278941 Magnetic Resonance Imaging As a Powerful Tool for Visualizing Controlled Release From Biodegradable Microparticles

Tuesday, October 30, 2012: 2:30 PM
Allegheny III (Westin )
Tianzhou Wu1,2, Lilian Ngobi1,2, Sam N. Rothstein1,2, Steven R. Yutzy3, Eric Wiener3, Robert S. Parker1,2,4 and Steven R. Little1,2,5,6, (1)Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA, (2)McGowan Institute for Regenerative Medicine, Pittsburgh, PA, (3)Department of Radiology, University of Pittsburgh, Pittsburgh, PA, (4)University of Pittsburgh Cancer Institute, Pittsburgh, PA, (5)Bioengineering, University of Pittsburgh, Pittsburgh, PA, (6)Immunology, University of Pittsburgh, Pittsburgh, PA

Controlled release technology has the potential to enhance drug safety and efficacy if proper control of the resulting in vivo drug distribution can be exhibited. While characterization studies and predictions of drug release in vitro have been performed extensively, the difficulty translating results to the clinic implies that these results do not correspond to the complex in vivo environment. Non-invasive visualization of the drug distribution in time and/or space originating from a controlled release system could aid in the characterization of factors that control local drug distribution and inhibit the achievement of undesired release behavior. We hypothesized that magnetic resonance imaging (MRI) could be used to noninvasively quantify concentration profiles of controllably released gadolinium contrast agent, which could ultimately be used to track controlled release in vivo non invasively.

MRI contrast agent gadolinium tetraaza-cyclododecanetetraacetic acid (Gd-DOTA) was encapsulated in biodegradable poly(lactic-co-glycolic acid (PLGA) microparticles using water-in-oil-in-water (w/o/w) double emulsion technique, controlling for the inherent osmotic gradient that results from Gd-DOTA solutions. Particle characterization was performed using SEM to examine morphology and size. Gadolinium loading and encapsulation efficiency were determined via inductive coupled plasma mass spectrometry (ICP-MS). Degradable microparticles were placed under a hydrogel composed of 5% carboxylmethyl cellulose (CMC) (mimicking a depot injected into extracellular matrix). The releasing microparticle depot surrounded by hydrogel was analyzed using a 7-T MRI scanner repeatedly over a period of 22 days. Spin-echo sequence was applied and imaging was based on T1-weighted measurement. Quantification of Gd-DOTA was obtained by nonlinear least square error curve fitting. Concentrations of agent were plotted with respect to the distance from the release depot over various time points.

The w/o/w double emulsion fabrication consistently yielded spherical particles with smooth surfaces, with size ranging from 10mm to 40mm. ICP-MS analysis determined that Gd-DOTA loading was between 5.6-34.4 mg/mg polymer, corresponding to an encapsulation efficiency of 30-70%. Through high-resolution scanning, Gd-DOTA appeared to be highly concentrated in each individual particle, which is significantly different from blank particles as control. Similar behavior was observed in the microparticle depot in which Gd-DOTA loaded microparticles showed in black because of high concentration of loading. Analysis of signal intensity from MRI yielded spatio-temporal concentration profiles of Gd-DOTA in the surrounding hydrogel. These profiles were established at time 0 by a depot of Gd-DOTA loaded microparticles and reached equilibrium within 8 days. This result was consistent for all four Gd-DOTA loading levels tested which spanned an order of magnitude.

Noninvasive visualization and quantitative monitoring of drug distribution can provide physiological insight into the local drug delivery system, providing insight into the spatial distribution of drug radially outward from the release system. Our study has revealed that degradable, PLGA microparticles can act as an effective carrier for imaging agent that can subsequently be visualized via MRI. The hydrogel “phantom” system has demonstrated to be a suitable model to monitor release from a depot. Future work will compare this data to models of diffusion and distribution as well as using these models to make predictions on live imaging data collected from depots injected into mice.

References:

1. S.N. Rothstein. J Mater. Chem. 2011;21:29-39.

2. A.L. Doiron. PNAS. 2008;105:17232-17237.

3. J. Siepmann. Adv. Drug Deliv. Rev. 2001;48:139-157.

4. A.L. Doiron. Pharm. Res. 2009;26:674-682.


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