Skip to main content
SpringerLink
Log in

Harnessing the gene delivery, anti-cancer and antimicrobial potential of polyethylene biguanides and their nanotized forms

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

Abstract

Here, linear polyethylenimines (lPEI, 2.5 and 25 kDa) and their nanoparticles (prepared via reaction with a crosslinker, 1,4-butanediol diglycidyl ether) have been reacted with dicyandiamide (DCDA) to form the corresponding polyethylene biguanides (PEBs) and their corresponding nanoparticles (PEB NPs) in a single step. Further, these have been examined in terms of their ability to transport nucleic acids and antibacterial activity. Biophysical characterization revealed that PEB and PEB NPs interacted efficiently with pDNA and formed stable complexes in the size range of 150–321 nm exhibiting zeta potential in the range of + 21–30 mV. Conversion of secondary amines into biguanides did not induce toxicity i.e. modified polymers and their nanoparticles remained non-toxic in HEK 293 T cells. However, these showed anti-proliferative effects in cancerous MCF-7 and A549 cells. Further, in vitro transfection assays, performed on mammalian cells (HEK 293 T and MCF-7 cells), revealed the exhibition of the highest transfection efficiency by polyethylene biguanide (2.5 kDa) nanoparticle/pDNA (PEB2.5NP/pDNA) complex, while it decreased in the case of PEB25NP/pDNA complex. Antimicrobial studies revealed that PEB2.5 and PEB25 polymers exhibited excellent activity against clinical isolates as well as methicillin resistant Staphylococcus aureus (MRSA) and multidrug resistant Pseudomonas aeruginosa (MDR-PA). Their corresponding nanoformulations didn’t exhibit reasonable antimicrobial activity. Altogether, the results present promising potential of the low molecular weight polyethylene biguanides as efficient carrier of nucleic acids along with the therapy for multidrug resistant infections.

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
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Zu H, Gao D (2021) Non-viral vectors in gene therapy: Recent development, challenges, and prospects. AAPS J 23:78

    Article  Google Scholar 

  2. Sung Y, Kim S (2019) Recent advances in the development of gene delivery systems. Biomaterials Research 23:8

    Article  CAS  Google Scholar 

  3. Kumar S, Garg P, Pandey S, Kumari M, Hoon S, Jang K-J, Kapavarapu R, Choung P-H, Sobral AJ, Chung JH (2015) Enhanced chitosan–DNA interaction by 2-acrylamido-2-methylpropane coupling for an efficient transfection in cancer cells. Journal of Materials Chemistry B 3:3465–3475

    Article  CAS  Google Scholar 

  4. Jaiswal S, Dutta P, Kumar S, Koh J, Pandey S (2019) Methyl methacrylate modified chitosan: Synthesis, characterization and application in drug and gene delivery. Carbohyd Polym 211:109–117

    Article  CAS  Google Scholar 

  5. Garg P, Kumar S, Pandey S, Seonwoo H, Choung P-H, Koh J, Chung JH (2013) Triphenylamine coupled chitosan with high buffering capacity and low viscosity for enhanced transfection in mammalian cells, in vitro and in vivo. Journal of Materials Chemistry B 1:6053–6065

    Article  CAS  Google Scholar 

  6. Azzam T, Eliyahu H, Makovitzki A, Linial M, Domb AJ (2004) Hydrophobized dextran-spermine conjugate as potential vector for in vitro gene transfection. J Control Release 96:309–323

    Article  CAS  Google Scholar 

  7. Yi Y, Jong Noh M, Hee Lee K (2011) Current advances in retroviral gene therapy. Curr Gene Therapy 11:218–228

  8. Vargas JR, Stanzl EG, Teng NN, Wender PA (2014) Cell-penetrating, guanidinium-rich molecular transporters for overcoming efflux-mediated multidrug resistance. Mol Pharm 11:2553–2565

    Article  CAS  Google Scholar 

  9. Wender PA, Kreider E, Pelkey ET, Rothbard J, van Deusen CL (2005) Dendrimeric molecular transporters: synthesis and evaluation of tunable polyguanidino dendrimers that facilitate cellular uptake. Org Lett 7:4815–4818

    Article  CAS  Google Scholar 

  10. Maiti KK, Lee WS, Takeuchi T, Watkins C, Fretz M, Kim DC, Futaki S, Jones A, Kim KT, Chung SK (2007) Guanidine-containing molecular transporters: sorbitol-based transporters show high intracellular selectivity toward mitochondria. Angew Chem 119:5984–5988

