Article
Open Access
The spatial orientation of histidine via five-armed alkylamino siloxane improved the properties of the cationic gene delivery vector
Viola B. Morris1,2,∗Chandra P. Sharma1,∗
1 Division of Biosurface technology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Science and Technology, Thiruvananthapuram, India
2 Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
Abstract

The efficiency of gene transfection using cationic polymers primarily depends on factors such as compact polyplex formation, cellular uptake, endosomal escape, cytoplasmic transport, nuclear entry, and the dissociation and release of plasmid from the polyplex. These factors can be manipulated through the chemical modification of cationic polymers. Branched polyethyleneimine (PEI) has been considered the "gold standard" in gene delivery due to its high transfection efficiency. However, cytotoxicity and serum sensitivity limit its therapeutic use. In the present study, we aimed to reduce cytotoxicity while maintaining or enhancing transfection efficiency by chemically modifying PEI with the amino acid histidine via five-armed alkylamino siloxane. We anticipated that the spatial orientation of histidine could enhance cellular uptake and endosomal escape. Histidine-modified PEI, termed P(S-His)1, improved gene transfection efficiency due to elevated cellular uptake through multiple pathways and rapid endosomal escape via the proton sponge effect, compared to PEI and other derivatives with higher histidine conjugation. When the same polymer was further chemically modified with polyethylene glycol-folic acid (PEG-FA) to facilitate receptor-mediated cellular targeting, cellular uptake improved through additional pathways; however, the transfection efficiency unexpectedly decreased. This reduction in transfection efficiency is likely due to the absence of plasmid release from the polyplex for gene transcription, caused by the reduced ionic strength of the polyplex resulting from the high molecular weight PEG.

Keywords

folate receptor; buffering capacity; endosomal escape; histidine; poly(ethyleneimine)

