Imaging‐Guided Targeted Drug Delivery using Stimuli‐Sensitive Theranostic Nanoparticles: Characterization and In Vivo Trafficking Patterns

Abstract

Purpose : In type 1 diabetes (T1D), the existing delivery systems for insulin all suffer from the inability to regulate insulin without patient intervention. A major unmet medical need is to develop innovative strategy, which would increase the efficacy of immune therapeutics but also, reduce their toxicity. Targeted drug carriers using polymeric nanoparticles (NP) holds particular promise to enhance the delivery of immunoregulatory agents to treat T1D. The aim of this study was to synthesize and characterize the in vivo trafficking patterns of stimuli-responsive, thermosensitive, immunoregulatory-carriers for potential use in image-guided targeted delivery and on site controlled release. Methods : A number of metal nanoparticles with hyperthermia magnetic (HMNs) properties made out of Gd-Zn-Fe were fabricated that intrinsically have the ability to self-regulate their heating level to the desired therapeutic range, Curie temperature (Tc). Production of particles of uniform size and shape was ensured by constant reaction kinetics and efficient physical and chemical reactions in solution. The particles morphology was examined using electron microscopy. The size distribution was evaluated using Malvern Nanosizer device. Magnetic resonance imaging (MRI) relaxivities of HMNs were measured over a range of 25-45°C. Non-targeted and MECA79-targeted HMNs were engineered using self-assembly nanoprecipitation method. Targeted trafficking of MECA79-HMNs in skin transplanted NOD mice with distinctive lymphatic draining to the draining lymph nodes (DLN) was evaluated. To be able to image the particles, particles were coated with IRDye 800CW. Using iBox, live fluorescence imaging was carried out 8 days post transplantation (24 hours post IV administration). Results : The temperature of HMN (with Tc 38-40°C) rose only up to the Tc when the particles were subjected to an oscillating magnetic field, and further increasing the intensity of the field did not increase heating beyond their Tc. Increasing Gd ratio modulated Tc linearly with amount of Gd-substituted Zn Ferrite particles (Figure 1A). NPs TEM micrograph showed a dispersion of spherical particles with a narrow size distribution (Figure 1B). MRI relaxivities, R1 and R2, showed linear increase of the relaxation rate. Twenty-four hours post IV administration, there was a significant increase in the trafficking of MECA79 conjugated particles as compared to the non-targeted NPs to the DLN in the skin transplanted NOD mice (Figure 2). Conclusion : Nanomedicine's application of ITS to T1D remains to be developed. While there are a number of delivery approaches that target the LN, virtually all of them rely on passive lymphatic absorption (i.e., intradermal injection). Data presented here represent major achievements to establish for the first time systemic delivery of particles to specific sites in diabetic mice. These experiments serve the basis for developing more of multifunctional NPs.