Enhancement of drug delivery in tumors by using interaction of nanoparticles with ultrasound radiation.

Efficacy and safety of cancer chemo- and biotherapy are limited by poor penetration of anti-cancer drugs from blood into tumor cells. Tumor blood vessel wall, slow diffusion in the interstitium, and cancer cell membrane create physiological barriers for anti-cancer drugs, in particular promising macromolecular agents. Recently, we proposed to use selective accumulation of exogenous nano- and microparticles in tumors followed by ultrasound-induced cavitation for safe and efficient drug and gene delivery. In this paper, we first investigated the influence of polystyrene nanoparticles (100 and 280 nm in diameter and concentration up to 0.2% w/w) on cavitation threshold in water at the frequency of 20 kHz. Then, using optimal irradiation parameters found in the first part of this work, we studied efficacy of cancer chemotherapy with this technique. The experiments were performed in athymic nude mice bearing human colon KM20 tumors, which are highly resistant to chemotherapy. Ultrasound with the frequency of 20 kHz in combination with i.v. injected polystyrene nanoparticles was applied to enhance delivery of chemotherapeutic agent 5-fluorouracil. Our studies demonstrated that ultrasound irradiation in combination with the nanoparticle and drug injections significantly decreased tumor volume and resulted in complete tumor regression at optimal irradiation conditions, while the volume of control (non-irradiated) tumors increased despite drug injections. These data suggest that ultrasound-induced drug delivery may improve efficacy of current cancer treatment regimens.