Pharmaceutical Research

, Volume 24, Issue 8, pp 1405–1414 | Cite as

Poly(ethylene glycol)-modified Nanocarriers for Tumor-targeted and Intracellular Delivery

  • Lilian E. van Vlerken
  • Tushar K. Vyas
  • Mansoor M. AmijiEmail author
Expert Review


The success of anti-cancer therapies largely depends on the ability of the therapeutics to reach their designated cellular and intracellular target sites, while minimizing accumulation and action at non-specific sites. Surface modification of nanoparticulate carriers with poly(ethylene glycol) (PEG)/poly(ethylene oxide) (PEO) has emerged as a strategy to enhance solubility of hydrophobic drugs, prolong circulation time, minimize non-specific uptake, and allow for specific tumor-targeting through the enhanced permeability and retention effect. Furthermore, PEG/PEO modification has emerged as a platform for incorporation of active targeting ligands, thereby providing the drug and gene carriers with specific tumor-targeting properties through a flexible tether. This review focuses on the recent developments surrounding such PEG/PEO-surface modification of polymeric nanocarriers to promote tumor-targeting capabilities, thereby enhancing efficacy of anti-cancer therapeutic strategies.

Key words

intracellular delivery long-circulation poly(ethylene glycol) polymeric nanocarriers tumor targeting 


  1. 1.
    American Cancer Society. Cancer Facts & Figures 2006. (accessed September 12, 2006), part of (accessed September 12, 2006).
  2. 2.
    U.S. National Institute of Health. Cancer Statistics (accessed September 15, 2006).
  3. 3.
    S. H. Jang, M. G. Wientjes, D. Lu, and J. L.-S. Au. Drug delivery and transport to solid tumors. Pharm. Res. 20:1337–1350 (2003).PubMedCrossRefGoogle Scholar
  4. 4.
    Y. Matsumura and H. Maeda. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res. 46:6387–6392 (1986).PubMedGoogle Scholar
  5. 5.
    H. Maeda, J Wu, T. Sawa, Y. Matsumura, and K. Hori. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Rel. 65:271–284 (2000).CrossRefGoogle Scholar
  6. 6.
    D. E. Owens, III, and N. A. Peppas. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 307:93–102 (2006).PubMedCrossRefGoogle Scholar
  7. 7.
    V. P. Torchilin. Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu. Rev. Biomed. Eng. 8:343–375 (2006).PubMedCrossRefGoogle Scholar
  8. 8.
    USFDA Center for Drug Evaluation and Research. Guidance for Indrustry, Scale-up and Post approval Changes: Chemistry, Manufacturing and Control. (Accessed August 24, 2006), part of (accessed August 24, 2006).
  9. 9.
    R. Duncan. The dawning era of polymer therapeutics. Nat. Rev. Drug Discov. 2:347–360 (2003).PubMedCrossRefGoogle Scholar
  10. 10.
    K. E. Uhrich S. M. Cannizzaro, R. S. Langer, and K. M. Shakesheff. Polymeric systems for controlled drug release. Chem. Rev. 99:3181–3198 (1999).PubMedCrossRefGoogle Scholar
  11. 11.
    F. M. Veronese and G. Pasut. PEGylation, successful approach to drug delivery. Drug Discov. Today 10:1451–1458 (2005).PubMedCrossRefGoogle Scholar
  12. 12.
    J. M. Harris. Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical Applications. Plenum Press, New York, 1992.Google Scholar
  13. 13.
    M. L. Adams, A. Lavasanifar, and G. S. Kwon. Amphiphilic block copolymers for drug delivery. J. Pharm. Sci. 92:1343–1355 (2003).PubMedCrossRefGoogle Scholar
  14. 14.
    N. Kumar, M. N. Ravikumar, and A. J. Domb. Biodegradable block copolymers. Adv. Drug Deliv. Rev. 53:23–44 (2001).PubMedCrossRefGoogle Scholar
  15. 15.
