Effect of surface decoration on properties and drug release ability of nanogels
Graphical abstract
Introduction
Nano-systems are becoming very attractive materials in many biomedical applications such as drug delivery, tissue engineering or nanodiagnostics [[1], [2], [3]]. Widespread attention has been paid to targeted drug/gene delivery systems that allow the distribution of their cargos to target sites, increasing the therapeutic efficiency [4,5]. Indeed, these devices allow to localize drug effect, limit their side effects due to their lack of interaction with other tissues of the body, protect the drug in vivo from degradation and minimize symptoms and degenerative effects of diseases such as cancer, neurological injuries or cardiovascular diseases [6,7]. Commonly, targeted drug delivery is divided into either “passive” or “active” [8]. Passive drug delivery is based on the differences between normal areas and diseased tissues that determine the accumulation of the carrier in the altered zone and it relies on the different distribution of the drug by blood circulation. Active drug delivery is instead a method aiming to reach a specific biological target, for example thanks to the conjugation of the delivery system with a certain ligand, such as an antibody, specific for a receptor on the surface of a peculiar cell population [9].
Literature presents a wide variety of nanocarriers and especially nanoparticles are able to meet the requirements about targeted delivery, modulation of cell response and controlled release of the cargo [10,11]. Among them, nanogels (NGs) are a very interesting class of nanobiomaterials [12,13]. Their formulation is compatible with biological tissues, due to a high water content and a peculiar carbon-based composition, which impart them biocompatibility and biodegradability. Moreover, NGs have high specific surface, excellent drug encapsulation ability and significant swelling behaviour with a remarkable structure stability and fast response to environmental changes that makes them extremely suitable for the selective target delivery [14,15].
Because of all the aforementioned peculiarities, NGs can be a pivotal device to target cells and treat them with proper drugs and active substances, but the possibility to obtain a selective and effective targeting still remain a big challenge hampered by the high selectivity of absorption of many cellular populations and the multiple membrane barriers to be overcome [16,17].
In order to satisfy these requirements, nanogels surface functionalization may become a strategic tool to impose to the nanosystem specific properties and so tuning its behaviour overcoming biological limitations and unwanted effects [18,19]. Responsive chemical groups or specific molecules can be chemically or physically linked to the NG structure to promote specific interactions with cells receptors and to trigger the endocytosis of the nanocarrier inside the cytosol of the cells [[20], [21], [22], [23]] In fact, there are many examples in literature about how the presence of layers of different nature on a specific core is able to modify the properties of the entire system [[24], [25], [26], [27]].
We have already investigated this aspect in previous works [11,28,29]; nonetheless, since the NGs behaviour in vivo is influenced by the surface physical-chemical properties [30], in this work we are interested in studying how the moieties used to modify the NGs surfaces affect the physical properties of the system and in particular the drug release ability, using rhodamine B (RhB) as a model drug. The NGs tested for our purpose were synthetized with polyethylene glycol (PEG) and linear polyethyleneimine (PEI) and conjugated with a chromophore in order to ensure in vitro detection. The decorative functionalization strategies were realized using two different molecules: the 3-bromopropylamine hydrobromide and the 4-(bromoethyl)pyridine hydrobromide, selected in order to analyze the effect of the presence of an amine functionalization on the surface, in an aliphatic and aromatic form, respectively. Mesoscale simulations of each NG were carried out and established a link between NG properties and microscopic surface features.
Section snippets
Materials
Polymers: linear polyethyleneimine 2500 (Mw = 2.5 kDa, by Polysciences Inc., Warrington, USA) and polyethylene glycol 8000 (Mw = 8 kDa, by Merck KGaA, Darmstadt, Germany). All other chemicals where purchased from Merck (Merck KGaA, Darmstadt, Germany) and used as received, without any further purification. Solvents were of analytical-grade purity. All the rhodamine-based products were stored at 4 °C.
Characterization techniques
Fourier transform infrared (FT-IR) spectra were recorded using the KBr pellet technique for the
Nanogel chemical characterization
The nanogel synthesis was performed with the reaction between the bis-functionalized PEG-CDI and the rhodamine-PEI through the emulsification evaporation method (Fig. 1A). After sonication, the progressive evaporation of CH2Cl2 from the emulsion encourages the homogeneous dispersion of PEG chains around PEI. This conformation is a pivotal condition in order to meet the biocompatibility criteria with the cellular environment. In fact, PEI has shown toxic effects on cells especially when used
Conclusions
In this work we have proposed different decoration strategies on the same nanostructure core. The physical characterization of the final systems together with the drug release tests demonstrated that the presence of a different surface layer on the same nanostructure core determines on the whole system quantifiable differences in its behavior. Moreover, molecular modeling proofs the need of proper control and characterization of the functionalization as well as the role of the molecular
CRediT authorship contribution statement
Filippo Pinelli: Methodology, Validation, Writing - original draft. Fabio Pizzetti: Investigation, Validation. Arianna Rossetti: Methodology, Validation. Zbyšek Posel: Software. Maurizio Masi: Methodology. Alessandro Sacchetti: Investigation, Validation. Paola Posocco: Software, Supervision, Writing - review & editing. Filippo Rossi: Conceptualization, Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
ZP would like to acknowledge financial support from ERDF/ESF project "UniQSurf-Centre of biointerfaces and hybrid functional materials "(No. CZ.02.1.01/0.0/17_048/0007411) and from IGA UJEP (grant no. UJEP-IGA-TC-2019-53-02-2).
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