Advertisement

AAPS PharmSciTech

, Volume 19, Issue 3, pp 1029–1036 | Cite as

Evaluation of Efficiency of Modified Polypropylenimine (PPI) with Alkyl Chains as Non-viral Vectors Used in Co-delivery of Doxorubicin and TRAIL Plasmid

  • Mahboubeh Ebrahimian
  • Sahar Taghavi
  • Maryam Ghoreishi
  • Shahrzad Sedghi
  • Sara Amel Farzad
  • Mohammad Ramezani
  • Maryam Hashemi
Research Article
First Online:
Received:
Accepted:

Abstract

In this study, co-delivery system was achieved via plasmid encoding TNF related apoptosis inducing ligand (pTRAIL) and doxorubicin (DOX) using carrier based on polypropylenimine (PPI) modified with 10-bromodecanoic acid. Incorporation of alkylcarboxylate chain to PPIs (G4 and G5) could improve transfection efficiency via overcoming the plasma membrane barrier of the cells and decrease cytotoxicity of PPI. Characterization of fabricated NPs revealed that PPI G5 in which 30% of primary amines were substituted by alkyl carboxylate chain (PPI G5-Alkyl 30%) has higher drug loading as compared to the other formulations. PPI G5-Alkyl 30% indicated a decreased drug release may be due to alkyl chains on the surface of PPI, which serve as an additional hindrance for drug diffusion. In vitro cytotoxicity experiments demonstrated that co-delivery system induced apoptosis of tumor cells more efficiently than each of delivery system alone. Furthermore, these results revealed that our combined delivery platform of pTRAIL and DOX using Alkyl-modified PPI G5 can significantly improve the anti-tumor activity and this strategy might develop a new therapeutic window for cancer treatment.

