Insights into Protein-Ionic Liquid Interactions Aiming at Macromolecule Delivery Systems

Over the last few years, researchers have started to explore a particular class of compounds defined as ionic liquids (ILs) in attempts to use their unique characteristics. Since ILs have a very low vapor pressure, these fascinating compounds hold great potential as high performance chemicals for several applications in the (bio)pharmaceutical industry. In general, and unlike common organic solvents with comparable polarities, ILs are quite compatible with enzymes (enhancing their structural and chemical stability) and other proteins, since they can promote higher selectivities, faster reaction rates and greater enzyme stabilities in biocatalytic reactions providing, at the same time, a path for the structural and functional stabilization of protein entities. ILs appear to enhance the delivery of macromolecules, particularly protein entities, and their interactions with ILs will be tackled in detail in this review paper.

Keywords:
ionic liquids; structural and functional stabilization; protein stability; biopharmaceutical applications; transdermal drug delivery

Authorship

Liliam K. Harada

Grupo de Pesquisa Intelligent Biosensing and Biomolecule Stabilization (i(bs)²), Laboratório de Biofilmes e Bacteriófagos (PhageLab), Universidade de Sorocaba, 18023-000 Sorocaba-SP, BrazilUniversidade de SorocabaBrazilSorocaba, SP, BrazilGrupo de Pesquisa Intelligent Biosensing and Biomolecule Stabilization (i(bs)²), Laboratório de Biofilmes e Bacteriófagos (PhageLab), Universidade de Sorocaba, 18023-000 Sorocaba-SP, Brazil

Liliam K. Harada holds a degree in Pharmacy from the University of Sorocaba (2010). She has experience in the field of Pharmacy, with emphasis on allopathic, homeopathic and anthroposophical manipulation, as well as training in floral therapy, and post graduation in acupuncture. She completed a master's degree in Pharmaceutical Sciences from the University of Sorocaba, with a scholarship awarded by FAPESP (Ref. No. 2016/16641-3), and is currently developing research projects leading to the doctor degree, aiming at the development of a biosensor based in phage particles for the detection of Pseudomonas aeruginosa.

Jorge F. B. Pereira

Departamento de Bioprocessos e Biotecnologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista (Unesp), 14800-901 Araraquara-SP, BrazilUniversidade Estadual PaulistaBrazilAraraquara, SP, BrazilDepartamento de Bioprocessos e Biotecnologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista (Unesp), 14800-901 Araraquara-SP, Brazil

Jorge F. B. Pereira is since July 2014, Assistant Professor of the Department of Bioprocesses and Biotechnology of the Faculty of Pharmaceutical Sciences, Universidade Estadual Paulista (Unesp, Araraquara) and professor accredited in the Postgraduate Program in Biosciences and Biotechnology applied to Pharmacy (CAPES 7). He holds a Doctor of Chemical Engineering degree from the Department of Chemistry of the University of Aveiro (2009-2013). The main areas of activity are focused on the development of alternative separation and purification processes for the purification of biopharmaceuticals using ionic liquids; and study of molecular interactions of separation processes using ionic liquids.

Welida F. Campos

Welida F. Campos holds a degree in Bioprocess Engineering and Biotechnology from the University of Sorocaba (Uniso, 2017). For 11 months, she developed her research activities at the Laboratory of Biofilms and Bacteriophages (PhageLab, Uniso) in the scope of her undergraduate thesis, currently continuing as a Master's Student in Pharmaceutical Sciences in the same Laboratory. Her research project aims at the isolation and purification of bacteriophage particles aiming at their transdermal permeation using ionic liquids for the eradication of deep skin infections.

Erica C. Silva

Erica C. Silva holds a degree in Bioprocess Engineering and Biotechnology from the University of Sorocaba (Uniso, 2017). For 11 months, she developed her research activities at the Laboratory of Biofilms and Bacteriophages (PhageLab, Uniso) in the scope of her undergraduate thesis, currently continuing as a Master's Student in Pharmaceutical Sciences in the same Laboratory. Her research project aims at the isolation and purification of bacteriophage particles aiming at their incorporation in IL/O microemulsions for the eradication of skin infections in veterinary applications.

