Effect of surface decoration on properties and drug release ability of nanogels

Abstract

Nanogels are a central class of biomaterials widely used in the field of drug delivery for the treatment of different pathologies such as tumors, cardiovascular diseases or central nervous system disorders. The great peculiarity of these systems is that, if properly surface functionalized, they are able to target specific body tissues and exploit precise targeted drug delivery. Anyway, the presence of a surface layer on the nanoparticle core can affect not only the biological behavior of the whole system but also its physical and drug delivery properties. In this work we investigated how the presence of different surface functionalization strategies on the same PEG-PEI nanogel framework influences the aforementioned peculiarities. The nanogels were functionalized with amine and pyridinic groups, while the properties analyzed and compared were the hydrodynamic diameter, the ζ-potential and the drug release ability. Moreover, we performed the evaluation of the cytocompatibility of the final nano-carrier and a molecular analysis of the surface features of these systems at microscopic level.

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.