    Article  Google Scholar 

  11. Lee Y, Cho M-Y, Mo H-J, Nam K-H, Koo H-B, Jin G-W, Park J-S (2008) Enhancement of the transfection efficiency of poly (ethylenimine) by guanidylation. Bull Korean Chem Soc 29:666–668

    Article  CAS  Google Scholar 

  12. Stanzl EG, Trantow BM, Vargas JR, Wender PA (2013) Fifteen years of cell-penetrating, guanidinium-rich molecular transporters: basic science, research tools, and clinical applications. Acc Chem Res 46:2944–2954

    Article  CAS  Google Scholar 

  13. Mogaki R, Hashim P, Okuro K, Aida T (2017) Guanidinium-based “molecular glues” for modulation of biomolecular functions. Chem Soc Rev 46:6480–6491

    Article  CAS  Google Scholar 

  14. Lu M, Xing H, Cheng L, Liu H, Lang L, Yang T, Zhao X, Xu H, Ding P (2020) A dual-functional buformin-mimicking poly (amido amine) for efficient and safe gene delivery. J Drug Target 28:923–932

    Article  CAS  Google Scholar 

  15. Chivu A, Chindera K, Mendes G, An A, Davidson B, Good L, Song W (2021) Cellular gene delivery via poly (hexamethylene biguanide)/pDNA self-assembled nanoparticles. Eur J Pharm Biopharm 158:62–71

    Article  CAS  Google Scholar 

  16. Xing H, Cheng L, Lu M, Liu H, Lang L, Yang T, Zhao X, Xu H, Yang L, Ding P (2019) A biodegradable poly (amido amine) based on the antimicrobial polymer polyhexamethylene biguanide for efficient and safe gene delivery. Colloids Surf, B 182:110355

    Article  CAS  Google Scholar 

  17. Yu C, Tan E, Xu Y, Lv J, Cheng Y (2018) A guanidinium-rich polymer for efficient cytosolic delivery of native proteins. Bioconjug Chem 30:413–417

    Article  Google Scholar 

  18. Zhao Y, Wang W, Guo S, Wang Y, Miao L, Xiong Y, Huang L (2016) PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery, Nature. Communications 7:1–9

    Article  Google Scholar 

  19. Luo C, Miao L, Zhao Y, Musetti S, Wang Y, Shi K, Huang L (2016) A novel cationic lipid with intrinsic antitumor activity to facilitate gene therapy of TRAIL DNA. Biomaterials 102:239–248

    Article  CAS  Google Scholar 

  20. Shi K, Zhao Y, Miao L, Satterlee A, Haynes M, Luo C, Musetti S, Huang L (2017) Dual functional lipomet mediates envelope-type nanoparticles to combinational oncogene silencing and tumor growth inhibition. Mol Ther 25:1567–1579

    Article  CAS  Google Scholar 

  21. Xiong Y, Zhao Y, Miao L, Lin CM, Huang L (2016) Co-delivery of polymeric metformin and cisplatin by self-assembled core-membrane nanoparticles to treat non-small cell lung cancer. J Control Release 244:63–73

    Article  CAS  Google Scholar 

  22. Sun Y, Liu L, Zhou L, Yu S, Lan Y, Liang Q, Liu J, Cao A, Liu Y (2020) Tumor microenvironment-triggered charge reversal polymetformin-based nanosystem co-delivered doxorubicin and IL-12 cytokine gene for chemo–gene combination therapy on metastatic breast cancer. ACS Appl Mater Interfaces 12:45873–45890

    Article  CAS  Google Scholar 

  23. Liu Y, Sun J, Huang Y, Chen Y, Li J, Liang L, Xu J, Wan Z, Zhang B, Li Z (2021) Metformin-conjugated micellar system with intratumoral pH responsive de-shielding for co-delivery of doxorubicin and nucleic acid. Biochem Pharmacol 189:114453

    Article  CAS  Google Scholar 

  24. Goyal R, Tripathi SK, Tyagi S, Sharma A, Ram KR, Chowdhuri DK, Shukla Y, Kumar P, Gupta KC (2012) Linear PEI nanoparticles: efficient pDNA/siRNA carriers in vitro and in vivo, Nanomedicine: Nanotechnology. Biology and Medicine 8:167–175

    CAS  Google Scholar 

  25. Yadav S, Mahato M, Pathak R, Jha D, Kumar B, Deka SR, Gautam HK, Sharma AK (2014) Multifunctional self-assembled cationic peptide nanostructures efficiently carry plasmid DNA in vitro and exhibit antimicrobial activity with minimal toxicity. Journal of Materials Chemistry B 2:4848–4861