    M. Yokoyama. Block copolymers as drug carriers. Crit. Rev. Ther. Drug Carr. Syst. 9:213–248 (1992).Google Scholar
  16. 16.
    D. B. Shenoy and M. M. Amiji. Poly(ethylene oxide)-modified poly(epsilon-caprolactone) nanoparticles for targeted delivery of tamoxifen in breast cancer. Int. J. Pharm. 293:261–270 (2005).PubMedCrossRefGoogle Scholar
  17. 17.
    USFDA. Interactive Ingredient Guide (Redacted) January 1996. (accessed August 26, 2006), part of (accessed August 26, 2006).
  18. 18.
    T. Yamaoka, Y. Tabata, and Y. Ikada. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J. Pharm. Sci. 83:601–606 (1994).PubMedCrossRefGoogle Scholar
  19. 19.
    C. Monfardini, O. Schiavon, P. Caliceti, M. Morpurgo, J. M. Harris, and F. M. Veronese. A branched monomethoxypoly(ethylene glycol) for protein modification. Bioconjug. Chem. 6:62–69 (1995).PubMedCrossRefGoogle Scholar
  20. 20.
    S. Kommareddy, S. B. Tiwari, and M. M. Amiji. Long-circulating polymeric nanovectors for tumor-selective gene delivery. Technol. Cancer Res. Treat. 4:615–625 (2005).PubMedGoogle Scholar
  21. 21.
    M. Hamidi, A. Azadi, and P. Rafiei. Pharmacokinetic consequences of pegylation. Drug Deliv. 13:399–409 (2006).PubMedCrossRefGoogle Scholar
  22. 22.
    R. Gref, Y. Minamitake, M. T. Peracchia, V. Trubetskoy, V. Torchilin, and R. Langer. Biodegradable long-circulating polymeric nanospheres. Science 263:1600–1603 (1994).PubMedCrossRefGoogle Scholar
  23. 23.
    R. Gref, A. Domb, P. Quellec, T. Blunk, R. H. Müller, J. M. Verbavatz, et al. The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres. Adv. Drug Deliv. Rev. 16:215–233 (1999).CrossRefGoogle Scholar
  24. 24.
    S. M. Moghimi, H. Hedeman, I. S. Muir, L. Illum, and S. Davis. An investigation of the filtration capacity and the fate of large filtered sterically-stabilized microspheres in rat spleen. Biochem. Biophys. Acta 1157:233–240 (1993).PubMedGoogle Scholar
  25. 25.
    S. M. Moghimi, A. C. Hunter, and J. C. Murray. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev. 53:283–318 (2001).PubMedGoogle Scholar
  26. 26.
    S. Mao, M. Neu, O. Germershaus, O. Merkel, J. Sitterberg, U. Bakowsky, et al. Influence of polyethylene glycol chain length on the physicochemical and biological properties of poly(ethylene imine)-graft-poly(ethylene glycol) block copolymer/SiRNA polyplexes. Bioconjug. Chem. 17:1209–1218 (2006).PubMedCrossRefGoogle Scholar
  27. 27.
    S. Kommareddy and M. Amiji. Biodistribution and pharmacokinetic analysis of long-circulating thiolated gelatin nanoparticles following systemic administration in breast cancer-bearing mice. J. Pharm. Sci. 96:397–407 (2007).PubMedCrossRefGoogle Scholar
  28. 28.
    D. Shenoy, S. Little, R. Langer, and M. Amiji. Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 2. In vivo distribution and tumor localization studies. Pharm. Res. 22:2107–2114 (2005).PubMedCrossRefGoogle Scholar
  29. 29.
    G. Kaul and M. Amiji. Biodistribution and targeting potential of poly(ethylene glycol)-modified gelatin nanoparticles in subcutaneous murine tumor model. J. Drug Target 12:585–591 (2004).PubMedCrossRefGoogle Scholar
  30. 30.
    G. Kaul and M. Amiji. Long-circulating poly(ethylene glycol)-modified gelatin nanoparticles for intracellular delivery. Pharm. Res. 19:1061–1077 (2002).PubMedCrossRefGoogle Scholar
  31. 31.
