Theranostics refers to the combination of disease diagnosis and therapy. Microbubbles, nanobubbles and bubble liposomes hold significant potential for theranostic applications, given their propensity to be visualized in vivo with extremely high sensitivity, their ability to improve drug delivery across biologic barriers, and the possible of loading therapeutic molecules into or onto their shell. The combination of ultrasound exposure and bubbles can be utilized to enhance drug delivery efficiency in ultrasound-mediated delivery systems. Ultrasound-induced microstreams/microjets in fluid surrounding the bubbles form transient pores in the plasma membrane through which exogenous materials such as plasmid DNA, siRNA, proteins and/or drugs in the fluid can then enter the cell. Cells suspended with bubbles and plasmid DNA or siRNA are exposed to ultrasound for up to a few tens of seconds to allow for transfection over a short period of time. Plasmid DNA and siRNA are directly introduced into the cytoplasm, enabling effective and rapid transfection in the presence of high serum nuclease levels.
The combination of ultrasound exposure and bubbles is also a novel strategy for antigen delivery in dendritic cell (DC)-based cancer immunotherapy, thus making the prevention of metastasis in therapeutic models of antigen delivery into DCs possible.
Arg-Gly-Asp (RGD)-bubble liposomes represent a novel echo contrast agent, which can markedly enhance ultrasonic thrombus imaging in vitro and in vivo, and may be useful for noninvasively diagnosing acute thrombotic vessel occlusion. Furthermore, the induced cavitation of RGD-bubble liposomes by low-frequency continuous-wave ultrasound, showed great potential to accelerate the thrombolytic effect in a rabbit thrombotic vessel occlusion model. Thus, RGD-bubble liposomes are useful as ultrasound theranostic agents for noninvasively diagnosis and thrombolysis of acute thrombotic vessel occlusion.
Lapatinib (LAP) is metabolized mainly by CYP3A4/5 and this metabolic pathway is inhibited by ketoconazole (KTZ), a strong CYP3A4 inhibitor. LAP is not only a substrate of CYP3A4, but also an inhibitor. It is known that the inhibition by LAP is a mechanism-based inhibition (MBI) as well as a competitive inhibition. We have reported the intestinal transit, absorption and metabolism-based pharmacokinetic (ITAM-PK) model, which can predict bioavailability (F) and drug-drug interactions quantitatively based on the in vitro metabolic and transport parameters. In this study, we aimed to predict F of LAP and KTZ, and also interactions of these drugs quantitatively.
Predicted F values with an ITAM-PK model were 0.0526 and 0.825 for LAP and KTZ, respectively. We also calculated CLtot/F using the predicted F and the total body clearance obtained with an ITAM-PK model. The calculated CLtot/F values for LAP and KTZ were consistent with those reported in humans. The AUC of LAP was calculated using an ITAM-PK model with or without KTZ co-administration. Predicted AUC increase of LAP by KTZ co-administration was similar to that reported in humans. The results demonstrated that the drug-drug interactions between LAP and KTZ can be quantitatively predicted in vitro using an ITAM-PK model.