Dalia El-Sherif

Ultrasound -Triggered Drug Delivery with Contrast Imaging: Effect of Microencapsulation Method

A method for preparation of hollow, biodegradable polymeric microcapsules for use as contrast agents is described, and strategies for their use in concomitant imaging and drug delivery are outlined. Compared with X-ray or magnetic resonance imaging, diagnostic ultrasound is a safe, relatively inexpensive imaging technique, which allows the physician to view real-time images. Contrast agents are being developed which will greatly enhance the contrast of the received image, when injected into the patients blood stream. We have developed hollow polymeric CA based upon the ability to microencapsulate a solid core of ammonium carbonate which is then removed by decomposition and freeze-drying. The polymer poly D,L(lactide- co -glycolide) (PLGA) was chosen for its FDA approval, and because it has the most rapid in vivo degradation of the α-hydroxy acid series. Spray dried and solvent extraction samples were used to test the concept of concomitant drug delivery and imaging. The method of fabrication had an important effect on the drug loading by adsorption, and on the amount of drug that was released when the capsules were insonated with ultrasound in the medical imaging range. Both were greater for spray dried samples. Both frequency and pressure of insonation also influenced release. The most dramatic increase in release was after 5 minutes for the 10 Mhz low (1.25 MPa) pressure insonation, which showed 316% greater release than control, a total of 1.89 mg.

Development of biodegradable PLGA microspheres for use as ultrasound contrast agents

The authors have developed a method for producing hollow/porous poly (lactide co-glycolide) (PLGA) microcapsules with a mean size of 1 /spl mu/m by a modified double emulsion, solvent evaporation technique. Besides being biocompatible and biodegradable, these microspheres exhibit acoustic enhancements that make them useful as contrast agents for diagnostic imaging using ultrasound. Moreover, they are very stable and give a prolonged acoustic enhancement, as compared to other ultrasound contrast agents.

Ultrasound induced degradation of hollow PLGA microcapsules

We have investigated the effect of ultrasound energy on the degradation pattern of hollow PLGA microcapsules. These microcapsules work as ultrasound contrast agents, giving an in vitro acoustic enhancement of up to 25 dB. The dose response at 5 and 10 MHz was compared to the degradation pattern of the polymer capsules at the same two frequencies. Controlling the degradation is especially important with regard to drug-loaded microcapsules.

Surface modification of PLGA microspheres for targeting

RGD peptide was conjugated to hollow microspheres to develop PLGA ultrasound contrast agents that enhance ultrasound imaging. The microcapsules were coated with an RGD peptide that targets integrins specific to angiogenesis, /spl alpha/v/spl beta/3 and /spl alpha/v/spl beta/5. The microcapsules were then bound to rat neuroblastoma cells in vitro within 6 hours. The RGD peptide modified microcapsules makes them ideal candidates for targeted therapeutic imaging and drug delivery vehicles.

Effect of polymer composition on in vivo ultrasound contrast agent performance

Polymer composition, the ratio of lactic acid (LA) to glycolic acid (GA), was evaluated for its contribution to the acoustic enhancement of a poly (co-lactic-glycolic) acid (PLGA) ultrasound contrast agent. Contrast agents were prepared from four different polymer compositions (LA:GA): 100:0, 85:15, 75:25, 50:50 and tested in vivo. The results indicate that all contrast agents perform well in vivo but the 50:50, which had the shortest usable life-time. The performance of the contrast agents was dependent on the ratio of LA to GA and should be considered in the design of polymeric contrast agents.

Effect of polymer composition on ultrasound contrast agent performance

Polymer composition was evaluated for its contribution to the acoustic enhancement with a polymeric ultrasound contrast agent using poly (co-lactic-glycolic) acid (PLGA). Contrast agents were prepared from two different polymer compositions with varying ratios of lactic (LA) to glycolic acid (GA) (LA:GA): 100:0 and 50:50 and tested in vitro at room temperature and 37/spl deg/C. The results indicate that the 100:0 sample preformed better than the 50:50 sample and was able to withstand further processing. The performance of the contrast agents was dependent on the ratio of LA to GA and should be considered in the design of polymeric contrast agents.