KEY WORDS

co-delivery polypropyleneimine TRAIL plasmid doxorubicin 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Saraswathy M, Gong S. Recent developments in the co-delivery of siRNA and small molecule anticancer drugs for cancer treatment. Mater Today. 2014;17(6):298–306.CrossRefGoogle Scholar
  2. 2.
    Yang Z, Gao D, Cao Z, Zhang C, Cheng D, Liu J, et al. Drug and gene co-delivery systems for cancer treatment. Biomater Sci. 2015;3(7):1035–49.CrossRefPubMedGoogle Scholar
  3. 3.
    Guan X, Li Y, Jiao Z, Lin L, Chen J, Guo Z, et al. Codelivery of antitumor drug and gene by a pH-sensitive charge-conversion system. ACS Appl Mater Interfaces. 2015;7(5):3207–15.CrossRefPubMedGoogle Scholar
  4. 4.
    Khan M, Ong ZY, Wiradharma N, Attia ABE, Yang YY. Advanced materials for co-delivery of drugs and genes in cancer therapy. Adv Healthc Mater. 2012;1(4):373–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Taghavi S, Nia AH, Abnous K, Ramezani M. Polyethylenimine-functionalized carbon nanotubes tagged with AS1411 aptamer for combination gene and drug delivery into human gastric cancer cells. Int J Pharm. 2017;516(1):301–12.CrossRefPubMedGoogle Scholar
  6. 6.
    Wang S, Konorev EA, Kotamraju S, Joseph J, Kalivendi S, Kalyanaraman B. Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms intermediacy of H2O2-and p53-dependent pathways. J Biol Chem. 2004;279(24):25535–43.CrossRefPubMedGoogle Scholar
  7. 7.
    Han Y, Zhang P, Chen Y, Sun J, Kong F. Co-delivery of plasmid DNA and doxorubicin by solid lipid nanoparticles for lung cancer therapy. Int J Mol Med. 2014;34(1):191–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Liu C, Liu F, Feng L, Li M, Zhang J, Zhang N. The targeted co-delivery of DNA and doxorubicin to tumor cells via multifunctional PEI-PEG based nanoparticles. Biomaterials. 2013;34(10):2547–64.CrossRefPubMedGoogle Scholar
  9. 9.
    Zhao J, Feng S-S. Nanocarriers for delivery of siRNA and co-delivery of siRNA and other therapeutic agents. Nanomedicine. 2015;10(14):2199–228.CrossRefPubMedGoogle Scholar
  10. 10.
    Liu S, Guo Y, Huang R, Li J, Huang S, Kuang Y, et al. Gene and doxorubicin co-delivery system for targeting therapy of glioma. Biomaterials. 2012;33(19):4907–16.CrossRefPubMedGoogle Scholar
  11. 11.
    Wang C, Li M, Yang T, Ding X, Bao X, Ding Y, et al. A self-assembled system for tumor-targeted co-delivery of drug and gene. Mater Sci Eng C. 2015;56:280–5.CrossRefGoogle Scholar
  12. 12.
    Liu F, Shollenberger LM, Huang L. Non-immunostimulatory nonviral vectors. FASEB J. 2004;18(14):1779–81.Google Scholar
  13. 13.
    Kim E, Jung Y, Choi H, Yang J, Suh JS, Huh YM, et al. Prostate cancer cell death produced by the co-delivery of Bcl-xL shRNA and doxorubicin using an aptamer-conjugated polyplex. Biomaterials. 2010;31(16):4592–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhu C, Jung S, Luo S, Meng F, Zhu X, Park TG, et al. Co-delivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers. Biomaterials. 2010;31(8):2408–16.CrossRefPubMedGoogle Scholar
  15. 15.
    Ebrahimian M, Taghavi S, Mokhtarzadeh A, Ramezani M, Hashemi M. Co-delivery of doxorubicin encapsulated PLGA nanoparticles and Bcl-xL shRNA using alkyl-modified PEI into breast cancer cells. Appl Biochem Biotechnol. 2017;183(1):126–36.Google Scholar
  16. 16.
    Wang Y, Gao S, Ye WH, Yoon HS, Yang YY. Co-delivery of drugs and DNA from cationic core–shell nanoparticles self-assembled from a biodegradable copolymer. Nat Mater. 2016;5(10):791–6.Google Scholar
  17. 17.
    Hashemi M, Parhiz H, Mokhtarzadeh A, Tabatabai SM, Farzad SA, Shirvan HR, et al. Preparation of effective and safe gene carriers by grafting alkyl chains to generation 5 polypropyleneimine. AAPS PharmSciTech. 2015;16(5):1002–12.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Menjoge AR, Kannan RM, Tomalia DA. Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications. Drug Discov Today. 2010;15(5–6):171–85.CrossRefPubMedGoogle Scholar
  19. 19.
    Tripathy S, Das MK. Dendrimers and their applications as novel drug delivery carriers. J Appl Pharm Sci. 2013;3(9):142–9.Google Scholar
  20. 20.
    Wang F, Cai X, Su Y, Hu J, Wu Q, Zhang H, et al. Reducing cytotoxicity while improving anti-cancer drug loading capacity of polypropylenimine dendrimers by surface acetylation. Acta Biomater. 2012;8(12):4304–13.CrossRefPubMedGoogle Scholar
  21. 21.
