# Multiresponsive Hybrid Microparticles for Stimuli-Responsive Delivery of Bioactive Compounds
## 1 Introduction  
The use of stimuli-responsive or \"smart\" materials is a promising approach in drug delivery to improve the pharmacokinetic parameters and selectivity of active pharmaceutical ingredients (API) while reducing the dosage and side effects [1; 2]. The use of stimuli-responsive materials to develop carriers for drug delivery has been found to be of particular interest in cancer therapy, in which these materials take advantage of the different features of the tumoral environment compared to the healthy one, e.g., lowered interstitial pH [3], high intracellular concentration of glutathione [4; 5] and expression of different enzymes [6; 7], which can be used as triggers. Besides the physiological triggers, the useof external stimuli can also be applied to stimulate and control the release of the payload from the carrier. In cancer therapy, ultrasonic and magnetic fields are the most attractive external stimuli; in fact, their application can increase the temperature of a selected area, providing the \"on-demand\" release of the therapeutic and simultaneously causing cell death by hyperthermia [8]. Hybrid carriers made by combining organic and inorganic materials have demonstrated the ability to respond simultaneously to physical, chemical or biological stimuli and provide a release profile suitable for the API to improve therapeutic efficacy and reduce side effects. Core-shell hybrid systems, where the core is composed of inorganic material and the shell is composed of organic material, generally polymers, are attracting great attention [9]. Iron- and iron-oxide-based particles are good candidates, and they have been extensively investigated in biomedical field as delivery systems and contrast agents and in hyperthermia therapy [10; 11; 12]. However, their main drawback is related to their low stability in solution and their accompanying tendency to form large aggregates and precipitate. Several strategies aiming to overcome this drawback have been reported, in particular dealing with the surface modification by introduction of, e.g., amino, hydroxy and carboxylic functional groups. Polymer coating represents another widely used approach, as it provides a steric barrier improving the colloidal stability and preventing the agglomeration [13; 14]. The properties of the resulting carrier depend on the nature of the coating agent, such as its chemical structure (e.g., hydrophilicity/hydrophobicity and biodegradation characteristics), molecular weight and mechanism of anchoring or attachment (e.g., electrostatic or covalent bonding) [15; 16; 17; 18]. To develop core-shell carriers, natural or synthetic polymers have been considered for the shell [19], among which polysaccharides have received considerable attention due to peculiarities like biodegradability, biocompatibility, low toxicity and presence of different functional groups which allow chemical modification [20]. Among the polysaccharides, chitosan has received great attention due to the high versatility provided by its chemical structure. Chitosan is made of D-glucosamine and N-acetyl D-glucosamine units. The two hydroxyl groups in C3 and C6 and the amino group in the deacetylated D-glucosamine unit are the active sites for further conjugation with inorganic core, therapeutics, targeting ligands and imaging agents. Following the positive results obtained by our group in a previous study [12] in which the aim was to enhance the stability of iron nanoparticles in solution by surface modification and coating, the main aim in the present study was to make the system sensitive to magnetic and ultrasonic fields and variation in the surrounding pH to control the release rate and intensity of a chemotherapeutic drug. Doxorubicin (DOX), has been considered as a model drug. It is an anthracycline antibiotic, and it is currently used in the treatment of leukemia, breast cancer, ovarian cancer and lymphoma [21; 22] Besides the therapeutic efficacy, DOX exhibits severe side effects, such as cardiotoxicity, related to the low selectivity.