Environment-Sensitive Multifunctional Drug Delivery Systems

Abstract: Drug delivery systems (DDS) with multiple functionalities such as environment-sensitive drug release mechanisms and visualization agents have motivated the biomedical community as well as materials chemists for more than a decade. This dissertation is concerned with the development of nanoparticles for multifunctional DDS  to tackle several crucial challenges in these complex systems, including polymeric nanospheres which respond to temperature change, superparamagnetic iron oxide nanoparticles/polymeric composite for magnetic resonance imaging contrast agents and drug carriers, immunoresponse of nanomaterials and injectable magnetic field sensitive ferrogels.The biocompatible and biodegradable polylactide (PLA) was employed as matrix materials for polymeric nanosphere-based DDS. The thermosensitive polymeric nanospheres have been constructed through a “modified double-emulsion method”. The inner shell containing the thermosensitive poly(N-isopropylacrylamide) (PNIPAAm) undergoes a “hydrophilic-to-hydrophobic” phase transition around the human body temperature. The sensitivity of the polymer to the temperature can facilitate drug release at an elevated temperature upon administration. In addition, gold nanoparticles were assembled on the dual-shell structure to form a layer of gold shell. The cell viability was found to be enhanced due to the gold layer. The immunoresponse of the gold nanoparticles has been considered even if no acute cytotoxicity was observed.Imaging is another functionality of multifunctional DDS. This work focuses on magnetic resonance imaging (MRI) and involves synthesis and surface modification of superparamagnetic iron oxide nanoparticles (SPIONs) for contrast agents. The SPIONs have been prepared through a high temperature decomposition method. Surface modification was carried out in different ways. Poly(L,L-lactide) (PLLA) was grafted on SPIONs through surface-initiated ring-opening polymerization. The hydrophobic model drug indomethacin was loaded in the PLLA layer of the composite particles. For biomedical applications, it is essential to modify the hydrophobic particles so that they can be dispersed in physiological solutions. A series of protocols including using small charged molecules and amphiphilic polymers has been established. Pluronic F127 (PF127), a triblock copolymer was applied as a phase transfer reagent. Most interestingly, PF127@SPIONs show remarkable efficacy as T2 contrast agents. The PF127@SPIONs have been successfully applied to image the cochlea in a rat model. As another phase transfer reagent, poly(maleic anhydride-alt-octadecene)-graft-PNIPAAm (PMAO-graft-PNIPAAm) was created for surface modification of SPIONs. This new copolymer provides the modified SPIONs with thermosensitivity together with water-dispersibility.As another form of DDS, ferrogel made of PF127 copolymer and SPIONs was developed. Gelation process depends on the temperature of the SPIONs/PF127 mixture. This property makes it possible to use the ferrogel as an injectable drug carrier. Unlike other ferrogels based on crosslinked polymeric network, the PF127 ferrogel can entrap and release hydrophobic drugs. Application of an external magnetic field is found to enhance the drug release rate. This property can find application in externally stimulated local drug release applications.