Biodegradable Gene Carriers Containing Rigid Aromatic Linkage with Enhanced DNA Binding and Cell Uptake
Abstract
:1. Introduction
2. Experimental Section
2.1. Materials and Methods
2.2. Synthesis of the Target Polymers
2.2.1. Preparation and Characterization of Linker L1–L3
2.2.2. Preparation and Characterization of Target Polymer CyM, PhM, and NaM
2.3. Agarose Gel Retardation Assay
2.4. Ethidium Bromide Displacement Assay
2.5. Dynamic Light Scattering (DLS)
2.6. Transmission Electron Microscopy (TEM)
2.7. Cell Culture
2.8. Amplification and Purification of Plasmid DNA
2.9. Cell Viability Assay
2.10. Gene Transfection Efficiency Assay In Vitro
2.11. Cellular Uptake of Plasmid DNA
2.12. Confocal Laser Scanning Microscopy (CLSM)
2.13. Statistical Analysis
3. Results and Discussion
3.1. Preparation and Characterization of Target Polymers
3.2. Interaction with DNA and the Biodegradable Properties
3.3. Characterization of the Polyplexes
3.4. Cytotoxicity
3.5. In Vitro Gene Transfection
3.6. Cellular Uptake
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Hayakawa, K.; Uchida, S.; Ogata, T.; Tanaka, S.; Kataoka, K.; Itaka, K. Intrathecal injection of a therapeutic gene-containing polyplex to treat spinal cord injury. J. Control. Release 2015, 197, 1–9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karimi, M.; Ghasemi, A.; Zangabad, P.S.; Rahighi, R.; Basri, S.M.M.; Mirshekari, H.; Amiri, M.; Pishabad, Z.S.; Aslani, A.; Bozorgomid, M.; et al. Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. Chem. Soc. Rev. 2016, 45, 1457–1501. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kumar, M.D.; Dravid, A.; Kumar, A.; Sen, D. Gene therapy as a potential tool for treating neuroblastoma-a focused review. Cancer Gene Ther. 2016, 23, 115–124. [Google Scholar] [CrossRef] [PubMed]
- Naldini, L. Gene therapy returns to centre stage. Nature 2015, 526, 351–360. [Google Scholar] [CrossRef] [PubMed]
- Tan, X.Y.; Li, B.B.; Lu, X.G.; Jia, F.; Santori, C.; Menon, P.; Li, H.; Zhang, B.H.; Zhao, J.J.; Zhang, K. Light-triggered, self-immolative nucleic Acid-Drug nanostructures. J. Am. Chem. Soc. 2015, 137, 6112–6115. [Google Scholar] [CrossRef] [PubMed]
- Ullah, I.; Muhammad, K.; Akpanyung, M.; Nejjari, A.; Neve, A.L.; Guo, J.T.; Feng, Y.K.; Shi, C.C. Bioreducible, hydrolytically degradable and targeting polymers for gene delivery. J. Mater. Chem. B 2017, 5, 3253–3276. [Google Scholar] [CrossRef] [Green Version]
- Eltoukhy, A.A.; Chen, D.L.; Alabi, C.A.; Langer, R.; Anderson, D.G. Degradable terpolymers with alkyl side chains demonstrate enhanced gene delivery potency and nanoparticle stability. Adv. Mater. 2013, 25, 1487–1493. [Google Scholar] [CrossRef] [PubMed]
- Pandey, A.P.; Sawant, K.K. Polyethylenimine: A versatile, multifunctional non-viral vector for nucleic acid delivery. Mat. Sci. Eng. C-Mater. 2016, 68, 904–918. [Google Scholar] [CrossRef] [PubMed]
- Machitani, M.; Yamaguchi, T.; Shimizu, K.; Sakurai, F.; Katayama, K.; Kawabata, K.; Mizuguchi, H. Adenovirus vector-derived VA-RNA-mediated innate immune responses. Pharmaceutics 2011, 3, 338. [Google Scholar] [CrossRef] [PubMed]