    D. Shenoy, S. Little, R. Langer, and M. Amiji. Poly(ethylene oxide)-modified poly (beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 1. In vitro evaluations. Mol. Pharmacol. 2:357–366 (2005).CrossRefGoogle Scholar
  32. 32.
    S. Kommareddy and M. Amiji. Preparation and evaluation of thiol-modified gelatin nanoparticles for intracellular DNA delivery in response to glutathione. Bioconjug. Chem. 16:1423–1432 (2005).PubMedCrossRefGoogle Scholar
  33. 33.
    L. K. Shah and M. M. Amiji. Intracellular delivery of saquinavir in biodegradable polymeric nanoparticles for HIV/AIDS. Pharm. Res. 23:2638–2645 (2006).PubMedCrossRefGoogle Scholar
  34. 34.
    J. S. Chawla and M. M. Amiji. Biodegradable poly (epsilon-caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen. Int. J. Pharm. 249:127–138 (2002).PubMedCrossRefGoogle Scholar
  35. 35.
    I. Brigger, J. Morizet, L. Laudani, G. Aubert, M. Appel, V. Velasco, et al. Negative preclinical results with stealth nanospheres-encapsulated Doxorubicin in an orthotopic murine brain tumor model. J. Control. Release 100:29–40 (2004).PubMedCrossRefGoogle Scholar
  36. 36.
    Z. Xu, W. Gu, J. Huang, H. Sui, Z. Zhou, Y. Yang, et al. In vitro and in vivo evaluation of actively targetable nanoparticles for paclitaxel delivery. Int. J. Pharm. 288:361–368 (2005).PubMedCrossRefGoogle Scholar
  37. 37.
    C. Fang, B. Shi, Y. Y. Pei, M. H. Hong, J. Wu, and H. Z. Chen. In vivo tumor targeting of tumor necrosis factor-alpha-loaded stealth nanoparticles: effect of MePEG molecular weight and particle size. Eur. J. Pharm. Sci. 27:27–36 (2006).PubMedCrossRefGoogle Scholar
  38. 38.
    G. Kaul and M. Amiji. Cellular interactions and in vitro DNA transfection studies with poly(ethylene glycol)-modified gelatin nanoparticles. J. Pharm. Sci. 94:184–198 (2005).PubMedCrossRefGoogle Scholar
  39. 39.
    G. Kaul and M. Amiji. Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles: in vitro and in vivo studies. Pharm. Res. 22:951–961 (2005).PubMedCrossRefGoogle Scholar
  40. 40.
    C. Sun, R. Sze, and M. Zhang. Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MRI. J. Biomed. Mater. Res. 78:550–557 (2006).CrossRefGoogle Scholar
  41. 41.
    S. H. Kim, J. H. Jeong, K. W. Chun, and T. G. Park. Target-specific cellular uptake of PLGA nanoparticles coated with poly(L-lysine)-poly(ethylene glycol)-folate conjugate. Langmuir 21:8852–8857 (2005).PubMedCrossRefGoogle Scholar
  42. 42.
    M. O. Oyewumi, S. Liu, J. A. Moscow, and R. J. Mumper. Specific association of thiamine-coated gadolinium nanoparticles with human breast cancer cells expressing thiamine transporters. Bioconjug. Chem. 14:404–411 (2003).PubMedCrossRefGoogle Scholar
  43. 43.
    R. M. Schiffelers, A. Ansari, J. Xu, Q. Zhou, Q. Tang, G. Storm, et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 32:e149 (2004).PubMedCrossRefGoogle Scholar
  44. 44.
    D. Simberg, T. Duza, J. H. Park, M. Essler, J. Pilch, L. Zhang, et al. Biomimetic amplification of nanoparticle homing to tumors. PNAS 104:932–936 (2007).PubMedCrossRefGoogle Scholar
  45. 45.
