methotrexate in non-neoplastic diseases. Clin Pharmacokinet 42(2):139–151

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Cutolo M et al (2001) Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 60(8):729–735

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Lee DM, Weinblatt ME (2001) Rheumatoid arthritis. Lancet 358(9285):903–911

    PubMed  CAS  Article  Google Scholar 

  6. 6.

    Tarner IH, Müller-Ladner U (2008) Drug delivery systems for the treatment of rheumatoid arthritis. Expert Opin Drug Deliv 5(9):1027–1037

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Rahman LK, Chhabra SR (1988) The chemistry of methotrexate and its analogues. Med Res Rev 8(1):95–155

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Chatterji DC, Gallelli JF (1978) Thermal and photolytic decomposition of methotrexate in aqueous solutions. J Pharm Sci 67(4):526–531

    PubMed  CAS  Article  Google Scholar 

  9. 9.

    Genestier L et al (2000) Mechanisms of action of methotrexate. Immunopharmacology 47(2–3):247–257

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Cutolo M et al (2000) Antiproliferative and antiinflammatory effects of methotrexate on cultured differentiating myeloid monocytic cells (THP-1) but not on synovial macrophages from patients with rheumatoid arthritis. J Rheumatol 27(11):2551–2557

    PubMed  CAS  Google Scholar 

  11. 11.

    Hillson JL, Furst DE (1997) Pharmacology and pharmacokinetics of methotrexate in rheumatic disease. Practical issues in treatment and design. Rheum Dis Clin North Am 23(4):757–778

    PubMed  CAS  Article  Google Scholar 

  12. 12.

    Cronstein BN (1997) The mechanism of action of methotrexate. Rheum Dis Clin North Am 23(4):739–755

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Paxton JW (1982) The protein binding and elimination of methotrexate after intravenous infusions in cancer patients. Clin Exp Pharmacol Physiol 9(3):225–234

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    Bleyer WA, Nelson JA, Kamen BA (1997) Accumulation of methotrexate in systemic tissues after intrathecal administration. J Pediatr Hematol Oncol 19(6):530–532

    PubMed  CAS  Article  Google Scholar 

  15. 15.

    Creaven PJ et al (1973) Methotrexate in liver and bile after intravenous dosage in man. Br J Cancer 28(6):589–591

    PubMed  CAS  Article  Google Scholar 

  16. 16.

    Iqbal MP (1998) Accumulation of methotrexate in human tissues following high-dose methotrexate therapy. J Pak Med Assoc 48(11):341–343

    PubMed  CAS  Google Scholar 

  17. 17.

    Fiehn C (2010) Methotrexate transport mechanisms: the basis for targeted drug delivery and beta-folate-receptor-specific treatment. Clinical and Experimental Rheumatology. 28(5): S40-S45

    Google Scholar 

  18. 18.

    Edno L et al (1996) Total and free methotrexate pharmacokinetics in rheumatoid arthritis patients. Ther Drug Monit 18(2):128–134

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Whitehead VM et al (2005) Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts and treatment outcome in children with B-progenitor-cell acute lymphoblastic leukemia: a pediatric oncology group study. Leukemia 19(4):533–536

    PubMed  CAS  Google Scholar 

  20. 20.

    Visser K, van der Heijde DM (2009) Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature. Clin Exp Rheumatol 27(6):1017–1025

    PubMed  CAS  Google Scholar 

  21. 21.

    van Ede AE et al (1998) Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity. Semin Arthritis Rheum 27(5):277–292

    PubMed  Article  Google Scholar 

  22. 22.

    Koch AE, Distler O (2007) Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis. Arthritis Res Ther 9(Suppl 2):S3

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Koning GA et al (2006) Targeting of angiogenic endothelial cells at sites of inflammation by dexamethasone phosphate-containing RGD peptide liposomes inhibits experimental arthritis. Arthritis Rheum 54(4):1198–1208

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Gaffo A, Saag KG, Curtis JR (2006) Treatment of rheumatoid arthritis. Am J Health Syst Pharm 63(24):2451–2465

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Levick JR (1981) Permeability of rheumatoid and normal human synovium to specific plasma proteins. Arthritis Rheum 24(12):1550–1560

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Levick JR (1995) Microvascular architecture and exchange in synovial joints. Microcirculation 2(3):217–233

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Levick JR (1990) Hypoxia and acidosis in chronic inflammatory arthritis; relation to vascular supply and dynamic effusion pressure. J Rheumatol 17(5):579–582

    PubMed  CAS  Google Scholar 

  28. 28.

