Surface Exposure of PEG and Amines on Biodegradable Nanoparticles as a Strategy to Tune Their Interaction with Protein-Rich Biological Media
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Polymer Synthesis
2.2.1. Synthesis of mPEG-PCL Diblock Copolymers
2.2.2. Synthesis of Diamine-PCL (NH2-PCL4k-NH2)
2.3. Polymer Characterization
2.4. Preparation and Characterization of Nanoparticles
2.5. Evaluation of NP Surface Features
2.6. Interactions with Proteins
2.7. Permeation of NPs through Gel-Like Barriers
2.8. NP Interaction with Human Immune Cells
2.8.1. Monocyte Isolation
2.8.2. NP Uptake
2.8.3. Monocyte Activation
3. Results and Discussion
3.1. Synthesis and Characterization of the Polymers
3.2. Nanoparticle Properties
3.3. Extent of Nanoparticle PEGylation
3.4. Nanoparticle Interactions with Proteins in Solution
3.5. Permeation through Protein-Rich Gels
3.6. Uptake and Immune Activation
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Grossen, P.; Witzigmann, D.; Sieber, S.; Huwyler, J. PEG-PCL-based nanomedicines: A biodegradable drug delivery system and its application. J. Control. Release 2017, 260, 46–60. [Google Scholar] [CrossRef] [PubMed]
- Conte, C.; d’Angelo, I.; Miro, A.; Ungaro, F.; Quaglia, F. PEGylated polyester-based nanoncologicals. Curr. Top. Med. Chem. 2014, 14, 1097–1114. [Google Scholar] [CrossRef] [PubMed]
- Venuta, A.; Moret, F.; Dal Poggetto, G.; Esposito, D.; Fraix, A.; Avitabile, C.; Ungaro, F.; Malinconico, M.; Sortino, S.; Romanelli, A.; et al. Shedding light on surface exposition of poly(ethylene glycol) and folate targeting units on nanoparticles of poly(epsilon-caprolactone) diblock copolymers: Beyond a paradigm. Eur. J. Pharm. Sci. 2018, 111, 177–185. [Google Scholar] [CrossRef] [PubMed]
- Quaglia, F.; Ostacolo, L.; De Rosa, G.; La Rotonda, M.I.; Ammendola, M.; Nese, G.; Maglio, G.; Palumbo, R.; Vauthier, C. Nanoscopic core-shell drug carriers made of amphiphilic triblock and star-diblock copolymers. Int. J. Pharm. 2006, 324, 56–66. [Google Scholar] [CrossRef] [PubMed]
- Harris, J.M.; Chess, R.B. Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov. 2003, 2, 214–221. [Google Scholar] [CrossRef] [PubMed]
- Swierczewska, M.; Lee, K.C.; Lee, S. What is the future of PEGylated therapies? Expert Opin. Emerg. Drugs 2015, 20, 531–536. [Google Scholar] [CrossRef] [PubMed]
- Xu, Q.; Ensign, L.M.; Boylan, N.J.; Schon, A.; Gong, X.; Yang, J.C.; Lamb, N.W.; Cai, S.; Yu, T.; Freire, E.; et al. Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo. ACS Nano 2015, 9, 9217–9227. [Google Scholar] [CrossRef] [PubMed]
- Huckaby, J.T.; Lai, S.K. PEGylation for enhancing nanoparticle diffusion in mucus. Adv. Drug Deliv. Rev. 2018, 124, 125–139. [Google Scholar] [CrossRef] [PubMed]
- Shen, Z.; Nieh, M.-P.; Li, Y. Decorating Nanoparticle Surface for Targeted Drug Delivery: Opportunities and Challenges. Polymers 2016, 8, 83. [Google Scholar] [CrossRef] [PubMed]
- Chen, B.; Le, W.; Wang, Y.; Li, Z.; Wang, D.; Ren, L.; Lin, L.; Cui, S.; Hu, J.J.; Hu, Y.; et al. Targeting Negative Surface Charges of Cancer Cells by Multifunctional Nanoprobes. Theranostics 2016, 6, 1887–1898. [Google Scholar] [CrossRef]
- Wang, H.-X.; Zuo, Z.-Q.; Du, J.-Z.; Wang, Y.-C.; Sun, R.; Cao, Z.-T.; Ye, X.-D.; Wang, J.-L.; Leong, K.W.; Wang, J. Surface charge critically affects tumor penetration and therapeutic efficacy of cancer nanomedicines. Nano Today 2016, 11, 133–144. [Google Scholar] [CrossRef]