Carla G. Moutinho

Energy, Environment and Health Research Unit (FP-ENAS), University Fernando Pessoa, 4249-004 Porto, PortugalUniversity Fernando PessoaPortugalPorto, PortugalEnergy, Environment and Health Research Unit (FP-ENAS), University Fernando Pessoa, 4249-004 Porto, Portugal

Carla S. G. Moutinho graduated in Pharmaceutical Chemistry from the University of Porto in 2000. She is an Associate Professor at University Fernando Pessoa (Porto, Portugal). She has published 38 articles in specialized magazines and 49 works in event proceedings, has 2 book chapters and 3 books published. She participated in 52 events abroad and two in Portugal. She works in the areas of Medical Sciences with emphasis on Health Sciences and Exact Sciences with emphasis on Chemistry, specifically with anti-neoplastics, liposomes, mixed micelles, fatty acids, antioxidants, beta-blockers and benzodiazepines, and micellar systems (mixed and simple).

Marta M. D. C. Vila

Marta M. D. C. Vila holds a bachelor's degree in Pharmacy and Biochemistry from the University of São Paulo (1984), a degree in Industrial Pharmacy from the Pontifical Catholic University of Campinas (1985), a Master's degree in Food Technology from the State University of Campinas (1996) and a PhD in Chemistry from the State University of Campinas (2002). She is a lecturer at the University of Sorocaba (Uniso) in the Graduate Program in Pharmaceutical Sciences. She has developed projects related to the study of new formulations, bioavailability of active principles and new systems of drug release.

José M. Oliveira Jr.

José M. Oliveira Jr. is a bachelor in Physics from the State University of Londrina (1985), Master in Nuclear Physics from the University of São Paulo (1988) and PhD in Sciences, with emphasis in Nuclear Physics by the University of São Paulo (1994). Currently holds the position of Pro-Rector of Postgraduate, Research, Extension and Innovation of the University of Sorocaba. He is full professor of the Postgraduate Program in Pharmaceutical Sciences. He has worked mainly in the study of nuclear reactions and spectroscopic properties of exotic nuclei; use of CT technique and attenuation of gamma radiation and X-rays in non-destructive studies of biological materials and systems.

José A. Teixeira

Centre of Biological Engineering (CEB), University of Minho, 4710-057 Braga, PortugalUniversity of MinhoPortugalBraga, PortugalCentre of Biological Engineering (CEB), University of Minho, 4710-057 Braga, Portugal

José A. Teixeira holds a degree in Chemical Engineering from the University of Porto (1980) and a PhD in Chemical Engineering from the Faculty of Engineering of the University of Porto (1988). He is currently Professor at the Biological Engineering Department of the University of Minho, Braga, Portugal. He has experience in Chemical Engineering, with emphasis in Chemical Engineering and Biotechnology, working mainly in the following subjects: biological reactors, multiphase systems, food technology, biological separation processes.

Victor M. Balcão ^**e-mail: victor.balcao@prof.uniso.br; tubino@iqm.unicamp.br

Victor M. Balcão is an Adjunct Professor I, RG at the University of Sorocaba (Brazil), where he also coordinates the Laboratory of Biofilms and Bacteriophages (PhageLab), being a Productivity in Research fellow, level 2, of CNPq (308208/2017-0). He graduated in 1991 in Food Engineering from the College of Biotechnology of the Portuguese Catholic University (ESB-UCP), and received a doctorate in Biotechnology in 12/1998 from ESB-UCP. On 04/11/2013, he obtained Recognition of the Doctor degree from University of São Paulo (Diploma registered under number 116247, Article 48 of Law 9394/96). Its scientific activity has focused on the structural and functional stabilization of protein entities for (bio)pharmaceutical applications.