Preview
References
  • [1] Chang KL, Higuchi Y, Kawakami S, Yamashita F, Hashida M. Efficient gene transfection by histidine-modified chitosan through enhancement of endosomal escape. Bioconjug. Chem. 2010, 21(6):1087–1095.
  • [2] Hashemi M, Parhiz BH, Hatefi A, Ramezani M. Modified polyethyleneimine with histidine-lysine short peptides as gene carrier. Cancer Gene Ther. 2011, 18(1):12–19.
  • [3] Bertrand E, Goncalves C, Billiet L, Gomez JP, Pichon C, et al. Histidinylated linear PEI: a new efficient non-toxic polymer for gene transfer. Chem. Commun. (Camb.) 2011, 47(46):12547–12549.
  • [4] Morris VB, Sharma CP. Folate mediated histidine derivative of quaternised chitosan as a gene delivery vector. Int. J. Pharm. 2010, 389(1–2):176–185.
  • [5] Kichler A, Sabourault N, Decor R, Leborgne C, Schmutz M, et al. Preparation and evaluation of a new class of gene transfer reagents: poly(-alkylaminosiloxanes). J. Control. Release. 2003, 93(3):403–414.
  • [6] Lu S, Morris VB, Labhasetwar V. Codelivery of DNA and siRNA via arginine-rich PEI-based polyplexes. Mol. Pharm. 2015, 12(2):621–629.
  • [7] Morris VB, Labhasetwar V. Arginine-rich polyplexes for gene delivery to neuronal cells. Biomaterials 2015, 60:151–160.
  • [8] Morris VB, Sharma CP. Enhanced in-vitro transfection and biocompatibility of L-arginine modified oligo (-alkylaminosiloxanes)-graft-polyethylenimine. Biomaterials 2010, 31(33):8759–8769.
  • [9] Morris VB, Sharma CP. Folate mediated l-arginine modified oligo (alkylaminosiloxane) graft poly (ethyleneimine) for tumor targeted gene delivery. Biomaterials 2011, 32(11):3030–3041.
  • [10] Nouri F, Sadeghpour H, Heidari R, Dehshahri A. Preparation, characterization, and transfection efficiency of low molecular weight polyethylenimine-based nanoparticles for delivery of the plasmid encoding CD200 gene. Int. J. Nanomedicine 2017, 12:5557–5569.
  • [11] Shi J, Schellinger JG, Johnson RN, Choi JL, Chou B, et al. Influence of histidine incorporation on buffer capacity and gene transfection efficiency of HPMA-co-oligolysine brush polymers. Biomacromolecules 2013, 14(6):1961–1970.
  • [12] Wang DA, Narang AS, Kotb M, Gaber AO, Miller DD, et al. Novel branched poly(ethylenimine)-cholesterol water-soluble lipopolymers for gene delivery. Biomacromolecules 2002, 3(6):1197–1207.
  • [13] Yu Y, Wang J, Kaul SC, Wadhwa R, Miyako E. Folic Acid Receptor-Mediated Targeting Enhances the Cytotoxicity, Efficacy, and Selectivity of Withania somnifera Leaf Extract: In vitro and in vivo Evidence. Front Oncol 2019, 9:602.
  • [14] Young O, Ngo N, Lin L, Stanbery L, Creeden JF, et al. Folate Receptor as a Biomarker and Therapeutic Target in Solid Tumors. Curr. Probl. Cancer 2023, 47(1):100917.
  • [15] Boogerd LS, Boonstra MC, Beck AJ, Charehbili A, Hoogstins CE, et al. Concordance of folate receptor-alpha expression between biopsy, primary tumor and metastasis in breast cancer and lung cancer patients. Oncotarget 2016, 7(14):17442–17454.
  • [16] Schnoell J, Jank BJ, Kadletz-Wanke L, Stoiber S, Gurnhofer E, et al. Protein Expression of Folate Receptor Alpha in Adenoid Cystic Carcinoma of the Head and Neck. Onco Targets Ther. 2022, 15:531–538.
  • [17] Ahmadi M, Ritter CA, von Woedtke T, Bekeschus S, Wende K. Package delivered: folate receptor-mediated transporters in cancer therapy and diagnosis. Chem. Sci. 2024, 15(6):1966–2006.
  • [18] Rosenholm JM, Meinander A, Peuhu E, Niemi R, Eriksson JE, et al. Targeting of porous hybrid silica nanoparticles to cancer cells. ACS Nano. 2009, 3(1):197–206.
  • [19] Park EK, Kim SY, Lee SB, Lee YM. Folate-conjugated methoxy poly (ethylene glycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery. J. Control. Release. 2005, 109(1–3):158–168.
  • [20] Benns JM, Mahato RI, Kim SW. Optimization of factors influencing the transfection efficiency of folate-PEG-folate-graft-polyethylenimine. J. Control. Release 2002, 79(1–3):255–269.
  • [21] Corsi K, Chellat F, Yahia L, Fernandes JC. Mesenchymal stem cells, MG63 and HEK293 transfection using chitosan-DNA nanoparticles. Biomaterials 2003, 24(7):1255–1264.
  • [22] Agarwal A, Unfer R, Mallapragada SK. Novel cationic pentablock copolymers as non-viral vectors for gene therapy. J. Control Release 2005, 103(1):245–258.
  • [23] Kim TI, Baek JU, Yoon JK, Choi JS, Kim K, et al. Synthesis and characterization of a novel arginine-grafted dendritic block copolymer for gene delivery and study of its cellular uptake pathway leading to transfection. Bioconjug. Chem. 2007, 18(2):309–317.
  • [24] Tracey SR, Smyth P, Herron UM, Burrows JF, Porter AJ, et al. Development of a cationic polyethyleneimine-poly(lactic-co-glycolic acid) nanoparticle system for enhanced intracellular delivery of biologics. RSC Adv. 2023, 13(48):33721–33735.
  • [25] Wang X, Niu D, Hu C, Li P. Polyethyleneimine-Based Nanocarriers for Gene Delivery. Curr. Pharm. Des. 2015, 21(42):6140–6156.
  • [26] Chandrasekaran AR. Nuclease resistance of DNA nanostructures. Nat. Rev. Chem. 2021, 5(4):225–239.
  • [27] Hansen MF, Jensen SO, Fuchtbauer EM, Martensen PM. High folic acid diet enhances tumour growth in PyMT-induced breast cancer. Br. J. Cancer 2017, 116(6):752–761.
  • [28] Hwang SY, Kang YJ, Sung B, Jang JY, Hwang NL, et al. Folic acid is necessary for proliferation and differentiation of C2C12 myoblasts. J. Cell. Physiol. 2018, 233(2):736–747.
  • [29] Grandinetti G, Smith AE, Reineke TM. Membrane and nuclear permeabilization by polymeric pDNA vehicles: efficient method for gene delivery or mechanism of cytotoxicity? Mol. Pharm. 2012, 9(3):523–538.
  • [30] Ross NL, Munsell EV, Sabanayagam C, Sullivan MO. Histone-targeted Polyplexes Avoid Endosomal Escape and Enter the Nucleus During Postmitotic Redistribution of ER Membranes. Mol. Ther. Nucleic Acids 2015, 4(2):e226.
  • [31] Ross NL, Sullivan MO. Overexpression of caveolin-1 in inflammatory breast cancer cells enables IBC-specific gene delivery and prodrug conversion using histone-targeted polyplexes. Biotechnol. Bioeng. 2016, 113(12):2686–2697.
  • [32] Winkeljann B, Keul DC, Merkel OM. Engineering poly-and micelleplexes for nucleic acid delivery-A reflection on their endosomal escape. J. Control. Release 2023, 353:518–534.
  • [33] Hillaireau H, Couvreur P. Nanocarriers' entry into the cell: relevance to drug delivery. Cell. Mol. Life Sci. 2009, 66(17):2873–2896.
  • [34] Liu P, Anderson RG. Spatial organization of EGF receptor transmodulation by PDGF. Biochem. Biophys. Res. Commun. 1999, 261(3):695–700.
  • [35] Goncalves C, Mennesson E, Fuchs R, Gorvel JP, Midoux P, et al. Macropinocytosis of polyplexes and recycling of plasmid via the clathrin-dependent pathway impair the transfection efficiency of human hepatocarcinoma cells. Mol. Ther. 2004, 10(2):373–385.
  • [36] Wang LH, Rothberg KG, Anderson RG. Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. J. Cell Biol. 1993, 123(5):1107–1117.
  • [37] Guo W, Lee RJ. Efficient gene delivery via non-covalent complexes of folic acid and polyethylenimine. J. Control. Release 2001, 77(1–2):131–138.
Office Locations

Room 704, Cheuk Nang Centre, 9 Hillwood Road, Tsim Sha Tsui, Kowloon, Hong Kong

No.169th Liangui Road, Dongjing Street, Yuhua District, Changsha 410116, Hunan Province, China

Useful Links
About

ELSPublishing (ELSP) is an international publishing house dedicated to publishing high-quality journals, books, proceedings, and providing free conference system. ELSP is committed to promote scholarly communication and sharing, to build a globally integrated scholarly ecosystem, and to advance the cause for a wide range of scholars.

Website Copyright © 2024 ELSP