Skip to main content
SpringerLink
Log in

The effect of polyethylene glycol spacer chain length on the tumor-targeting potential of folate-modified PPI dendrimers

  • Research Paper
  • Published:
Journal of Nanoparticle Research Aims and scope Submit manuscript

Abstract

The objective of the present investigation was to assess the tumor-targeting potential of ligand-spacer-engineered poly (propylene imine) (PPI) dendrimers as nanoscale drug delivery units for site-specific delivery of a model anticancer agent, docetaxel (DTX). PPI dendrimers were engineered by direct and indirect conjugation of folic acid (FA) via different types of polyethylene glycols (PEGs) [Mw (molecular weight): 1,000, 4,000, 6,000, 7,500] as spacers. The synthesized nanoconjugates (PPIFA, PPIP1FA, PPIP4FA, PPIP6FA, and PPIP7.5FA) were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance (1H-NMR) and transmission electron microscopic (TEM) studies. Nanoconjugates were evaluated for entrapment, in vitro drug release (under various pH conditions) and hemolytic studies. Cell uptake and cytotoxicity studies were performed on human malignant cell lines (MCF-7) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [MTT] assay. This debut study explored the effect of PEG spacer length on the targeting potential of folate-conjugated 5.0 G PPI dendrimer. DTX entrapment and in vitro drug release from nanoconjugates augmented, and hemolytic toxicity of nanoconjugates slashed with the molecular weight of PEGs. Further, nanoconjugates with PEG 4000 displayed highest tumor-targeting potential as compared to other spacer conjugated nanoconjugates due to optimized steric hindrance and receptor mediated endocytosis among other PEGs. This work is expected to shed new light on the role of spacer chain length in targeting potential of folate-anchored dendrimer.

Graphical Abstract

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Scheme 2
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Agarwal A, Gupta U, Asthana A, Jain NK (2009) Dextran conjugated dendrtitic nanoconstructs as potential vectors for anti-cancer agent. Biomaterials 30:3588–3596

    Article  CAS  Google Scholar 

  • Agashe HB, Babbar AK, Jain S, Sharma RK, Mishra AK, Asthana A, Garg M, Dutta T, Jain NK (2007) Investigations on biodistribution of technetium-99 m-labeled carbohydrate-coated poly(propylene imine) dendrimers. Nanomedicine 3:120–127

    Article  CAS  Google Scholar 

  • Asthana A, Chauhan AS, Diwan PV, Jain NK (2005) Poly(amidoamine) (PAMAM) dendritic nanostructures for controlled site-specific delivery of acidic anti-inflammatory active ingredient. AAPS PharmSciTech 6:E536–E542

    Article  Google Scholar 

  • Bhadra D, Bhadra S, Jain S, Jain NK (2003) A PEGylated dendritic nanoparticulate carrier of fluorouracil. Int J Pharm 25:7111–7124

    Google Scholar 

  • Bhadra D, Bhadra S, Jain NK (2005) PEGylated lysine based copolymeric dendritic micelles for solubilization and delivery of artemether. J Pharm Sci 8:467–482

    CAS  Google Scholar 

  • Brannon-Peppas L, Blanchette JO (2004) Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 56:1649–1659

    Article  CAS  Google Scholar 

  • Brigger I, Dubernet C, Couvreur P (2002) Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev 54:631–651

    Article  CAS  Google Scholar 

  • De Brabander-van Den Berg EMM, Meijer EW (1993) PPI dendrimers: large-scale synthesis by hetereogeneously catalyzed hydrogenations. Angew Chem Int Ed Engl 32:1308–1311

    Article  Google Scholar 

  • Dutta T, Jain NK (2007) Targeting potential and anti-HIV activity of lamivudine loaded mannosylated poly (propyleneimine) dendrimer. Biochim Biophys Acta 1770:681–686

    Article  CAS  Google Scholar 

  • Dutta T, Agashe HB, Garg M, Balakrishnan P, Kabra M, Jain NK (2007) Poly (propyleneimine) dendrimer based nanocontainers for targeting of efavirenz to human monocytes/macrophages in vitro. J Drug Target 15:89–98

    Article  CAS  Google Scholar 

  • Dutta T, Garg M, Jain NK (2008) Poly(propyleneimine) dendrimer and dendrosome mediated genetic immunization against hepatitis B. Vaccine 26:3389–3394