    Halin C, Neri D (2001) Antibody-based targeting of angiogenesis. Crit Rev Ther Drug Carrier Syst 18(3):299–339

    PubMed  CAS  Article  Google Scholar 

  29. 29.

    Nagai T et al (2006) In vitro and in vivo efficacy of a recombinant immunotoxin against folate receptor beta on the activation and proliferation of rheumatoid arthritis synovial cells. Arthritis Rheum 54(10):3126–3134

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Trachsel E et al (2007) Antibody-mediated delivery of IL-10 inhibits the progression of established collagen-induced arthritis. Arthritis Res Ther 9(1):R9

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Stehle G et al (1999) Methotrexate-albumin conjugate causes tumor growth delay in Dunning R3327 HI prostate cancer-bearing rats. Anticancer Drugs 10(4):405–411

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Wunder A et al (1998) Antitumor activity of methotrexate-albumin conjugates in rats bearing a Walker-256 carcinoma. Int J Cancer 76(6):884–890

    PubMed  CAS  Article  Google Scholar 

  33. 33.

    Wunder A et al (2003) Albumin-based drug delivery as novel therapeutic approach for rheumatoid arthritis. J Immunol 170(9):4793–4801

    PubMed  CAS  Google Scholar 

  34. 34.

    Nakashima-Matsushita N et al (1999) Selective expression of folate receptor beta and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis Rheum 42(8):1609–1616

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Fiehn C et al (2004) Albumin-coupled methotrexate (MTX-HSA) is a new anti-arthritic drug which acts synergistically to MTX. Rheumatology (Oxford) 43(9):1097–1105

    CAS  Article  Google Scholar 

  36. 36.

    Fiehn C et al (2008) Targeted drug delivery by in vivo coupling to endogenous albumin: an albumin-binding prodrug of methotrexate (MTX) is better than MTX in the treatment of murine collagen-induced arthritis. Annals Rheum Dis 67(8):1188–1191

    CAS  Article  Google Scholar 

  37. 37.

    Han J et al (2001) Altered pharmacokinetics and liver targetability of methotrexate by conjugation with lactosylated albumins. Drug Deliv J Deliv Target Therapeutic Agents 8(3):125–134

    CAS  Google Scholar 

  38. 38.

    Han JH et al (1999) Enhanced hepatocyte uptake and liver targeting of methotrexate using galactosylated albumin as a carrier. Int J Pharm 188(1):39–47

    PubMed  CAS  Article  Google Scholar 

  39. 39.

    Chau Y, Tan FE, Langer R (2004) Synthesis and characterization of dextran-peptide-methotrexate conjugates for tumor targeting via mediation by matrix metalloproteinase II and matrix metalloproteinase IX. Bioconjug Chem 15(4):931–941

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    Chau Y et al (2006) Investigation of targeting mechanism of new dextran-peptide-methotrexate conjugates using biodistribution study in matrix-metalloproteinase-overexpressing tumor xenograft model. J Pharm Sci 95(3):542–551

    PubMed  CAS  Article  Google Scholar 

  41. 41.

    Nevozhay D et al (2006) The effect of the substitution level of some dextran-methotrexate conjugates on their antitumor activity in experimental cancer models. Anticancer Res 26(3A):2179–2186

    PubMed  CAS  Google Scholar 

  42. 42.

    Nevozhay D et al (2006) Antitumor properties and toxicity of dextran-methotrexate conjugates are dependent on the molecular weight of the carrier. Anticancer Res 26(2A):1135–1143

    PubMed  CAS  Google Scholar 

  43. 43.

    Yousefi G et al (2010) Synthesis and characterization of methotrexate polyethylene glycol esters as a drug delivery system. Chem Pharm Bull (Tokyo) 58(2):147–153

    CAS  Article  Google Scholar 

  44. 44.

