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Theranostic constructs combine both therapeutic and diagnostic properties in a single platform (1,2). As such, these systems have recently gained significant attention because of their promise in visualizing therapeutic intervention. Recent progress in both the nanotechnology fabrication front and diagnostic modalities are advancing the design and application of these tools for different disease states (3–7). The attractive aspects of the approach stems from the idea that such systems can simultaneously function to improve drug therapy by localizing drug delivery (6,8–11), guide the delivery process by visualizing the biodistribution of nanoparticle-based therapies and hence facilitate “positioning the dose” for early-stage particulate-based drug development process (6,8–11), or improve upon conventional therapies such as radiation or hyperthermia (12–14). Toward that goal of combining multiple functionalities into a single platform, one of the encumbering issues remains optimization of the therapeutic and imaging agent concentrations in the theranostic platform for realization of effective localized drug delivery and noninvasive imaging. Progress in this area, especially with safe biodegradable materials will yield an optimal platform that function effectively for both treatment and monitoring of targeted drug delivery. Of the different imaging systems available to researchers and clinicians, magnetic resonance (MR) imaging is attractive for noninvasive imaging. Not only because of its ability to image deep into tissue with sufficient sensitivity, and spatiotemporal resolution through the use of appropriate contrast agents, but also because of its safety, wide availability of magnetic resonance imaging (MRI) scanners, and hence, clinical relevance. In MR, the signal strength is directly related to the relaxation rates of protons in the local environment, (r1, the longitudinal relaxation rate, and r2, the transverse relaxation rate). Because of this correlation, agents that enhance the rate of either relaxation are important as MR contrast agents. While commercially available dextran-coated superparamagnetic iron oxides (SPIOs) (e.g., Molday Ion) are excellent r2 (or T2-inverse relaxation rate) contrast agents, their theranostic utility is limited (Table 1) (15). For example, dextran-coated SPIO are limited in their drug loading capacity and the weak associations of these coatings can often lead to aggregation and precipitation under physiological conditions (16). For these reasons, alternative iron-oxide-polymer hybrid systems (3,4,17–20) have been sought. Of those, polyester-based systems, such as poly(lactide), poly(glycolide), or their copolymer (poly(lactide-co-glycolide) (PLGA)), coated iron oxides have gained attention because of their established physiological biocompatibility, tunable biodegradation, and well-understood formulation conditions for encapsulation and release of a wide range of therapeutics (21–23). These iron-oxide-polymer hybrid systems are nontoxic and have demonstrated utility for in vivo cell tracking and therapeutic delivery such as simultaneous priming of antigen and imaging of cell trafficking (22). Table 1 Commercial Superparamagnetic Iron Oxide Agents (15) In this work, we developed a multifunctional theranostic platform that facilitates targeting through a new method for surface modification of biodegradable polyester systems (24), controlled release of therapeutics, and maintenance of MR imaging capability during controlled release. One of the main motivations behind the design of the platform was to demonstrate the ability to not only incorporate multiple functions but to introduce a methodology for maintaining imaging capabilities during controlled release. We demonstrate the versatile use of fatty acids as hydrophobic anchors that strongly associate with the PLGA matrix (24,25), affording presentation of targeting ligand conjugates on the PLGA nanoparticle surface to increase cellular targeting and internalization into cells. Furthermore, we show that fatty acids not only allow co-encapsulation and prolonged retention as hydrophobic stabilizers for SPIO, but afford varying degrees of SPIO aggregation resulting in an enhanced and controllable system for MR imaging. This system, thus, preserves biocompatibility and maintains imaging characteristics without hindering the controlled release of small-molecule therapeutics. |
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