    Article  CAS  Google Scholar 

  • Gajbhiye V, Jain NK (2011) The treatment of Glioblastoma Xenografts by surfactant conjugated dendritic nanoconjugates. Biomaterials 32:6213–6225

    CAS  Google Scholar 

  • Gajbhiye V, Kumar PV, Tekade RK, Jain NK (2007) Pharmaceutical and biomedical potential of PEGylated dendrimers. Curr Pharm Des 13:415–429

    Article  CAS  Google Scholar 

  • Goddard JM, Erickson D (2009) Bioconjugation techniques for microfluidic biosensors. Anal Bioanal Chem 394:469–479

    Article  CAS  Google Scholar 

  • Grabarek Z, Gergely J (1990) Zero-length crosslinking procedure with the use of active esters. Anal Biochem 185:131–135

    Article  CAS  Google Scholar 

  • Guillaudeu SJ, Fox ME, Haidar YM, Dy EE, Szoka FC, Fréchet JM (2008) PEGylated dendrimers with core functionality for biological applications. Bioconjug Chem 19:461–469

    Article  CAS  Google Scholar 

  • Gupta U, Agashe HB, Jain NK (2007) Polypropylene imine dendrimer mediated solubility enhancement: effect of pH and functional groups of hydrophobes. J Pharm Sci 10:358–367

    CAS  Google Scholar 

  • Ho J, Al-Deen FM, Al-Abboodi A, Selomulya C, Xiang SD, Plebanski M, Forde GM (2011) N,N′-Carbonyldiimidazole-mediated functionalization of superparamagnetic nanoparticles as vaccine carrier. Colloids Surf B Biointerfaces 83:83–90

    Article  CAS  Google Scholar 

  • Hwa KS, Hoon JJ, Joe CO, Gwan PT (2005) Folate receptor mediated intracellular protein delivery using PLL-PEG-FOL conjugate. J Control Rel 103:625–634

    Article  Google Scholar 

  • Jabr-Milane LS, Van Vlerken L, Yadav S, Amiji MM (2008) Multi-functional nanocarriers to overcome tumor drug resistance. Cancer Treat Rev 34:592–602

    Article  CAS  Google Scholar 

  • Jain NK, Asthana A (2007) Dendritic systems in drug delivery applications. Expert Opin Drug Deliv 4:495–512

    Article  CAS  Google Scholar 

  • Kaminskas LM, Kelly BD, McLeod VM, Sberna G, Owen DJ, Boyd BJ, Porter CJ (2011) Characterization and tumour targeting of PEGylated polylysine dendrimers bearing doxorubicin via a pH labile linker. J Control Release 152:241–248

    Article  CAS  Google Scholar 

  • Kannan S, Kolhe P, Raykova V, Glibatec M, Kannan RM, Lieh-Lai M, Bassett D (2004) Dynamics of cellular entry and drug delivery by dendritic polymers into human lung epithelial carcinoma cells. J Biomatter Sci Polym Ed 15:311–330

    Article  CAS  Google Scholar 

  • Kesharwani P, Tekade RK, Gajbhiye V, Jain K, Jain NK (2011) Cancer targeting potential of some ligand anchored poly(propylene imine) dendrimers: a comparison. Nanomedicine 7:295–304

    Article  CAS  Google Scholar 

  • Kim Y, Klutz AM, Jacobson KA (2008) Systematic investigation of polyamidoamine dendrimers surface-modified with poly(ethylene glycol) for drug delivery applications: synthesis, characterization, and evaluation of cytotoxicity. Bioconjug Chem 19:1660–1672

    Article  CAS  Google Scholar 

  • Kingsley JD, Dou H, Morehead J, Rabinow B, Gendelman HE, Destache CJ (2006) Nanotechnology: a focus on nanoparticles as a drug delivery system. J Neuroimmune Pharmacol 1(340):350

    Google Scholar 

  • Kobayashi H, Kawamoto S, Saga T, Sato N, Hiraga A, Ishimori T, Konishi J, To-Gashi K, Brechbiel MW (2001) Positive effects of polyethylene glycol conjugation to generation-4 polyamidoamine dendrimers as macromolecular MR contrast agents. Magn Reson Med 46:781–788

    Article  CAS  Google Scholar 

  • Kojima C, Regino C, Umeda Y, Kobayashi H, Kono K (2010) Influence of dendrimer generation and polyethylene glycol length on the biodistribution of PEGylated dendrimers. Int J Pharm 383:293–306