    Richter-Egger DL, Tesfai A, Tucker SA. Spectroscopic investigations of poly(propyleneimine)dendrimers using the solvatochromic probe phenol blue and comparisons to poly(amidoamine) dendrimers. Anal Chem. 2001;73(23):5743–51.CrossRefPubMedGoogle Scholar
  22. 22.
    Cheng Y, Xu T. The effect of dendrimers on the pharmacodynamic and pharmacokinetic behaviors of non-covalently or covalently attached drugs. Eur J Med Chem. 2008;43(11):2291–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Han M, Lv Q, Tang X-J, Hu Y-L, Xu D-H, Li F-Z, et al. Overcoming drug resistance of MCF-7/ADR cells by altering intracellular distribution of doxorubicin via MVP knockdown with a novel siRNA polyamidoamine-hyaluronic acid complex. J Control Release. 2012;163(2):136–44.CrossRefPubMedGoogle Scholar
  24. 24.
    Hashemi M, Tabatabai SM, Parhiz H, Milanizadeh S, Farzad SA, Abnous K, et al. Gene delivery efficiency and cytotoxicity of heterocyclic amine-modified PAMAM and PPI dendrimers. Mater Sci Eng C. 2016;61:791–800.CrossRefGoogle Scholar
  25. 25.
    Santos JL, Oliveira H, Pandita D, Rodrigues J, Pêgo AP, Granja PL, et al. Functionalization of poly(amidoamine) dendrimers with hydrophobic chains for improved gene delivery in mesenchymal stem cells. J Control Release. 2010;144(1):55–64.CrossRefPubMedGoogle Scholar
  26. 26.
    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.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Wang C, Chen T, Zhang N, Yang M, Li B, Lu X, et al. Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IkappaBalpha kinase-NFkappaB. J Biol Chem. 2009;284(6):3804–13.CrossRefPubMedGoogle Scholar
  28. 28.
    Holoch PA, Griffith TS. TNF-related apoptosis-inducing ligand (TRAIL): a new path to anti-cancer therapies. Eur J Pharmacol. 2009;625(1–3):63–72.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hashemi M, Sahraie Fard H, Amel Farzad S, Parhiz H, Ramezani M. Gene transfer enhancement by alkylcarboxylation of poly (propylenimine). Nanomedicine J. 2013;1(1):55–62.Google Scholar
  30. 30.
    Huihui Liao HL, Li Y, Zhang M, Tomas H, Shen M, Shi X. Antitumor efficacy of doxorubicin encapsulated within PEGylated poly(amidoamine) dendrimers. J Appl Polym Sci. 2014;131(11):1–10.Google Scholar
  31. 31.
    Zhu J, Xiong Z, Shen M, Shi X. Encapsulation of doxorubicin within multifunctional gadolinium-loaded dendrimer nanocomplexes for targeted theranostics of cancer cells. RSC Adv. 2015;5:30286–96.CrossRefGoogle Scholar
  32. 32.
    Taghavi S, HashemNia A, Mosaffa F, Askarian S, Abnous K, Ramezani M. Preparation and evaluation of polyethylenimine-functionalized carbon nanotubes tagged with 5TR1 aptamer for targeted delivery of Bcl-xL shRNA into breast cancer cells. Colloids Surf B: Biointerfaces. 2016;140:28–39.CrossRefPubMedGoogle Scholar
  33. 33.
    Martinho N, Florindo H, Silva L, Brocchini S, Zloh M, Barata T. Molecular modeling to study dendrimers for biomedical applications. Molecules. 2014;19(12):20424.CrossRefPubMedGoogle Scholar
  34. 34.
    Han L, Huang R, Li J, Liu S, Huang S, Jiang C. Plasmid pORF-hTRAIL and doxorubicin co-delivery targeting to tumor using peptide-conjugated polyamidoamine dendrimer. Biomaterials. 2011;32(4):1242–52.CrossRefPubMedGoogle Scholar
  35. 35.
    Schneider-Jakob S, Corazza N, Badmann A, Sidler D, Stuber-Roos R, Keogh A, et al. Synergistic induction of cell death in liver tumor cells by TRAIL and chemotherapeutic drugs via the BH3-only proteins Bim and Bid. Cell Death Dis. 2010;1:e86.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Fant K, Esbjorner EK, Jenkins A, Grossel MC, Lincoln P, Norden B. Effects of PEGylation and acetylation of PAMAM dendrimers on DNA binding, cytotoxicity and in vitro transfection efficiency. Mol Pharm. 2010;7(5):1734–46.CrossRefPubMedGoogle Scholar
  37. 37.
    Liu Z, Zhang Z, Zhou C, Jiao Y. Hydrophobic modifications of cationic polymers for gene delivery. Prog Polym Sci. 2010;35(9):1144–62.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Mahboubeh Ebrahimian
    • 1
    • 2
  • Sahar Taghavi
    • 2
  • Maryam Ghoreishi
    • 3
  • Shahrzad Sedghi
    • 3
  • Sara Amel Farzad
    • 2
  • Mohammad Ramezani
    • 2
  • Maryam Hashemi
    • 4
  1. 1.Division of Biotechnology, Faculty of Veterinary MedicineFerdowsi University of MashhadMashhadIran
  2. 2.Pharmaceutical Research CenterMashhad University of Medical SciencesMashhadIran
  3. 3.School of PharmacyMashhad University of Medical SciencesMashhadIran
  4. 4.Nanotechnology Research CenterMashhad University of Medical SciencesMashhadIran

Personalised recommendations

Cite article

Buy options