- Sun, Q.; Ojha, T.; Kiessling, F.; Lammers, T.; Shi, Y. Enhancing Tumor Penetration of Nanomedicines. Biomacromolecules 2017, 18, 1449–1459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stylianopoulos, T.; Soteriou, K.; Fukumura, D.; Jain, R.K. Cationic nanoparticles have superior transvascular flux into solid tumors: Insights from a mathematical model. Ann. Biomed. Eng. 2013, 41, 68–77. [Google Scholar] [CrossRef] [PubMed]
- Bilensoy, E. Cationic nanoparticles for cancer therapy. Expert Opin. Drug Deliv. 2010, 7, 795–809. [Google Scholar] [CrossRef] [PubMed]
- Reisch, A.; Runser, A.; Arntz, Y.; Mély, Y.; Klymchenko, A.S. Charge-Controlled Nanoprecipitation as a Modular Approach to Ultrasmall Polymer Nanocarriers: Making Bright and Stable Nanoparticles. ACS Nano 2015, 9, 5104–5116. [Google Scholar] [CrossRef] [PubMed]
- Esposito, D.; Conte, C.; Dal Poggetto, G.; Russo, A.; Barbieri, A.; Ungaro, F.; Arra, C.; Russo, G.; Laurienzo, P.; Quaglia, F. Biodegradable nanoparticles bearing amine groups as a strategy to alter surface features, biological identity and accumulation in a lung metastasis model. J. Mater. Chem. B 2018, 6, 5922–5930. [Google Scholar] [CrossRef]
- Monopoli, M.P.; Åberg, C.; Salvati, A.; Dawson, K.A. Biomolecular coronas provide the biological identity of nanosized materials. Nat. Nanotechnol. 2012, 7, 779. [Google Scholar] [CrossRef] [PubMed]
- Corbo, C.; Molinaro, R.; Parodi, A.; Toledano Furman, N.E.; Salvatore, F.; Tasciotti, E. The impact of nanoparticle protein corona on cytotoxicity, immunotoxicity and target drug delivery. Nanomedicine 2016, 11, 81–100. [Google Scholar] [CrossRef] [Green Version]
- Boraschi, D.; Italiani, P.; Palomba, R.; Decuzzi, P.; Duschl, A.; Fadeel, B.; Moghimi, S.M. Nanoparticles and innate immunity: New perspectives on host defence. Semin. Immunol. 2017, 34, 33–51. [Google Scholar] [CrossRef]
- Shi, B.; Fang, C.; Pei, Y. Stealth PEG-PHDCA niosomes: Effects of Chain Length of PEG and Particle Size on Niosomes Surface Properties, In Vitro Drug Release, Phagocytic Uptake, In Vivo Pharmacokinetics and Antitumor Activity. J. Pharm. Sci. 2006, 95, 1873–1887. [Google Scholar] [CrossRef]
- Abdelbary, A.A.; Li, X.; El-Nabarawi, M.; Elassasy, A.; Jasti, B. Effect of fixed aqueous layer thickness of polymeric stabilizers on zeta potential and stability of aripiprazole nanosuspensions. Pharm. Dev. Technol. 2013, 18, 730–735. [Google Scholar] [CrossRef]
- Ungaro, F.; d’Angelo, I.; Coletta, C.; d’Emmanuele di Villa Bianca, R.; Sorrentino, R.; Perfetto, B.; Tufano, M.A.; Miro, A.; La Rotonda, M.I.; Quaglia, F. Dry powders based on PLGA nanoparticles for pulmonary delivery of antibiotics: Modulation of encapsulation efficiency, release rate and lung deposition pattern by hydrophilic polymers. J. Control. Release 2012, 157, 149–159. [Google Scholar] [CrossRef]
- Conte, C.; Mastrotto, F.; Taresco, V.; Tchoryk, A.; Quaglia, F.; Stolnik, S.; Alexander, C. Enhanced uptake in 2D-and 3D-lung cancer cell models of redox responsive PEGylated nanoparticles with sensitivity to reducing extra- and intracellular environments. J. Control. Release 2018, 277, 126–141. [Google Scholar] [CrossRef]
- Wan, F.; Nylander, T.; Klodzinska, S.N.; Foged, C.; Yang, M.; Baldursdottir, S.G.; Nielsen, H.M. Lipid Shell-Enveloped Polymeric Nanoparticles with High Integrity of Lipid Shells Improve Mucus Penetration and Interaction with Cystic Fibrosis-Related Bacterial Biofilms. ACS Appl. Mater. Interfaces 2018, 10, 10678–10687. [Google Scholar] [CrossRef]