Matthieu Tubino ^**e-mail: victor.balcao@prof.uniso.br; tubino@iqm.unicamp.br

Instituto de Química, Universidade Estadual de Campinas (Unicamp), 13083-0970 Campinas-SP, BrazilUniversidade Estadual de CampinasBrazilCampinas, SP, BrazilInstituto de Química, Universidade Estadual de Campinas (Unicamp), 13083-0970 Campinas-SP, Brazil

Matthieu Tubino holds a Bachelor's Degree in Chemistry from the University of São Paulo (1970), a Master's Degree in Chemistry from the State University of Campinas (1975), a PhD in Chemistry from the State University of Campinas (1978), postdoctoral degree from Institut de Chimie Minérale et Analytique of the Université de Lausanne, Switzerland. He is a full professor at the Institute of Chemistry of the State University of Campinas. He has experience in reaction mechanisms, diffuse reflectance analysis in ultraviolet-visible, analytical methods for application in industrial matrices including biodiesel.

*e-mail: victor.balcao@prof.uniso.br; tubino@iqm.unicamp.br

Liliam K. Harada holds a degree in Pharmacy from the University of Sorocaba (2010). She has experience in the field of Pharmacy, with emphasis on allopathic, homeopathic and anthroposophical manipulation, as well as training in floral therapy, and post graduation in acupuncture. She completed a master's degree in Pharmaceutical Sciences from the University of Sorocaba, with a scholarship awarded by FAPESP (Ref. No. 2016/16641-3), and is currently developing research projects leading to the doctor degree, aiming at the development of a biosensor based in phage particles for the detection of Pseudomonas aeruginosa.

Jorge F. B. Pereira is since July 2014, Assistant Professor of the Department of Bioprocesses and Biotechnology of the Faculty of Pharmaceutical Sciences, Universidade Estadual Paulista (Unesp, Araraquara) and professor accredited in the Postgraduate Program in Biosciences and Biotechnology applied to Pharmacy (CAPES 7). He holds a Doctor of Chemical Engineering degree from the Department of Chemistry of the University of Aveiro (2009-2013). The main areas of activity are focused on the development of alternative separation and purification processes for the purification of biopharmaceuticals using ionic liquids; and study of molecular interactions of separation processes using ionic liquids.

Welida F. Campos holds a degree in Bioprocess Engineering and Biotechnology from the University of Sorocaba (Uniso, 2017). For 11 months, she developed her research activities at the Laboratory of Biofilms and Bacteriophages (PhageLab, Uniso) in the scope of her undergraduate thesis, currently continuing as a Master's Student in Pharmaceutical Sciences in the same Laboratory. Her research project aims at the isolation and purification of bacteriophage particles aiming at their transdermal permeation using ionic liquids for the eradication of deep skin infections.

Erica C. Silva holds a degree in Bioprocess Engineering and Biotechnology from the University of Sorocaba (Uniso, 2017). For 11 months, she developed her research activities at the Laboratory of Biofilms and Bacteriophages (PhageLab, Uniso) in the scope of her undergraduate thesis, currently continuing as a Master's Student in Pharmaceutical Sciences in the same Laboratory. Her research project aims at the isolation and purification of bacteriophage particles aiming at their incorporation in IL/O microemulsions for the eradication of skin infections in veterinary applications.

Carla S. G. Moutinho graduated in Pharmaceutical Chemistry from the University of Porto in 2000. She is an Associate Professor at University Fernando Pessoa (Porto, Portugal). She has published 38 articles in specialized magazines and 49 works in event proceedings, has 2 book chapters and 3 books published. She participated in 52 events abroad and two in Portugal. She works in the areas of Medical Sciences with emphasis on Health Sciences and Exact Sciences with emphasis on Chemistry, specifically with anti-neoplastics, liposomes, mixed micelles, fatty acids, antioxidants, beta-blockers and benzodiazepines, and micellar systems (mixed and simple).

Marta M. D. C. Vila holds a bachelor's degree in Pharmacy and Biochemistry from the University of São Paulo (1984), a degree in Industrial Pharmacy from the Pontifical Catholic University of Campinas (1985), a Master's degree in Food Technology from the State University of Campinas (1996) and a PhD in Chemistry from the State University of Campinas (2002). She is a lecturer at the University of Sorocaba (Uniso) in the Graduate Program in Pharmaceutical Sciences. She has developed projects related to the study of new formulations, bioavailability of active principles and new systems of drug release.