- Zhou, X.Y.; Zheng, Q.Q.; Wang, C.Y.; Xu, J.K.; Wu, J.P.; Kirk, T.B.; Ma, D.; Xue, W. Star-shaped amphiphilic hyperbranched polyglycerol conjugated with dendritic poly(l-lysine) for the codelivery of docetaxel and MMP-9 siRNA in cancer therapy. ACS Appl. Mater. Interfaces 2016, 8, 12609–12619. [Google Scholar] [CrossRef] [PubMed]
- Pan, J.J.; Yuan, Y.Q.; Wang, H.W.; Liu, F.; Xiong, X.H.; Chen, H.; Yuan, L. Efficient transfection by using PDMAEMA-modified SINWAs as a platform for Ca2+-dependent gene delivery. ACS Appl. Mater. Interfaces 2016, 8, 15138–15144. [Google Scholar] [CrossRef] [PubMed]
- Samanta, K.; Jana, P.; Backer, S.; Knauer, S.; Schmuck, C. Guanidiniocarbonyl pyrrole (GCP) conjugated PAMAM-G2, a highly efficient vector for gene delivery: The importance of DNA condensation. Chem. Commun. 2016, 52, 12446–12449. [Google Scholar] [CrossRef] [PubMed]
- Mintzer, M.A.; Simanek, E.E. Nonviral vectors for gene delivery. Chem. Rev. 2009, 109, 259–302. [Google Scholar] [CrossRef] [PubMed]
- Benjaminsen, R.V.; Mattebjerg, M.A.; Henriksen, J.R.; Moghimi, S.M.; Andresen, T.L. The possible “proton sponge” effect of polyethylenimine (PEI) does not include change in lysosomal pH. Mol. Ther. 2013, 21, 149–157. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schwartz, B.; Benoist, C.; Abdallah, B.; Rangara, R.; Hassan, A.; Scherman, D.; Demeneix, B.A. Gene transfer by naked DNA into adult mouse brain. Gene Ther. 1996, 3, 405–411. [Google Scholar] [PubMed]
- Morimoto, K.; Nishikawa, M.; Kawakami, S.; Nakano, T.; Hattori, Y.; Fumoto, S.; Yamashita, F.; Hashida, M. Molecular weight-dependent gene transfection activity of unmodified and galactosylated polyethyleneimine on hepatoma cells and mouse liver. Mol. Ther. 2003, 7, 254–261. [Google Scholar] [CrossRef]
- Wang, Y.H.; Zheng, M.; Meng, F.H.; Zhang, J.; Peng, R.; Zhong, Z.Y. Branched polyethylenimine derivatives with reductively cleavable periphery for safe and efficient in vitro gene transfer. Biomacromolecules 2011, 12, 1032–1040. [Google Scholar] [CrossRef] [PubMed]
- Taranejoo, S.; Chandrasekaran, R.; Cheng, W.L.; Hourigan, K. Bioreducible PEI-functionalized glycol chitosan: A novel gene vector with reduced cytotoxicity and improved transfection efficiency. Carbohydr. Polym. 2016, 153, 160–168. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.; Yu, M.; Wang, J.; Tang, R.P.; Yan, G.Q.; Yao, W.J.; Wang, X. Low molecular weight PEI-based vectors via Acid-Labile ortho ester linkage for improved gene delivery. Macromol. Biosci. 2016, 16, 1175–1187. [Google Scholar] [CrossRef] [PubMed]
- Han, H.; Son, S.; Son, S.; Kim, N.; Yhee, J.Y.; Lee, J.H.; Choi, J.S.; Joo, C.K.; Lee, H.; Lee, D.; et al. Reducible polyethylenimine nanoparticles for efficient siRNA delivery in corneal neovascularization therapy. Macromol. Biosci. 2016, 16, 1583–1597. [Google Scholar] [CrossRef] [PubMed]
- Davoodi, P.; Srinivasan, M.P.; Wang, C.H. Synthesis of intracellular reduction-sensitive amphiphilic polyethyleneimine and poly(ε-caprolactone) graft copolymer for on-demand release of doxorubicin and p53 plasmid DNA. Acta Biomater. 2016, 39, 79–93. [Google Scholar] [CrossRef] [PubMed]
