Skip to main content

Advertisement

SpringerLink
Log in

Generation Dependent Safety and Efficacy of Folic Acid Conjugated Dendrimer Based Anticancer Drug Formulations

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Folate conjugated poly(propyleneimine) (PPI) dendrimer (FPPI) mediated anticancer therapy is being extensively discovered throughout the world. The present investigation was aimed at exploring the targeting potential of Melphalan loaded FPPI of different generations (MP-FPPI) for effective management of cancer.

Methods

The MP-FPPI formulations were compared for drug entrapment efficiency, in vitro release profile, toxicology, folate receptor blockage assay, cell uptake assay, stability studies, and in vivo studies.

Results

Upon increasing the dendrimer generation from fourth to fifth, the drug delivery parameters improved negligibly except the toxicological profile that improved exponentially. MTT assay in case of MCF-7 cells depicted the IC 50 values of 8 ± 0.15, 0.9 ± 0.02, 0.2 ± 0.01 and 10 ± 0.17 μM, respectively in case of MP-FPPI3, MP-FPPI4, MP-FPPI5, and free Melphalan suggesting folate based targeting to be the efficacious approach to kill cancer cells. The median survival time for tumor bearing mice treated with MP-FPPI3, MP-FPPI4, MP-FPPI5 and free drug was found to be 23, 59, 62 and 26 days, respectively.

Conclusions

The study concludes fourth generation PPI dendrimer to be superior carrier for folate based tumor targeting compared to third and fifth generation based formulations. This work is expected to provide a significant clue in the selection of “dendrimer generation” for folate mediated cancer targeting therapy.

This debut study exploring the effect of generation on the targeting potential of folate-conjugated PPI dendrimer and the outcome is expected to shed valuable information in selection of dendrimer generation.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kesharwani P, Tekade RK, Jain K, Jain NK. Formulation development and in vitro-in vivo assessment of fourth generation PPI dendrimer as cancer targeting vector. Nanomed (Lond) 2014 [Epub ahead of print].

  2. Dutta T, Garg M, Jain NK. Poly (propyleneimine) dendrimer and dendrosome mediated genetic immunization against hepatitis B. Vaccine. 2008;26:3389–94.

    Article  CAS  PubMed  Google Scholar 

  3. Kesharwani P, Gajbhiye V, Jain NK. A review of nanocarriers for the delivery of small interfering RNA. Biomaterials. 2012;33:7138–50.

    Article  CAS  PubMed  Google Scholar 

  4. Jain S, Kesharwani P, Tekade RK, Jain NK. One platform comparison of solubilization potential of dendrimer with some solubilizing agents. Drug Dev Ind Pharm 2014 [Epub ahead of print].

  5. Kesharwani P, Tekade RK, Jain K, Jain NK. Generation dependent cancer targeting potential of poly(propyleneimine) dendrimer. Biomaterials. 2014;35:5539–48.

    Article  CAS  PubMed  Google Scholar 

  6. Shao N, Su Y, Hu J, Zhang J, Zhang H, Cheng Y. Comparison of generation 3 polyamidoamine dendrimer and generation 4 polypropylenimine dendrimer on drug loading, complex structure, release behavior, and cytotoxicity. Int J Nanomedicine. 2011;6:3361–72.

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Kesharwani P, Jain K, Jain NK. Dendrimer as nanocarrier for drug delivery. Prog Polym Sci. 2014;39:268–307.

    Article  CAS  Google Scholar 

  8. Tomalia DA, Naylor AM, Goddard III WA. Starburst dendrimers: molecular-level control of size, shape, surface chemistry, topology, and flexibility from atoms to macroscopic matter. Angew Chem Int Ed. 1990;29:138–75.

    Article  Google Scholar 

  9. Mishra V, Gupta U, Jain NK. Influence of different generations of poly(propylene imine) dendrimers on human erythrocytes. Pharmazie. 2010;65:891–5.

    CAS  PubMed  Google Scholar 

  10. Shah N, Steptoe RJ, Parekh HS. Low-generation asymmetric dendrimers exhibit minimal toxicity and effectively complex DNA. J Pept Sci. 2011;17:470–8.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Kukowska-Latallo JF, Candido KA, Cao Z, Nigavekar SS, Majoros IJ, Thomas TP, et al. Nanoparticle targeting of anti-cancer drug improves therapeutic response in animalmodel of human epithelial cancer. Cancer Res. 2005;65:5317–24.

    Article  CAS  PubMed  Google Scholar 

  13. Kono K, Liu M, Frechet JM. Design of dendriticmacromolecules containing folate or methotrexate residues. Bioconjug Chem. 1999;10:1115–21.

