Effect of ultrasound dosimetry on drug release from liposomes-implications for development of novel acoustically sensitive liposomes

A serious limitation of conventional chemotherapy is the rather unspecific body distribution of cytotoxic drugs resulting in reduced therapeutic efficacy and unwanted systemic side effects. To increase the therapeutic-to-toxicity (TTT) ratio, cytotoxic dr ugs have been formulated as nanoparticulate or liposomal delivery systems. Several liposomal cytotoxic drugs are already commercially available like liposomal doxorubicin (Caelyx®). However, despite an improved tumour accumulation, these liposomal drugs h ave disadvantages and the TTT ratio is still borderline. Various approaches have therefore been investigated to enhance targeted drug delivery by heat application, enzymatic and pH mediated strategies. Another promising means is to combine low frequency ultrasound (US) with US responsive drug carriers; US application to the target tissue enhances drug release from the carrier and increases concomitantly drug uptake into tumour cells. In a recent CancerCure (CC) study, it was shown for the first time that US treatment markedly increased the antitumoural effect of liposomal doxorubicin (Caelyx®). This represents a major breakthrough because liposomes can accomodate high drug loads and are routinely used in the clinics. The field of US mediated drug deliver y is still in its infancy. Little is known about the mechanism of interaction between US, drug carrier and tissue. Fine tuning of the drug carrier rendering it more US responsive is also mandatory. The remit of CCs initial research is to confirm in vitro the potential of US mediated drug release from known liposome carriers. Mechanistic studies will be performed with liposomal calcein as model substance. The effect of US dosimetry parameters on calcein release will be investigated in relevant models by m ultivariate design. The US parameters that are considered most critical for efficient drug release will be determined and subsequently used in the future evaluation of CCs own US responsive liposome candidates.