    U. B. Nielsen, D. B. Kirpotin, E. M. Pickering, K. Hong, J. W. Park, M. Refaat Shalaby, et al. Therapeutic efficacy of anti-ErbB2 immunoliposomes targeted by a phage antibody selected for cellular endocytosis. Biochem. Biophys. Acta 1591:109–118 (2002).PubMedCrossRefGoogle Scholar
  46. 46.
    N. C. Bellocq, S. H. Pun, G. S. Jensen, and M. E. Davis. Transferrin-containing, cyclodextrin polymer-based particles for tumor-targeted gene delivery. Bioconjug. Chem. 14:1122–1132 (2003).PubMedCrossRefGoogle Scholar
  47. 47.
    X. Gao, W. Tao, W. Lu, Q. Zhang, Y. Zhang, X. Jiang, et al. Lectin-conjugated PEG-PLA nanoparticles: preparation and brain delivery after intranasal administration. Biomaterials 27:3482–3490 (2006).PubMedCrossRefGoogle Scholar
  48. 48.
    T. A. Elbayoumi and V. P. Torchilin. Enhanced accumulation of long-circulating liposomes modified with the nucleosome-specific monoclonal antibody 2C5 in various tumours in mice: gamma-imaging studies. Eur. J. Nucl. Med. Mol. Imaging 33:1196–1205 (2006).PubMedCrossRefGoogle Scholar
  49. 49.
    M. E. Hayes, D. C. Drummond, K. Hong, W. W. Zheng, V. A. Khorosheva, J. A. Cohen, et al. Increased target specificity of anti-HER2 genospheres by modification of surface charge and degree of PEGylation. Mol. Pharmacol. 3:726–736 (2006).CrossRefGoogle Scholar
  50. 50.
    Y. I. Jeong, S. J. Seo, I. K. Park, H. C. Lee, I. C. Kang, T. Akaike, et al. Cellular recognition of paclitaxel-loaded polymeric nanoparticles composed of poly(gamma-benzyl L-glutamate) and poly(ethylene glycol) diblock copolymer endcapped with galactose moiety. Int. J. Pharm. 296:151–161 (2005).PubMedCrossRefGoogle Scholar
  51. 51.
    O. C. Farokhzad, J. Cheng, B. A. Teply, I. Sherifi, S. Jon, P. W. Kantoff, et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. PNAS 103:6315–6320 (2006).PubMedCrossRefGoogle Scholar
  52. 52.
    G. Russell-Jones, K. McTavish, J. McEwan, J. Rice, and D. Nowotnik. Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumours. J. Inorg. Biochem. 98:1625–1633 (2004).PubMedCrossRefGoogle Scholar
  53. 53.
    S. H. Kim, J. H. Jeong, K. W. Chun, and T. G. Park. Target-specific cellular uptake of PLGA nanoparticles coated with poly(L-lysine)-poly(ethylene glycol)-folate conjugate. Langmuir 21:8852–8857 (2005).PubMedCrossRefGoogle Scholar
  54. 54.
    Y. Hattori and Y. Maitani. Enhanced in vitro DNA transfection efficiency by novel folate-linked nanoparticles in human prostate cancer and oral cancer. J. Control. Release 97:173–183 (2004).PubMedCrossRefGoogle Scholar
  55. 55.
    S. H. Pun, F. Tack, N. C. Bellocq, J. Cheng, B. H. Grubbs, G. S. Jensen, et al. Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles. Cancer Biol. Ther. 3:641–650 (2004).PubMedCrossRefGoogle Scholar
  56. 56.
    A. Nori and J. Kopecek. Intracellular targeting of polymer-bound drugs for cancer chemotherapy. Adv. Drug Deliv. Rev. 57:609–636 (2005).PubMedCrossRefGoogle Scholar
  57. 57.
    H. Harada and S. Grant. Apoptosis regulators. Rev. Clin. Exp. Hematol. 7:117–138 (2003).PubMedGoogle Scholar
  58. 58.