    Article  CAS  Google Scholar 

  • Kolhe P, Khandare J, Pillai O, Kannan S, Lai ML, Kannan RM (2006) Preparation, cellular transport, and activity of polyamidoamine based dendritic nanodevices with a high drug payload. Biomaterials 27:660–669

    Article  CAS  Google Scholar 

  • Konda SD, Wang S, Brechbiel M, Wiener EC (2002) Biodistribution of a 153 Gd-folate dendrimer, generation = 4, in mice with folate-receptor positive and negative ovarian tumor xenografts. Invest Radiol 37:199–204

    Article  CAS  Google Scholar 

  • Kumar PV, Asthana A, Dutta T, Jain NK (2006) Intracellular macrophage uptake of rifampicin loaded mannosylated dendrimers. J Drug Target 14:546–556

    Article  CAS  Google Scholar 

  • Kumar PV, Agashe H, Dutta T, Jain NK (2007) PEGylated dendritic architecture for development of a prolonged drug delivery system for an antitubercular drug. Curr Drug Deliv 1:11–19

    Article  Google Scholar 

  • Kwon GS, Okano T (1996) Polymeric micelles as new drug carriers. Adv Drug Deliv Rev 16:107–116

    Article  Google Scholar 

  • Lee RJ, Low PS (1995) Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. Biochim Biophys Acta 1233:134–144

    Article  Google Scholar 

  • Lim J, Guo Y, Rostollan CL, Standfield J, Hsieh JT, Sun X, Simanek EE (2008) The role of the size and number of polyethylene glycol chains in the biodistribution and tumor localization of triazine dendrimers. Mol Pharm 5:540–547

    Article  CAS  Google Scholar 

  • Liu Y, Li K, Pan J, Liu B, Feng SS (2010) Folic acid conjugated nanoparticles of mixed lipid monolayer shell and biodegradable polymer core for targeted delivery of Docetaxel. Biomaterials 31:330–338

    Article  CAS  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  Google Scholar 

  • Nie S, Xing Y, Kim GJ, Simons JW (2007) Nanotechnology applications in cancer. Annu Rev Biomed Eng 9:257–288

    Article  CAS  Google Scholar 

  • Okuda T, Kawakami S, Akimoto N, Niidome T, Yamashita F, Hashida M (2006) PEGylated lysine dendrimers for tumor-selective targeting after intravenous injection in tumor-bearing mice. J Control Release 116:330–336

    Article  CAS  Google Scholar 

  • Patri AK, Majoros I, Baker JR (2002) Dendritic polymer macromolecular carriers for drug delivery. Curr Opin Chem Biol 6:466–471

    Article  CAS  Google Scholar 

  • Quintana A, Raczka E, Piehler L, Lee I, Myc A, Majoros I, Patri AK, Thomas T, Mule J, Baker JR (2002) Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor. Pharm Res 19:1310–1316

    Article  CAS  Google Scholar 

  • Sabharanjak S, Mayor S (2004) Folate receptor endocytosis and trafficking. Adv Drug Deliv Rev 56:1099–1109

    Article  CAS  Google Scholar 

  • Sideratou Z, Kontoyianni C, Drossopoulou GI, Paleos CM (2010) Synthesis of a folate functionalized PEGylated poly(propylene imine) dendrimer as prospective targeted drug delivery system. Bioorg Med Chem Lett 20:6513–6527

    Article  CAS  Google Scholar 

  • Singh P, Gupta U, Asthana A, Jain NK (2008) Folate and folate-PEG-PAMAM dendrimers: synthesis, characterization, and targeted anticancer drug delivery potential in tumor bearing mice. Bioconjug Chem 19:2239–2252

    Article  CAS  Google Scholar 

  • Singhai AK, Jain S, Jain NK (1997) Evaluation of an aqueous injection of Ketoprofen. Pharmazie 52:149–151

    CAS  Google Scholar 

  • Sinha R, Kim GJ, Nie S, Shin DM (2006) Nanotechnology in cancer therapeutics: bioconjugated nanoparticles for drug delivery. Mol Cancer Ther 5:1909–1917

    Article  CAS  Google Scholar 

  • Stewart BW, Kleihues P (2003) World Cancer Report WHO. International Agency for Research on Cancer, IARC Press, Lyon, France

  • Sudimack J, Lee RJ (2000) Targeted drug delivery via the folate receptor. Adv Drug Deliv Rev 41:147–162