- Giron-Gonzalez, M.D.; Salto-Gonzalez, R.; Lopez-Jaramillo, F.J.; Salinas-Castillo, A.; Jodar-Reyes, A.B.; Ortega-Munoz, M.; Hernandez-Mateo, F.; Santoyo-Gonzalez, F. Polyelectrolyte complexes of low molecular weight PEI and citric acid as efficient and nontoxic vectors for in vitro and in vivo gene delivery. Bioconjugate Chem. 2016, 27, 549–561. [Google Scholar] [CrossRef] [PubMed]
- Taranejoo, S.; Liu, J.; Verma, P.; Hourigan, K. A review of the developments of characteristics of PEI derivatives for gene delivery applications. J. Appl. Polym. Sci. 2015, 132, 8. [Google Scholar] [CrossRef]
- Fang, G.; Zeng, F.; Yu, C.M.; Wu, S.Z. Low molecular weight peis modified by hydrazone-based crosslinker and betaine as improved gene carriers. Colloid Surf. B-Biointerfaces 2014, 122, 472–481. [Google Scholar] [CrossRef] [PubMed]
- Kunath, K.; von Harpe, A.; Fischer, D.; Peterson, H.; Bickel, U.; Voigt, K.; Kissel, T. Low-molecular-weight polyethylenimine as a non-viral vector for DNA delivery: Comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecular-weight polyethylenimine. J. Control. Release 2003, 89, 113–125. [Google Scholar] [CrossRef]
- Barnard, A.; Posocco, P.; Pricl, S.; Calderon, M.; Haag, R.; Hwang, M.E.; Shum, V.W.T.; Pack, D.W.; Smith, D.K. Degradable self-assembling dendrons for gene delivery: Experimental and theoretical insights into the barriers to cellular uptake. J. Am. Chem. Soc. 2011, 133, 20288–20300. [Google Scholar] [CrossRef] [PubMed]
- Kuchelmeister, H.Y.; Karczewski, S.; Gutschmidt, A.; Knauer, S.; Schmuck, C. Utilizing combinatorial chemistry and rational design: Peptidic tweezers with nanomolar affinity to DNA can be transformed into efficient vectors for gene delivery by addition of a lipophilic tail. Angew. Chem. Int. Ed. 2013, 52, 14016–14020. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.H.; Wu, D.C.; Xu, H.X.; You, Y.Z. High DNA-binding affinity and gene-transfection efficacy of bioreducible cationic nanomicelles with a fluorinated core. Angew. Chem. 2016, 128, 765–769. [Google Scholar] [CrossRef]
- Yi, W.-J.; Yu, X.-C.; Wang, B.; Zhang, J.; Yu, Q.-Y.; Zhou, X.-D.; Yu, X.-Q. Tacn-based oligomers with aromatic backbones for efficient nucleic acid delivery. Chem. Commun. 2014, 50, 6454–6457. [Google Scholar] [CrossRef] [PubMed]
- Luan, C.R.; Liu, Y.H.; Zhang, J.; Yu, Q.Y.; Huang, Z.; Wang, B.; Yu, X.Q. Low molecular weight oligomers with aromatic backbone as efficient nonviral gene vectors. ACS Appl. Mater. Interfaces 2016, 8, 10743–10751. [Google Scholar] [CrossRef] [PubMed]
- Gong, J.H.; Wang, Y.; Xing, L.; Cui, P.F.; Qiao, J.B.; He, Y.J.; Jiang, H.L. Biocompatible fluorinated poly(β-amino ester)s for safe and efficient gene therapy. Int. J. Pharm. 2018, 535, 180–193. [Google Scholar] [CrossRef] [PubMed]
- Mastorakos, P.; Zhang, C.; Song, E.; Kim, Y.E.; Park, H.W.; Berry, S.; Choi, W.K.; Hanes, J.; Suk, J.S. Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors. J. Control. Release 2017, 262, 37–46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Leiro, V.; Garcia, J.P.; Moreno, P.M.D.; Spencer, A.P.; Fernandez-Villamarin, M.; Riguera, R.; Fernandez-Megia, E.; Pego, A.P. Biodegradable PEG-dendritic block copolymers: Synthesis and biofunctionality assessment as vectors of siRNA. J. Mater. Chem. B 2017, 5, 4901–4917. [Google Scholar] [CrossRef]