    E. Vives, P. Brodin, and B. Lebleu. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J. Biol. Chem. 272:16010–16017 (1997).CrossRefGoogle Scholar
  59. 59.
    D. A. Mann and A. D. Frankel. Endocytosis and targeting of exogenous HIV-1 Tat protein. EmBO J. 10:1733–1739 (1991).PubMedGoogle Scholar
  60. 60.
    E. Kleemann, M. Neu, N. Jekel, L. Fink, T. Schmehl, T. Gessler, et al. Nano-carriers for DNA delivery to the lung based upon a TAT-derived peptide covalently coupled to PEG-PEI. J. Control. Release 109:299–316 (2005).PubMedCrossRefGoogle Scholar
  61. 61.
    V. Del Gaizo, J. A. MacKenzie, and R. M. Payne. Targeting proteins to mitochondria using TAT. Mol. Genet. Metab. 80:170–180 (2003).PubMedCrossRefGoogle Scholar
  62. 62.
    M. Oishi, K. Kataoka, and Y. Nagasaki. pH-responsive three-layered PEGylated polyplex micelle based on a lactosylated ABC triblock copolymer as a targetable and endosome-disruptive nonviral gene vector. Bioconjug. Chem. 17:677–688 (2006).CrossRefGoogle Scholar
  63. 63.
    I. M. Hafez, N. Maurer, and P. R. Cullis. On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther. 8:1188–1196 (2001).PubMedCrossRefGoogle Scholar
  64. 64.
    J. Wang, D. Mongayt, and V. P. Torchilin. Polymeric micelles for delivery of poorly soluble drugs: preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on poly(ethylene glycol)-lipid conjugate and positively charged lipids. J. Drug Target. 13:73–80 (2005).PubMedCrossRefGoogle Scholar
  65. 65.
    S. Mishra, P. Webster, and M. E. Davis. PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur. J. Cell Biol. 83:97–111 (2004).PubMedCrossRefGoogle Scholar
  66. 66.
    W. Li, Z. Huang, J. A. MacKay, S. Grube, and F. C. Szoka, Jr. Low-pH-sensitive poly(ethylene glycol) (PEG)-stabilized plasmid nanolipoparticles: effects of PEG chain length, lipid composition and assembly conditions on gene delivery. J. Gene Med. 7:67–79 (2005).PubMedCrossRefGoogle Scholar
  67. 67.
    R. M. Sawant, J. P. Hurley, S. Salmaso, A. Kale, E. Tolcheva, T. S. Levchenko, et al. “SMART” drug delivery systems: double-targeted pH-responsive pharmaceutical nanocarriers. Bioconjug. Chem. 17:943–949 (2006).PubMedCrossRefGoogle Scholar
  68. 68.
    C. A. Fustin, C. Colard, M. Filali, P. Guillet, A. S. Duwez, M. A. Meier, et al. Tuning the hydrophilicity of gold nanoparticles templated in star block copolymers. Langmuir 22:6690–6695 (2006).PubMedCrossRefGoogle Scholar
  69. 69.
    C. Hiemstra, Z. Zhong, L. Li, P. J. Dijkstra, and J. Feijen. In-Situ Formation of Biodegradable Hydrogels by Stereocomplexation of PEG-(PLLA) (8) and PEG-(PDLA) (8) Star Block Copolymers. Biomacromolecules 7:2790–2795 (2006).PubMedCrossRefGoogle Scholar
  70. 70.
    T. Satomi, K. Ueno, Y. Fujita H. Kobayashi, J. Tanaka, Y. Mitamura, et al. Synthesis of ploypyridine-graft-PEG copolymer for protein repellent and stable interface. J. Nanosci. Nanotechnol. 6:1792–1796 (2006).PubMedCrossRefGoogle Scholar
  71. 71.
    M. L. Forrest, A. Zhao, C. Y. Won, A. W. Malick, and G. S. Kwon. Lipophilic prodrugs of Hsp90 inhibitor geldanamycin for nanoencapsulation in poly(ethylene glycol)-b-poly(epsilon-caprolactone) micelles. J. Control. Rel. 116:139–149 (2006).CrossRefGoogle Scholar
  72. 72.