    Article  CAS  Google Scholar 

  • Tekade RK, Dutta T, Tyagi A, Bharti AC, Das BC, Jain NK (2008) Surface-engineered dendrimers for dual drug delivery: a receptor up-regulation and enhanced cancer targeting strategy. J Drug Target 16:758–772

    Article  CAS  Google Scholar 

  • Tekade RK, Dutta T, Gajbhiye V, Jain NK (2009a) Exploring dendrimers towards dual–drug delivery: pH responsive simultaneous kinetics. J Microencapsul 26:287–296

    Article  CAS  Google Scholar 

  • Tekade RK, Kumar PV, Jain NK (2009b) Dendrimers in oncology: an expanding horizon. Chem Rev 109:49–87

    Article  CAS  Google Scholar 

  • Thomas TP, Majoros IJ, Kotlyar A, Kukowska-Latallo JF, Bielinska A, Myc A, Baker JR (2005) Targeting and inhibition of cell growth by an engineered dendritic nanodevice. J Med Chem 48:3729–3735

    Article  CAS  Google Scholar 

  • Tomalia DA (1996) Starburst dendrimers-nanoscopic supermolecules according dendritic rules and principles. Macromol Symp 101:243–255

    Article  CAS  Google Scholar 

  • Tomalia DA, Naylor AM, Goddard WA (1990) Starburst dendrimers: molecular-level control of size, shape, surface chemistry, topology, and flexibility from atoms to macroscopic matter. Angew Chem Int Ed Engl 29:138–175

    Article  Google Scholar 

  • Tsuruo T, Naito M, Tomida A, Fujita N, Mashima T, Sakamoto H (2003) Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. Cancer Sci 94:15–21

    Article  CAS  Google Scholar 

  • Wolinsky JB, Grinstaff MW (2008) Therapeutic and diagnostic applications of dendrimers for cancer treatment. Adv Drug Deliv Rev 60:1037–1055

    Article  CAS  Google Scholar 

  • Yang H, Stephanie T, Lopina ST (2003) Penicillin V-conjugated PEG-PAMAM star polymers. J Biomater Sci Polym 14:1043–1056

    Article  CAS  Google Scholar 

  • Zange R, Li Y, Kissel T (1998) Biocompatibility testing of ABA copolymers consisting of poly (l-lactic-co-glycolic acid) A blocks attached to a central poly (ethylene oxide) B block under in vitro conditions using different L929 mouse fibroblast cell culture models. J Control Release 56:249–258

    Article  CAS  Google Scholar 

  • Zhai G, Wu J, Xiang G, Mao W, Yu B, Li H, Piao L, Lee LJ, Lee RJ (2009) Preparation, characterization and pharmacokinetics of folate receptor-targeted liposomes for docetaxel delivery. J Nanosci Nanotechnol 9:2155–2161

    Article  CAS  Google Scholar 

  • Zhao XF, Dong L, Zheng W (2011) PEGylated thermo sensitive poly(amidoamine) dendritic drug delivery systems. Int J Pharm 100:123–131

    Google Scholar 

  • Zhou QS, Jiang XH, Yu JR, Li KJ (2006) Synthesis and characterization of PEG-scutellarin conjugates, a potential PEG ester prodrug for the oral delivery of scutellarin. Chin Chem Lett 1:85–88

    Google Scholar 

  • Zhu S, Hong M, Tang G, Qian L, Lin J, Jiang Y, Pei Y (2010) Partly PEGylated polyamidoamine dendrimer for tumor-selective targeting of doxorubicin: the effects of PEGylation degree and drug conjugation style. Biomaterials 31:1360–1371

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge University Grants Commission (UGC) New Delhi, India, for the financial support to conduct this study.

Author information

Authors and Affiliations

  1. Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour University, Sagar, 470003, Madhya Pradesh, India

    Shrikant Thakur, Prashant Kesharwani & Narendra K. Jain

  2. College of Pharmacy, University of Hawai’i at Hilo, Hilo, HI, 96720, USA

    Rakesh K. Tekade

Authors
  1. Shrikant Thakur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rakesh K. Tekade
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Prashant Kesharwani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Narendra K. Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Narendra K. Jain.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thakur, S., Tekade, R.K., Kesharwani, P. et al. The effect of polyethylene glycol spacer chain length on the tumor-targeting potential of folate-modified PPI dendrimers. J Nanopart Res 15, 1625 (2013). https://doi.org/10.1007/s11051-013-1625-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11051-013-1625-2

Keywords

Search

Navigation