    Shukla G et al (2008) Polyethylene glycol conjugates of methotrexate and melphalan: synthesis, radiolabeling and biologic studies. Cancer Biother Radiopharm 23(5):571–579

    PubMed  CAS  Article  Google Scholar 

  45. 45.

    Riebeseel K et al (2002) Polyethylene glycol conjugates of methotrexate varying in their molecular weight from MW 750 to MW 40000: synthesis, characterization, and structure-activity relationships in vitro and in vivo. Bioconjug Chem 13(4):773–785

    PubMed  CAS  Article  Google Scholar 

  46. 46.

    Homma A et al (2009) Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment. Bioorg Med Chem 17(13):4647–4656

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Homma A et al (2012) Synthesis and optimization of hyaluronic acid-methotrexate conjugates to maximize benefit in the treatment of osteoarthritis. Bioorganic Med Chem 18(3):1062–1075

    Article  CAS  Google Scholar 

  48. 48.

    Bowman BJ, Ofner Iii CM (2000) Characterization and in vitro methotrexate release from methotrexate/gelatin conjugates of opposite conjugate bond polarity. Pharm Res. 17(10):1309–1315

    Google Scholar 

  49. 49.

    Smith GK et al (1997) Toward antibody-directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase A1 and novel in vivo stable prodrugs of methotrexate. J Biol Chem 272(25):15804–15816

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    Ou XH et al (2004) Receptor binding characteristics and cytotoxicity of insulin-methotrexate. World J Gastroenterol 10(16):2430–2433

    PubMed  CAS  Google Scholar 

  51. 51.

    Lindgren M et al (2006) Overcoming methotrexate resistance in breast cancer tumour cells by the use of a new cell-penetrating peptide. Biochem Pharmacol 71(4):416–425

    PubMed  CAS  Article  Google Scholar 

  52. 52.

    Wu Z et al (2012) Development of methotrexate proline prodrug to overcome resistance by MDA-MB-231 cells. Bioorganic Med Chem Lett 20(17):5108–5112

    Article  CAS  Google Scholar 

  53. 53.

    Hudecz F et al (1993) Influence of carrier on biodistribution and in vitro cytotoxicity of methotrexate-branched polypeptide conjugates. Bioconjug Chem 4(1):25–33

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Williams AS et al (1995) Differential effects of methotrexate and liposomally conjugated methotrexate in rat adjuvant-induced arthritis. Clin Exp Immunol 102(3):560–565

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Williams AS et al (1996) A single intra-articular injection of liposomally conjugated methotrexate suppresses joint inflammation in rat antigen-induced arthritis. Br J Rheumatol 35(8):719–724

    PubMed  CAS  Article  Google Scholar 

  56. 56.

    Williams AS et al (2001) Amelioration of rat antigen-induced arthritis by liposomally conjugated methotrexate is accompanied by down-regulation of cytokine mRNA expression. Rheumatology (Oxford) 40(4):375–383

    CAS  Article  Google Scholar 

  57. 57.

    Metselaar JM et al (2004) Liposomal targeting of glucocorticoids to synovial lining cells strongly increases therapeutic benefit in collagen type II arthritis. Ann Rheum Dis 63(4):348–353

    PubMed  CAS  Article  Google Scholar 

  58. 58.

    Metselaar JM et al (2003) Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes. Arthritis Rheum 48(7):2059–2066

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Hong MS et al (2001) Prolonged blood circulation of methotrexate by modulation of liposomal composition. Drug Deliv 8(4):231–237

    PubMed  CAS  Article  Google Scholar 

  60. 60.

    Prabhu P et al (2012) Investigation of nano lipid vesicles of methotrexate for anti-rheumatoid activity. Int J Nanomed 7:177–186

    CAS  Article  Google Scholar 

  61. 61.

    Pignatello R et al (2005) Lipophilic conjugates of methotrexate with glucosyl-lipoamino acids: calorimetric study of the interaction with a biomembrane model. Thermochim Acta 426(1–2):163–171

    CAS  Article  Google Scholar 

  62. 62.

