ABSTRACT
Figure 3.1 A thermoresponsive nanogel in its swollen state (T < VPTT) and in its shrunken state (T > VTPP) and schematic representation of a swollen and collapsed nanoparticle. The most frequently used family of responsive polymers in the synthesis of sensitive nanogels is that of temperature-sensitive poly(alkylacrylamides), more specifically poly(Nisopropylacrylamide (PNIPAM). However, its toxicity prevents its use in biomedical applications (Ramos et al., 2012). Nevertheless, during the past few years a number of articles and patents have appeared on this type of nanogels. Among biocompatible and temperature-sensitive monomers there is N-vinylcaprolactam (VCL) (Vihola et al., 2005), which is a water-soluble monomer. The corresponding polymer, poly(N-vinylcaprolactam) (PVCL),
combines useful and important properties because, together with its biocompatibility, it has a phase transition in the physiological temperature region (32°C-38°C). This combination of properties allows it to be considered as an adequate material for the design of biomedical devices and useful in drug delivery systems (Ramos et al., 2014). Another type of sensitivity that is relevant to biomedical applications is the response to pH changes. This is the case of pHsensitive nanogels: they swell when pH approximates the pKa of the ionic monomer incorporated by copolymerization in the crosslinked chains constituting the particles. These nanogels are useful in the case of releasing a biologically active compound in a physiological medium in which the main characteristic is the change in pH. pH-sensitive nanogels are composed of crosslinked polyelectrolytes with weakly acidic (i.e., carboxylic) or weakly basic (i.e., amino) groups that can be used either as proton donors or receptors or through a combination of both. The choice of polymer depends on the physiological conditions of the target in which the delivery is needed. pH-responsive nanogels are able to swell in response to small pH variations, showing a volume phase transition pH (VPTpH). Below this transition pH, nanogel particles are swollen, and above it, they are shrunken. The volume change is ascribed to the enhanced electrostatic repulsion among charges within the polymer network that appears due to the ionization of ionizable groups varying the pH. Considering this interesting property, they can be used at different levels: at the organ level, as the gastrointestinal tract is characterized by pH gradients; at the tissue level, taking advantage of the characteristic acidic extracellular environment of unhealthy tissues different from healthy tissues; and at the cellular level, since endolysosomes are more acidic in comparison to the cytoplasm (Gao et al., 2010; Zha et al., 2011). As commented above, RPNPs for biomedical applications are complex nanomaterials demanding multifunctional properties. In this sense, apart from thermosensitivity other responsiveness is usually required. The design of multisensitive nanogels is well documented in the literature and basically it can be obtained by incorporating different stimulus responsive polymers into their network via (i) copolymerization of several monomers or (ii) “seed and feed” process.