    Z. Sezgin, N. Yuksel, and T. Baykara. Preparation and characterization of polymeric micelles for solubilization of poorly soluble anticancer drugs. Eur. J. Pharm. Biopharm. 64:261–268 (2006).PubMedCrossRefGoogle Scholar
  73. 73.
    H. Hatakeyama, H. Akita, K. Kogure, M. Oishi, Y. Nagasaki, Y. Kihira, et al. Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid. Gene. Ther. 14:68–77 (2007).PubMedCrossRefGoogle Scholar
  74. 74.
    T. Kushibiki and Y. Tabata. Preparation of poly(ethylene glycol)-introduced cationized gelatin as a non-viral gene carrier. J. Biomater. Sci. Polym. Ed. 16:1447–1461 (2005).PubMedCrossRefGoogle Scholar
  75. 75.
    Y. Murakami, M. Yokohama, T. Okano, H. Nishida, Y. Tomizawa, M. Endo, et al. A novel synthetic tissue-adhesive hydrogel using a crooslinkable polymeric micelle. J. Biomed. Mater. Res. A. 80:421–427 (2006).Google Scholar
  76. 76.
    A. Prabhutendolkar, X. Liu, E. V. Mathias, Y. Ba, and J. A. Kornfield. Synthesis of Chlorambucil-Tempol Adduct and its Delivery using Fluoroalkyl Double-Ended Poly (Ethylene Glycol) Micelles. Drug. Deliv. 13:433–440 (2006).PubMedCrossRefGoogle Scholar
  77. 77.
    L. Jongpaiboonkit, Z. Zhou, X. Ni, Y. Z. Wang, and J. Li. Self-association and micelle formation of biodegredable poly(ethylene glycol)-poly(L-lactid acid) amphiphilic di-block co-polymers. J. Biomater. Sci. Polym. Ed. 17:747–763 (2006).PubMedCrossRefGoogle Scholar
  78. 78.
    T. G. Park and H. S. Yoo. Dexamethasone nano-aggregates composed of PEG-PLA-PEG triblock copolymers for anti-proliferation of smooth muscle cells. Int. J. Pharm. 326:169–173 (2006).PubMedCrossRefGoogle Scholar
  79. 79.
    Y. Bae, W. D. Jang, N. Nishiyama, S. Fukushima, and K. Kataoka. Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery. Mol. Biosyst. 1:242–250 (2005).PubMedCrossRefGoogle Scholar
  80. 80.
    M. O. Oyewumi, R. A. Yokel, M. Jay, T. Coakley, and R. J. Mumper. Comparison of cell uptake, biodistribution, and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor bearing mice. J. Control. Rel. 95:613–626 (2004).CrossRefGoogle Scholar
  81. 81.
    S. Kubetzko, E. Balic, R. Waibel, U. Zangemeister-Wittke, and A. Pluckthun. PEGylation and Multimerization of the Anti-p185-HER-2 single-chain Fv fragment 4D5: Effects on tumor targeting. J. Biol. Chem. 281:35186–35201 (2006).PubMedCrossRefGoogle Scholar
  82. 82.
    D. C. Bibby, J. E. Talmadge, M. K. Dalal, S. G. Kurz, K. M. Chytil, S. E. Barry, et al. Phrmacokinetics and biodistribution of RGD-targeted doxorubicin-loaded nanoparticles in tumor-bearing mice. Int. J. Pharm. 293:281–290 (2005).PubMedCrossRefGoogle Scholar
  83. 83.
    S. Utreja, A. J. Khopade, and N. K. Jain. Lipoprotein-mimicking biovectorized systems for methotrexate delivery. Pharm. Acta. Helv. 73:275–279 (1999).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Lilian E. van Vlerken
    • 1
  • Tushar K. Vyas
    • 1
  • Mansoor M. Amiji
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA

Personalised recommendations