    Pignatello R et al (2003) Effect of liposomal delivery on in vitro antitumor activity of lipophilic conjugates of methotrexate with lipoamino acids. Drug Deliv 10(2):95–100

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    Pignatello R et al (2001) Lipophilic methotrexate conjugates with glucose-lipoamino acid moieties: synthesis and in vitro antitumor activity. Drug Develop Res 52(3):454–461

    CAS  Article  Google Scholar 

  64. 64.

    Kuznetsova N et al (2009) Liposomes loaded with lipophilic prodrugs of methotrexate and melphalan as convenient drug delivery vehicles. J Drug Deliv Sci Technol 19(1):51–59

    CAS  Google Scholar 

  65. 65.

    Timothy DH et al (1983) Antibody-targeted liposomes: increase in specific toxicity of methotrexate-gamma aspartate. Proc Natl Acad Sci U S A 80:1377–1381

    Article  Google Scholar 

  66. 66.

    Singh M et al (1989) Targeting of methotrexate-containing liposomes with a monoclonal antibody against human renal cancer. Cancer Res 49(14):3976–3984

    PubMed  CAS  Google Scholar 

  67. 67.

    Singh M et al (1991) Inhibition of human renal cancer by monoclonal antibody targeted methotrexate-containing liposomes in an ascites tumor model. Cancer Lett 56(2):97–102

    PubMed  CAS  Article  Google Scholar 

  68. 68.

    Oommen E et al (1999) Niosome entrapped β-cyclodextrin methotrexate complex as a drug delivery system. Indian J Pharmacol 31(4):279–284

    CAS  Google Scholar 

  69. 69.

    Sheena IP et al (1997) Niosomal entrapment of hydroxypropyl-β-cylodextrin-methotrexate complex as a drug delivery device. Pharm Sci 3(12):579–582

    CAS  Google Scholar 

  70. 70.

    Singh UV, Udupa N (1997) In vitro characterization of methotrexate loaded poly(lactic-co-glycolic) acid microspheres and antitumor efficacy in Sarcoma-180 mice bearing tumor. Pharm Acta Helv 72(3):165–173

    PubMed  CAS  Article  Google Scholar 

  71. 71.

    Singh UV et al (1997) Preparation, characterization, and antitumor efficacy of biodegradable poly(lactic acid) methotrexate implantable films. Drug Deliv 4(2):101–106

    CAS  Article  Google Scholar 

  72. 72.

    Singh UV, Udupa N (1998) In vitro characterization of methotrexate-loaded poly(lactic acid) microspheres of different molecular weights. Drug Deliv J Deliv Targeting Therapeutic Agents 5(1):57–61

    CAS  Google Scholar 

  73. 73.

    Liang LS et al (2004) Methotrexate loaded poly(l-lactic acid) microspheres for intra-articular delivery of methotrexate to the joint. J Pharm Sci 93(4):943–956

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Narayani R, Panduranga Rao K (1993) Preparation, characterisation and in vitro stability of hydrophilic gelatin microspheres using a gelatin-methotrexate conjugate. Int J Pharm 95(1–3):85–91

    CAS  Article  Google Scholar 

  75. 75.

    Narayani R, Panduranga Rao K (1994) Controlled release of anticancer drug methotrexate from biodegradable gelatin microspheres. J Microencapsul 11(1):69–77

    PubMed  CAS  Article  Google Scholar 

  76. 76.

    Narayani R, PandurangaRao K (1995) pH-responsive gelatin microspheres for oral delivery of anticancer drug methotrexate. J Appl Polym Sci 58(10):1761–1769

    CAS  Article  Google Scholar 

  77. 77.

    Narayani R, PandurangaRao K (1996) Solid tumor chemotherapy using injectable gelatin microspheres containing free methotrexate and conjugated methotrexate. Int J Pharm 142(1):25–32

    CAS  Article  Google Scholar 

  78. 78.

    Sun Y et al (2009) The effect of chitosan molecular weight on the characteristics of spray-dried methotrexate-loaded chitosan microspheres for nasal administration. Drug Dev Ind Pharm 35(3):379–386

    PubMed  CAS  Article  Google Scholar 

  79. 79.