    Article  CAS  Google Scholar 

  26. Yadav S, Priyam A, Mahato M, Deka SR, Sharma AK (2014) Ligands with delocalized charge density and hydrophobicity significantly affect the transfection efficacy of the PAMAM dendrimer, Pharmaceutical. Nanotechnology 2:196–207

    CAS  Google Scholar 

  27. Yadav S, Sharma AK, Kumar P (2021) Tight binding of plasmid DNA with self-assembled tetramethylguanidinium conjugated polyethylenimine suppresses transfection efficiency. Frontiers in Nanotechnology 3:50

    Article  Google Scholar 

  28. Yadav S, Deka SR, Jha D, Gautam HK, Sharma AK (2016) Amphiphilic azobenzene-neomycin conjugate self-assembles into nanostructures and transports plasmid DNA efficiently into the mammalian cells. Colloids Surf, B 148:481–486

    Article  CAS  Google Scholar 

  29. Tripathi SK, Yadav S, Gupta KC, Kumar P (2012) Synthesis and evaluation of N-(2, 3-dihydroxypropyl)-PEIs as efficient vectors for nucleic acids. Mol BioSyst 8:1426–1434

    Article  CAS  Google Scholar 

  30. Signore A, Anzola KL, Auletta S, Varani M, Petitti A, Pacilio M, Galli F, Lauri C (2018) Current status of molecular imaging in inflammatory and autoimmune disorders. Curr Pharm Des 24:743–753

    Article  CAS  Google Scholar 

  31. Kuroda K, Caputo GA, DeGrado WF (2009) The role of hydrophobicity in the antimicrobial and hemolytic activities of polymethacrylate derivatives. Chem–A Eur J 15:1123–1133

  32. Chen F, Moat J, McFeely D, Clarkson G, Hands-Portman IJ, Furner-Pardoe JP, Harrison F, Dowson CG, Sadler PJ (2018) Biguanide iridium (III) complexes with potent antimicrobial activity. J Med Chem 61:7330–7344

    Article  CAS  Google Scholar 

  33. Wang L, Hu C, Shao L (2017) The antimicrobial activity of nanoparticles: present situation and prospects for the future. Int J Nanomed 12:1227–1249

    Article  CAS  Google Scholar 

  34. Spirescu VA, Chircov C, Grumezescu AM, Andronescu E (2021) Polymeric nanoparticles for antimicrobial therapies: An up-to-date overview. Polymers 13:724

    Article  CAS  Google Scholar 

  35. Agnihotri S, Pathak R, Jha D, Roy I, Gautam HK, Sharma AK, Kumar P (2015) Synthesis and antimicrobial activity of aminoglycoside-conjugated silica nanoparticles against clinical and resistant bacteria. New J Chem 39:6746–6755

    Article  CAS  Google Scholar 

  36. Yadav S, Mahato M, Jha D, Ahmadi Z, Gautam H, Sharma A (2018) Enhanced antibacterial activity of tetramethylguanidinium-conjugated linear polyethylenimine polymers, International Journal of Polymeric Materials and Polymeric. Biomaterials 67:889–895

    CAS  Google Scholar 

Download references

Acknowledgements

Authors gratefully acknowledge the financial grant from CSIR project (OLP 1144). SY thanks Indian Council of Medical Research (ICMR), New Delhi, India, for awarding Research Associateship (ICMR Reference No.: 45/39/2020-Nan-BMS) to carry out the projected work. Authors also acknowledge USIC, Delhi University, Delhi, for spectroscopic analysis of the compounds.

Author information

Authors and Affiliations

  1. Nucleic Acids Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India

    Santosh Yadav & Pradeep Kumar

  2. Immunology and Infectious Disease Biology Laboratory, CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India

    Diksha Jha & Hemant K. Gautam

Authors
  1. Santosh Yadav
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diksha Jha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hemant K. Gautam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pradeep Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SY: Validation, Data curation, Writing- Original draft preparation. DJ: Data curation, formal analysis HKG: Supervision, Reviewing PK: Reviewing, editing, supervision.

Corresponding author

Correspondence to Pradeep Kumar.

Ethics declarations

Conflict of interest

Authors do not have any conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yadav, S., Jha, D., Gautam, H.K. et al. Harnessing the gene delivery, anti-cancer and antimicrobial potential of polyethylene biguanides and their nanotized forms. J Polym Res 29, 290 (2022). https://doi.org/10.1007/s10965-022-03142-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10965-022-03142-y

Keywords

Search

Navigation