José M. Oliveira Jr. is a bachelor in Physics from the State University of Londrina (1985), Master in Nuclear Physics from the University of São Paulo (1988) and PhD in Sciences, with emphasis in Nuclear Physics by the University of São Paulo (1994). Currently holds the position of Pro-Rector of Postgraduate, Research, Extension and Innovation of the University of Sorocaba. He is full professor of the Postgraduate Program in Pharmaceutical Sciences. He has worked mainly in the study of nuclear reactions and spectroscopic properties of exotic nuclei; use of CT technique and attenuation of gamma radiation and X-rays in non-destructive studies of biological materials and systems.

José A. Teixeira holds a degree in Chemical Engineering from the University of Porto (1980) and a PhD in Chemical Engineering from the Faculty of Engineering of the University of Porto (1988). He is currently Professor at the Biological Engineering Department of the University of Minho, Braga, Portugal. He has experience in Chemical Engineering, with emphasis in Chemical Engineering and Biotechnology, working mainly in the following subjects: biological reactors, multiphase systems, food technology, biological separation processes.

Victor M. Balcão is an Adjunct Professor I, RG at the University of Sorocaba (Brazil), where he also coordinates the Laboratory of Biofilms and Bacteriophages (PhageLab), being a Productivity in Research fellow, level 2, of CNPq (308208/2017-0). He graduated in 1991 in Food Engineering from the College of Biotechnology of the Portuguese Catholic University (ESB-UCP), and received a doctorate in Biotechnology in 12/1998 from ESB-UCP. On 04/11/2013, he obtained Recognition of the Doctor degree from University of São Paulo (Diploma registered under number 116247, Article 48 of Law 9394/96). Its scientific activity has focused on the structural and functional stabilization of protein entities for (bio)pharmaceutical applications.

Matthieu Tubino holds a Bachelor's Degree in Chemistry from the University of São Paulo (1970), a Master's Degree in Chemistry from the State University of Campinas (1975), a PhD in Chemistry from the State University of Campinas (1978), postdoctoral degree from Institut de Chimie Minérale et Analytique of the Université de Lausanne, Switzerland. He is a full professor at the Institute of Chemistry of the State University of Campinas. He has experience in reaction mechanisms, diffuse reflectance analysis in ultraviolet-visible, analytical methods for application in industrial matrices including biodiesel.

SCIMAGO INSTITUTIONS RANKINGS

Figures

Figures (11)

Thumbnail

Figure 1
Comparison between a typical inorganic salt (a), e.g. sodium chloride, and a typical ionic liquid (b).

Thumbnail

Figure 2
Putative interactions (dotted lines representing hydrogen bonding and arrows representing strong Coulomb interactions) between solvent species with a protein surface, at high ion concentrations (adapted from reference 51).

Thumbnail

Figure 3
Relationship between ILs and poorly soluble (macro)molecules in the development of IL-protein formulations for transdermal delivery (adapted from ^{reference 105}105 Wiest, J.; Saedtler, M.; Balk, A.; Merget, B.; Widmer, T.; Bruhn, H.; Raccuglia, M.; Walid, E.; Picard, F.; Stopper, H.; Dekant, W.; Lühmann, T.; Sotriffer, C.; Galli, B.; Holzgrabe, U.; Meinel, L.; J. Controlled Release 2017, 268, 314.).

Figure 1 Comparison between a typical inorganic salt (a), e.g. sodium chloride, and a typical ionic liquid (b).

Figure 2 Putative interactions (dotted lines representing hydrogen bonding and arrows representing strong Coulomb interactions) between solvent species with a protein surface, at high ion concentrations (adapted from reference 51).

Figure 3 Relationship between ILs and poorly soluble (macro)molecules in the development of IL-protein formulations for transdermal delivery (adapted from ^{reference 105}105 Wiest, J.; Saedtler, M.; Balk, A.; Merget, B.; Widmer, T.; Bruhn, H.; Raccuglia, M.; Walid, E.; Picard, F.; Stopper, H.; Dekant, W.; Lühmann, T.; Sotriffer, C.; Galli, B.; Holzgrabe, U.; Meinel, L.; J. Controlled Release 2017, 268, 314.).

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Insights into Protein-Ionic Liquid Interactions Aiming at Macromolecule Delivery Systems

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[1] *e-mail: victor.balcao@prof.uniso.br; tubino@iqm.unicamp.br