    Sun Y et al (2012) Methotrexate-loaded microspheres for nose to brain delivery: in vitro/in vivo evaluation. J Drug Deliv Sci Technol 22(2):167–174

    CAS  Google Scholar 

  80. 80.

    Taheri A et al (2011) Nanoparticles of conjugated methotrexate-human serum albumin: preparation and cytotoxicity evaluations. J Nanomaterials, Art ID 768201

  81. 81.

    Taheri A et al (2012) The in vivo antitumor activity of LHRH targeted methotrexate-human serum albumin nanoparticles in 4T1 tumor-bearing Balb/c mice. Int JPharm 431(1–2):183–189

    CAS  Article  Google Scholar 

  82. 82.

    Taheri A et al (2012) Enhanced anti-tumoral activity of methotrexate-human serum albumin conjugated nanoparticles by targeting with luteinizing hormone-releasing hormone (LHRH) peptide. Int J Mol Sci 12(7):4591–4608

    Google Scholar 

  83. 83.

    Taheri A et al (2012) Targeted delivery of methotrexate to tu mor cells using biotin functionalized methotrexate-human serum albumin conjugated nanoparticles. J Biomed Nanotechnol 7(6):743–753

    Article  CAS  Google Scholar 

  84. 84.

    Taheri A et al (2012) Use of biotin targeted methotrexate-human serum albumin conjugated nanoparticles to enhance methotrexate antitumor efficacy. Int J Nanomed 6:1863–1874

    Google Scholar 

  85. 85.

    Taheri A et al (2012) Trastuzumab decorated methotrexate-human serum albumin conjugated nanoparticles for targeted delivery to HER2 positive tumor cells. Eur J Pharm Sci 47(2):331–340

    PubMed  CAS  Article  Google Scholar 

  86. 86.

    Jain S et al (2011) Synthesis, pharmacoscintigraphic evaluation and antitumor efficacy of methotrexate-loaded, folate-conjugated, stealth albumin nanoparticles. Nanomedicine (Lond) 6(10):1733–1754

    CAS  Article  Google Scholar 

  87. 87.

    Trapani A et al (2011) Methotrexate-loaded chitosan- and glycol chitosan-based nanoparticles: a promising strategy for the administration of the anticancer drug to brain tumors. AAPS Pharm Sci Tech 12(4):1302–1311

    CAS  Article  Google Scholar 

  88. 88.

    Azadi A et al (2012) Preparation and optimization of surface-treated methotrexate-loaded nanogels intended for brain delivery. Carbohydrate Polym 90(1):462–471

    CAS  Article  Google Scholar 

  89. 89.

    Ji JG et al (2012) Preparation, characterization, and in vitro release of folic acid-conjugated chitosan nanoparticles loaded with methotrexate for targeted delivery. Polym Bull 68(6):1707–1720

    CAS  Article  Google Scholar 

  90. 90.

    Reddy LH, Murthy RR (2004) Influence of polymerization technique and experimental variables on the particle properties and release kinetics of methotrexate from poly(butylcyanoacrylate) nanoparticles. Acta Pharmaceutica 54(2):103–118

    PubMed  CAS  Google Scholar 

  91. 91.

    Gao K, Jiang X (2006) Influence of particle size on transport of methotrexate across blood brain barrier by polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Int J Pharm 310(1–2):213–219

    PubMed  CAS  Article  Google Scholar 

  92. 92.

    Cascone MG et al (2002) Gelatin nanoparticles produced by a simple W/O emulsion as delivery system for methotrexate. J Mater Sci Mater Med 13(5):523–526

    PubMed  CAS  Article  Google Scholar 

  93. 93.

    Kong SY et al. (2008) Preparation and in vitro release of methotrexate complexation with PEGylated dendrimers. Chinese Pharm J. 43(14): 1085 + 1086–1091

    Google Scholar 

  94. 94.

    Gurdag S et al (2006) Activity of dendrimer-methotrexate conjugates on methotrexate-sensitive and -resistant cell lines. Bioconjug Chem 17(2):275–283

    PubMed  CAS  Article  Google Scholar 

  95. 95.