    Article  CAS  PubMed  Google Scholar 

  14. Pinguet F, Joulia JM, Martel P, Grosse PY, Astre C, Bressolle F. High-performance liquid chromatographic assay for melphalan in human plasma. Application to pharmacokinetic studies. J Chromatogr B Biomed Appl. 1996;686:43–9.

    Article  CAS  PubMed  Google Scholar 

  15. Sashidhara KV, Rosaiah JN, Kumar A, Bid HK, Konwar R, Chattopadhyay N. Cell growth inhibitory action of an unusual labdane diterpene, 13-epi-sclareol in breast and uterine cancers in vitro. Phytother Res. 2007;21:1105–8.

    Article  CAS  PubMed  Google Scholar 

  16. Cory AH, Owen TC, Barltrop JA, Cory JG. Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun. 1991;3:207–12.

    CAS  PubMed  Google Scholar 

  17. Patri AK, Kukowska-Latallo JF, Baker JR. Targeted drug delivery with dendrimers: comparison of the release kinetics of covalently conjugated drug and non-covalent drug inclusion complex. Adv Drug Deliv Rev. 2005;57:2203–14.

    Article  CAS  PubMed  Google Scholar 

  18. Hao H, Qi H, Ratnam M. Modulation of the folate receptor type beta gene by coordinate actions of retinoic acid receptors at activator Sp1/ets and repressor AP-1 sites. Blood. 2003;101:4551–60.

    Article  CAS  PubMed  Google Scholar 

  19. Perumal OP, Inapagolla R, Kannan S, Kannan RM. The effect of surface functionality on cellular trafficking of dendrimers. Biomaterials. 2008;29:3469–76.

    Article  CAS  PubMed  Google Scholar 

  20. Yoo HS, Park TG. Folate-receptor-targeted delivery of doxorubicin nanoaggregates stabilized by doxorubicin–PEG–folate conjugate. J Control Rel. 2004;100:247–56.

    Article  CAS  Google Scholar 

  21. Thakur S, Tekade RK, Kesharwani P, Jain NK. The effect of polyethylene glycol spacer chain length on the tumor-targeting potential of folate-modified PPI dendrimers. J Nanoparticle Res. 2013;15:1625–40.

    Article  Google Scholar 

  22. Kojima C, Kono K, Maruyama K, Takagishi T. Synthesis of polyamidoamine dendrimers having poly(ethylene glycol) grafts and their ability to encapsulate anticancer drugs. Bioconjug Chem. 2000;11:910–17.

    Article  CAS  PubMed  Google Scholar 

  23. Sikka PK, McMartin KE. Determination of folate transport pathways in cultured rat proximal tubule cells. Chem Biol Interact. 1998;114:15–31.

    Article  CAS  PubMed  Google Scholar 

  24. Bhadra D, Yadav AK, Bhadra S, Jain NK. Glycodendrimeric nanoparticulate carriers of primaquine phosphate for liver targeting. Int J Pharm. 2005;295:221–33.

    Article  CAS  PubMed  Google Scholar 

  25. Birdhariya B, Kesharwani P, Jain NK. Effect of surface capping on targeting potential of folate decorated poly (propylene imine) dendrimers. Drug Dev Ind Pharm. 2014:1-7 [Epub ahead of print].

  26. Kesharwani P, Gajbhiye V, Tekade RK, Jain NK. Evaluation of dendrimer safety and efficacy through cell line studies. Curr Drug Targets. 2011;12:1478–97.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

Prashant Kesharwani acknowledges Indian Council of Medical Research (ICMR), New Delhi, India for providing Senior Research Fellowship.

Author information

Authors and Affiliations

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

    Prashant Kesharwani & Narendra K. Jain

  2. Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave Room 3601, Detroit, Michigan, 48201, USA

    Prashant Kesharwani

  3. Preclinical Nuclear Imaging Laboratory (Advanced Imaging Research Center), Dallas, Texas, USA

    Prashant Kesharwani

  4. UT Southwestern Medical Center, Harry Hines Blvd., Dallas, Texas, 5323, USA

    Rakesh K. Tekade

  5. Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Jalan Jalil Perkasa 19, 57000, Kuala Lumpur, Malaysia

    Rakesh K. Tekade

Authors
  1. Prashant Kesharwani
    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. Narendra K. Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Prashant Kesharwani or Narendra K. Jain.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 136 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kesharwani, P., Tekade, R.K. & Jain, N.K. Generation Dependent Safety and Efficacy of Folic Acid Conjugated Dendrimer Based Anticancer Drug Formulations. Pharm Res 32, 1438–1450 (2015). https://doi.org/10.1007/s11095-014-1549-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-014-1549-2

KEY WORDS

Search

Navigation