- Liu, S.; Gao, Y.S.; Sigen, A.; Zhou, D.Z.; Greiser, U.; Guo, T.Y.; Guo, R.; Wang, W.X. Biodegradable highly branched poly(β-amino ester)s for targeted cancer cell gene transfection. ACS Biomater. Sci. Eng. 2017, 3, 1283–1286. [Google Scholar] [CrossRef]
- Mangraviti, A.; Tzeng, S.Y.; Kozielski, K.L.; Wang, Y.; Jin, Y.K.; Gullotti, D.; Pedone, M.; Buaron, N.; Liu, A.; Wilson, D.R.; et al. Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo. ACS Nano 2015, 9, 1236–1249. [Google Scholar] [CrossRef] [PubMed]
- Kang, M.T.; Meng, M.; Tan, Y.N.; Cheng, T.; Liu, C.Y. Tuning the electronic coupling and electron transfer in Mo2 donor–acceptor systems by variation of the bridge conformation. Chemistry 2016, 22, 3115–3126. [Google Scholar] [CrossRef] [PubMed]
- Xun, M.M.; Zhang, J.H.; Liu, Y.H.; Zhang, J.; Xiao, Y.P.; Guo, Q.; Li, S.; Yu, X.Q. Polyethylenimine analogs for improved gene delivery: Effect of the type of amino groups. RSC Adv. 2016, 6, 5391–5400. [Google Scholar] [CrossRef]
- Lachelt, U.; Wagner, E. Nucleic acid therapeutics using polyplexes: A journey of 50 years (and beyond). Chem. Rev. 2015, 115, 11043–11078. [Google Scholar] [CrossRef] [PubMed]
- Jiang, W.; Kim, B.Y.S.; Rutka, J.T.; Chan, W.C.W. Nanoparticle-mediated cellular response is size-dependent. Nat. Nanotechnol. 2008, 3, 145–150. [Google Scholar] [CrossRef] [PubMed]
- LaManna, C.M.; Lusic, H.; Camplo, M.; McIntosh, T.J.; Barthelemy, P.; Grinstaff, M.W. Charge-reversal lipids, peptide-based lipids, and nucleoside-based lipids for gene delivery. Acc. Chem. Res. 2012, 45, 1026–1038. [Google Scholar] [CrossRef] [PubMed]
- Ma, M.; Li, F.; Yuan, Z.-F.; Zhuo, R.-X. Influence of hydroxyl groups on the biological properties of cationic polymethacrylates as gene vectors. Acta Biomater. 2010, 6, 2658–2665. [Google Scholar] [CrossRef] [PubMed]
- Zheng, M.; Zhong, Y.A.; Meng, F.H.; Peng, R.; Zhong, Z.Y. Lipoic acid modified low molecular weight polyethylenimine mediates nontoxic and highly potent in vitro gene transfection. Mol. Pharmaceut. 2011, 8, 2434–2443. [Google Scholar] [CrossRef] [PubMed]
- Cheng, L.; Li, Y.; Zhai, X.; Xu, B.; Cao, Z.; Liu, W. Polycation-b-polyzwitterion copolymer grafted luminescent carbon dots as a multifunctional platform for serum-resistant gene delivery and bioimaging. ACS Appl. Mater. Interfaces 2014, 6, 20487–20497. [Google Scholar] [CrossRef] [PubMed]
Polymers | Mw | PDI |
---|---|---|
CyM | 10,555 | 2.24 |
PhM | 11,940 | 2.50 |
NaM | 9075 | 1.90 |
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Zhang, J.-H.; Yang, H.-Z.; Zhang, J.; Liu, Y.-H.; He, X.; Xiao, Y.-P.; Yu, X.-Q. Biodegradable Gene Carriers Containing Rigid Aromatic Linkage with Enhanced DNA Binding and Cell Uptake. Polymers 2018, 10, 1080. https://doi.org/10.3390/polym10101080
Zhang J-H, Yang H-Z, Zhang J, Liu Y-H, He X, Xiao Y-P, Yu X-Q. Biodegradable Gene Carriers Containing Rigid Aromatic Linkage with Enhanced DNA Binding and Cell Uptake. Polymers. 2018; 10(10):1080. https://doi.org/10.3390/polym10101080
Chicago/Turabian StyleZhang, Ju-Hui, Hui-Zhen Yang, Ji Zhang, Yan-Hong Liu, Xi He, Ya-Ping Xiao, and Xiao-Qi Yu. 2018. "Biodegradable Gene Carriers Containing Rigid Aromatic Linkage with Enhanced DNA Binding and Cell Uptake" Polymers 10, no. 10: 1080. https://doi.org/10.3390/polym10101080