    Quintana A et al (2002) Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharm Res 19(9):1310–1316

    PubMed  CAS  Article  Google Scholar 

  96. 96.

    Zong H et al (2012) Bifunctional PAMAM dendrimer conjugates of folic acid and methotrexate with defined ratio. Biomacromolecules 13(4):982–991

    PubMed  CAS  Article  Google Scholar 

  97. 97.

    Choi SK et al (2012) Photochemical release of methotrexate from folate receptor-targeting PAMAM dendrimer nanoconjugate. Photochem Photobiol Sci 11(4):653–660

    PubMed  CAS  Article  Google Scholar 

  98. 98.

    Shukla R et al (2008) HER2 specific delivery of methotrexate by dendrimer conjugated anti-HER2 mAb. Nanotechnology 19(29):7

    Article  CAS  Google Scholar 

  99. 99.

    Kaminskas LM et al (2009) Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-l-lysine dendrimers. Mol Pharm 6(4):1190–1204

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Kaminskas LM et al (2010) Capping methotrexate alpha-carboxyl groups enhances systemic exposure and retains the cytotoxicity of drug conjugated PEGylated polylysine dendrimers. Mol Pharm 8(2):338–349

    Article  CAS  Google Scholar 

  101. 101.

    Kurmi BD et al (2011) Lactoferrin-conjugated dendritic nanoconstructs for lung targeting of methotrexate. J Pharm Sci 100(6):2311–2320

    PubMed  CAS  Article  Google Scholar 

  102. 102.

    Dhanikula RS et al (2008) Methotrexate loaded polyether-copolyester dendrimers for the treatment of gliomas: enhanced efficacy and intratumoral transport capability. Mol Pharm 5(1):105–116

    PubMed  CAS  Article  Google Scholar 

  103. 103.

    Dhanikula RS, Hildgen P (2007) Influence of molecular architecture of polyether-co-polyester dendrimers on the encapsulation and release of methotrexate. Biomaterials 28(20):3140–3152

    PubMed  CAS  Article  Google Scholar 

  104. 104.

    Kohler N et al (2006) Methotrexate-immobilized poly(ethylene glycol) magnetic nanoparticles for MR imaging and drug delivery. Small 2(6):785–792

    PubMed  CAS  Article  Google Scholar 

  105. 105.

    Kohler N et al (2005) Methotrexate-modified superparamagnetic nanoparticles and their intracellular uptake into human cancer cells. Langmuir 21(19):8858–8864

    PubMed  CAS  Article  Google Scholar 

  106. 106.

    Zhu L et al (2009) Targeted delivery of methotrexate to skeletal muscular tissue by thermosensitive magnetoliposomes. Int J Pharm 370(1–2):136–143

    PubMed  CAS  Article  Google Scholar 

  107. 107.

    Devineni D, Blanton CD, Gallo JM (1995) Preparation and in vitro evaluation of magnetic microsphere-methotrexate conjugate drug delivery systems. Bioconjug Chem 6(2):203–210

    PubMed  CAS  Article  Google Scholar 

  108. 108.

    Zhang X, Chen F, Ni J (2009) A novel method to prepare magnetite chitosan microspheres conjugated with methotrexate (MTX) for the controlled release of MTX as a magnetic targeting drug delivery system. Drug Deliv 16(5):280–288

    PubMed  CAS  Article  Google Scholar 

  109. 109.

    Jeong Y et al (2009) Methotrexate-incorporated polymeric micelles composed of methoxy poly(ethyleneglycol)-grafted chitosan. Macromol Res 17(7):538–543

    CAS  Article  Google Scholar 

  110. 110.

    Zhang Y, Jin T, Zhuo RX (2005) Methotrexate-loaded biodegradable polymeric micelles: preparation, physicochemical properties and in vitro drug release. Colloids Surf B Biointerfaces 44(2–3):104–109

    PubMed  CAS  Article  Google Scholar 

  111. 111.

