| Abstract
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Conventional, systemic chemotherapy has proved to be generally inefficient in the treatment of solid tumors, bearing harmful, toxic side effects. Targeted drug delivery systems can mitigate this. We develop methods to load drugs onto polymeric microbubbles, serving both as ultrasound contrast agents (CA) and drug carriers. These drug-loaded CA have the ability to release their payload in the vicinity of the tumor site. Our CA are fabricated using an adaptation of double emulsion method developed in our lab. Bovine serum albumin (BSA), sudan black (SB), 5-fluorouracil (5-FU) and doxorubicin (DOX) are individually loaded onto our CA, using three different loading methods, namely, incorporation, dry, and wet adsorption. The effects of different preparation parameters on drug yield and echogenicity, for each drug/loading method combination, are studied. Temperature, pH, drug concentration and incubation time, are found to affect BSA loading through dry adsorption. The highest loading efficiency (50.5%) was found for incubating BSA at pH 4.2 at 4°C but compromised its echogenicity, 19.0 dB. In contrast, by incorporation, only 21.9% BSA is loaded still maintaining an echogenicity of 20.9 dB. SB, as a hydrophobic material, is most suitably shell incorporated, yielding 100% loading efficiency while maintaining 21.9 dB echogenicity. Wet adsorption is found to be most suitable for loading 5-FU and DOX; 5-FU loading efficiency is 27.6% while echogenicity is 15.7 dB, and DOX loading efficiency is 79.1% while echogenicity is 15.8 dB. There is a clear trade-off between drug loading efficiency and CA echogenicity; we strive to load as much drug as possible while maintaining acoustic properties. In vivo feasibility studies show the stability and echogenicity of our drug-loaded CA in cancerous and healthy animal models. In addition, SB-loaded CA are shown to be suitable candidates for lymph channels and sentinel lymph nodes visualization, both through staining and US. Summarizing, complex relationships are found to exist among drugs, loading methods and CA shell polymers, i.e., specific loading methods should be used for specific drugs and CA. This work demonstrates that our CA are able to carry anticancer drugs, already in clinical use with proven therapeutic effects, while maintaining echogenicity and stability.
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