- Takeuchi, T.; Kitayama, Y.; Sasao, R.; Yamada, T.; Toh, K.; Matsumoto, Y.; Kataoka, K. Molecularly Imprinted Nanogels Acquire Stealth In Situ by Cloaking Themselves with Native Dysopsonic Proteins. Angew. Chem. Int. Ed. 2017, 56, 7088–7092. [Google Scholar] [CrossRef]
- Fleischer, C.C.; Payne, C.K. Nanoparticle-cell interactions: Molecular structure of the protein corona and cellular outcomes. Acc. Chem. Res. 2014, 47, 2651–2659. [Google Scholar] [CrossRef]
- Pozzi, D.; Colapicchioni, V.; Caracciolo, G.; Piovesana, S.; Capriotti, A.L.; Palchetti, S.; De Grossi, S.; Riccioli, A.; Amenitsch, H.; Laganà, A. Effect of polyethyleneglycol (PEG) chain length on the bio–nano-interactions between PEGylated lipid nanoparticles and biological fluids: From nanostructure to uptake in cancer cells. Nanoscale 2014, 6, 2782–2792. [Google Scholar] [CrossRef]
- Prego, C.; Torres, D.; Alonso, M.J. The potential of chitosan for the oral administration of peptides. Expert Opin. Drug Deliv. 2005, 2, 843–854. [Google Scholar] [CrossRef]
- D’Angelo, I.; Casciaro, B.; Miro, A.; Quaglia, F.; Mangoni, M.L.; Ungaro, F. Overcoming barriers in Pseudomonas aeruginosa lung infections: Engineered nanoparticles for local delivery of a cationic antimicrobial peptide. Colloids Surf. B Biointerfaces 2015, 135, 717–725. [Google Scholar] [CrossRef]
- Chen, H.T.; Kim, S.W.; Li, L.; Wang, S.Y.; Park, K.; Cheng, J.X. Release of hydrophobic molecules from polymer micelles into cell membranes revealed by Forster resonance energy transfer imaging. Proc. Natl. Acad. Sci. USA 2008, 105, 6596–6601. [Google Scholar] [CrossRef]
Code | Composition | Yield (%) | Poloxamer 2 (mg) | DH 3 (nm ± SD) | PI 3 | ζ 4 (mV ± SD) | |
---|---|---|---|---|---|---|---|
PEG-NPs | PEG1K-NPs | PEG1K-PCL4K | 80 | 2.2 | 78 ± 0.3 | 0.224 | −10.2 ± 2.0 |
PEG2K-NPs | PEG2K-PCL4K | 95 | 1.3 | 44 ± 1.3 | 0.160 | −17.1 ± 1.6 | |
PEG5K-NPs | PEG5K-PCL5K | 98 | 1.9 | 44 ± 3.6 | 0.175 | −7.4 ± 1.9 | |
Amine-NPs | Am-NPs | NH2-PCL4K-NH2 | 82 | - | 134 ± 0.3 | 0.128 | 34.3 ± 1.3 |
Amine/PEG-NPs 1 | Am/PEG1K-NPs | NH2-PCL4K-NH2k PEG1K-PCL4K | 93 | 2.4 | 121 ± 2.8 | 0.191 | 28.6 ± 1.0 |
Am/PEG2K-NPs | NH2-PCL4K-NH2 PEG2K-PCL4K | 95 | 1.0 | 99 ± 5.9 | 0.257 | 20.0 ± 2.3 | |
Am/PEG5K-NPs | NH2-PCL4K-NH2 PEG5K-PCL5K | 98 | 1.2 | 94 ± 6.8 | 0.250 | 21.3 ± 2.4 |
Type | Shell Thickness 1 (nm) | Surface PEG 2 (wt %) |
---|---|---|
PEG1K-NPs | 2.5 ± 0.4 | 3 |
PEG2K-NPs | 3.4 ± 0.8 | 11 |
PEG5K-NPs | 4.0 ± 0.2 | 5 |
Am/PEG1K-NPs | 3.5 ± 0.2 | 2 |
Am/PEG2K-NPs | 6.8 ± 1.2 | 4 |
Am/PEG5K-NPs | 11.8 ± 0.9 | 2 |
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Conte, C.; Dal Poggetto, G.; J. Swartzwelter, B.; Esposito, D.; Ungaro, F.; Laurienzo, P.; Boraschi, D.; Quaglia, F. Surface Exposure of PEG and Amines on Biodegradable Nanoparticles as a Strategy to Tune Their Interaction with Protein-Rich Biological Media. Nanomaterials 2019, 9, 1354. https://doi.org/10.3390/nano9101354
Conte C, Dal Poggetto G, J. Swartzwelter B, Esposito D, Ungaro F, Laurienzo P, Boraschi D, Quaglia F. Surface Exposure of PEG and Amines on Biodegradable Nanoparticles as a Strategy to Tune Their Interaction with Protein-Rich Biological Media. Nanomaterials. 2019; 9(10):1354. https://doi.org/10.3390/nano9101354
Chicago/Turabian StyleConte, Claudia, Giovanni Dal Poggetto, Benjamin J. Swartzwelter, Diletta Esposito, Francesca Ungaro, Paola Laurienzo, Diana Boraschi, and Fabiana Quaglia. 2019. "Surface Exposure of PEG and Amines on Biodegradable Nanoparticles as a Strategy to Tune Their Interaction with Protein-Rich Biological Media" Nanomaterials 9, no. 10: 1354. https://doi.org/10.3390/nano9101354