    Li Y, Kwon GS (1999) Micelle-like structures of poly(ethylene oxide)-block-poly(2- hydroxyethyl aspartamide)-methotrexate conjugates. Colloids Surf B Biointerfaces 16(1–4):217–226

    Article  Google Scholar 

  112. 112.

    Li Y, Kwon GS (2000) Methotrexate esters of poly(ethylene oxide)-block-poly(2-hydroxyethyl-l-aspartamide). Part I: effects of the level of methotrexate conjugation on the stability of micelles and on drug release. Pharm Res 17(5):607–611

    PubMed  CAS  Article  Google Scholar 

  113. 113.

    Pluta J, Karolewicz B (2006) In vitro studies of the properties of thermosensitive systems prepared on Pluronic F-127 as vehicles for methotrexate for delivery to solid tumours. Polim Med 36(3):37–53

    PubMed  CAS  Google Scholar 

  114. 114.

    Miao B, Song C, Ma G (2011) Injectable thermosensitive hydrogels for intra-articular delivery of methotrexate. J Appl Polym Sci 122(3):2139–2145

    CAS  Article  Google Scholar 

  115. 115.

    Karasulu HY et al (2009) Determining the cytotoxicity of methotrexate-loaded microemulsion on human breast, ovarian, and prostate carcinoma cell lines: a new modality for an old drug. Drug Develop Res 70(1):49–56

    CAS  Article  Google Scholar 

  116. 116.

    Karasulu HY et al (2007) Controlled release of methotrexate from w/o microemulsion and its in vitro antitumor activity. Drug Deliv 14(4):225–233

    PubMed  CAS  Article  Google Scholar 

  117. 117.

    Moura JA et al (2011) Novel formulation of a methotrexate derivative with a lipid nanoemulsion. Int J Nanomed 6:2285–2295

    CAS  Google Scholar 

  118. 118.

    Ruckmani K, Sivakumar M, Ganeshkumar PA (2006) Methotrexate loaded solid lipid nanoparticles (SLN) for effective treatment of carcinoma. J Nanosci Nanotechnol 6(9–10):2991–2995

    PubMed  CAS  Article  Google Scholar 

  119. 119.

    Utreja S, Khopade AJ, Jain NK (1999) Lipoprotein-mimicking biovectorized systems for methotrexate delivery. Pharm Acta Helv 73(6):275–279

    PubMed  CAS  Article  Google Scholar 

  120. 120.

    Yuan SH et al (2009) Slow release properties and liver-targeting characteristics of methotrexate erythrocyte carriers. Fundam Clin Pharmacol 23(2):189–196

    PubMed  CAS  Article  Google Scholar 

  121. 121.

    Mishra PR, Jain NK (2000) Surface modified methotrexate loaded erythrocytes for enhanced macrophage uptake. J Drug Target 8(4):217–224

    PubMed  CAS  Article  Google Scholar 

  122. 122.

    Mishra PR, Jain NK (2002) Biotinylated methotrexate loaded erythrocytes for enhanced liver uptake. ‘A study on the rat’. Int J Pharm 231(2):145–153

    PubMed  CAS  Article  Google Scholar 

  123. 123.

    Chen YH et al (2007) Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model. Mol Pharm 4(5):713–722

    PubMed  CAS  Article  Google Scholar 

  124. 124.

    Samori C et al (2010) Enhanced anticancer activity of multi-walled carbon nanotube-methotrexate conjugates using cleavable linkers. Chem Commun 46(9):1494–1496

    CAS  Article  Google Scholar 

Download references

Conflict of interest

The authors declare no conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Rassoul Dinarvand.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Abolmaali, S.S., Tamaddon, A.M. & Dinarvand, R. A review of therapeutic challenges and achievements of methotrexate delivery systems for treatment of cancer and rheumatoid arthritis. Cancer Chemother Pharmacol 71, 1115–1130 (2013). https://doi.org/10.1007/s00280-012-2062-0

Download citation

Keywords

  • Methotrexate
  • Cancer
  • Rheumatoid arthritis
  • Drug delivery
  • Nanoparticle
  • Drug conjugate
  • Human serum albumin
  • Liposome
  • Microsphere
  • Dendrimer