Ultrasound sensitive polymeric drug carriers for treatment of solid tumors

Abstract

Ultrasound contrast agents (UCA) are comprised of microbubbles stabilized by a shell. The benefits of ultrasound (US) to parenteral drug delivery are well documented. In conjunction with US-induced cavitation of co-administered UCA they include an increase in drug efficacy due to increases in both vascular gap junctions and cellular membrane permeabilities. We have developed a drug-loaded UCA which upon reaching the desired site (generally a solid tumor) ruptures under the influence of the focused US. UCA cavitation, combined with acoustic radiation forces, and the enhanced permeation and retention effect (EPR) are expected to increase tumor uptake of the produced fragments, providing a sustained, intratumoralrelease of any associated drug.In this thesis, poly (lactic acid) (PLA) UCA have been developed for drug delivery utilizing doxorubicin (Dox). These agents provide 15-20 dB of US contrast enhancement both in vitro and in vivo. The agents have been optimized to encapsulate Dox while maintaining a high sensitivity to US. Prior to sonication these agents have a mean diameter of 1.4-1.8 μm, restricting them to the vasculature until rupture. In vitro data indicate particles reach sizes of 200-400 nm after sonication. Electron microscopy of ruptured particles depicts both fragmentation and shriveling of shells, resulting in sub-micron, drug loaded particles.In vitro these agents become significantly more potent to the human breast cancer cell line MDA-MB-231 after sonication, nearly doubling the degree of cell death compared to non-insonated controls (p=0.0272). Microscopy shows that Dox from the fragments is transported to the cell nucleus once within the cell. Additionally, during US triggered generation, Dox eluting species can be forced through a 0.4 μm membrane. These data demonstrate potential for a PLA-Dox UCA platform to deliver Dox eluting nanoparticles to the tumor interstitium. Elution profiles have been measured, indicating that 76% of drug payload is released over a 24 day period.Studies using VX2 tumors in rabbits show the activated platform is detectable within tumor vasculature and results in substantial increases in intratumoral drug levels with greater than a 100% increase in delivery efficiency compared to the noninsonated platform (p=0.004)%%%%Ph.D., Biomedical Engineering – Drexel University, 2010