Ultrasound-Responsive Nanoparticulate for Selective Amplification of Chemotherapeutic Potency for Ablation of Solid Tumors

Precision medicine requests preferential transportation of the pharmaceutical substances to the pathological site and impartation of localized therapeutic activities to the targeted cells. To accomplish this goal, we attempted a facile nanoscaled ultrasound-responsive delivery system, characterized by doxorubicin assembled with an amphiphilic copolymer (multiple of hydrophobic stearic segments tethered onto the hydrophilic pullulan backbone through ultrasound-labile oxyl-alkylhydroxylamine linkage). As a consequence of the strategically installed ultrasound-labile oxyl-alkylhydroxylamine linkage to elicit the tailored segregation of the hydrophilic pullulan and the hydrophobic stearic segments upon ultrasound impetus, the constructed nanoscaled self-assembly presented distinctive structural destabilization behaviors and afforded spatiotemporal controlled liberation of the cytotoxic drugs. It is worthy to note that the ultrasound was determined to markedly lower the IC50 of the proposed system from over 10 μg/mL to 2.33 μg/mL (approximate 4-fold), thereby serving as a facile impetus to amplify the cytotoxic potency of the proposed drug delivery vehicles. Furthermore, drastic tumor ablation was validated by dosage of the proposed doxorubicin delivery system to T41 tumor-bearing mice accompanied by the tumor-localized ultrasound impetus, while no observable adverse side effect was confirmed. Therefore, the results advocated our ultrasound-responsive delivery vehicle as a tempting strategy for precise spatiotemporal control of the release of the drug cargo, thus affording selectively amplified cytotoxic potency to the ultrasound-imposed site, which should be highlighted as important progress toward precision medicine.