Development and characterization of ultrasound-activated polymeric microdroplets for targeted chemotherapy.

Abstract

Potent antineoplastic agents such as afatinib and freebase doxorubicin exhibit promising antitumor activity but are limited by systemic toxicity, poor aqueous solubility, and restricted delivery to brain tumors. Here, we developed a co-evaporation synthesis strategy that extends a previously validated ultrasound-responsive methoxy poly(ethylene glycol)-poly(D,L-lactide) (mPEG-PDLLA) diblock copolymer-based carrier platform to efficiently encapsulate highly hydrophobic antineoplastic agents while preserving pressure-dependent, ultrasound-triggered drug release within a 300 kHz focused-ultrasound field. The resulting microdroplets are designed to serve as intravascular drug depots that retain their payload in the absence of ultrasound and release it on demand at the ultrasound focus, with the fraction released governed by the applied acoustic pressure. The polymeric microdroplets achieved encapsulation efficiencies of 39.6% for afatinib and 46.6% for doxorubicin. Both drugs exhibited reproducible pressure-dependent release; simultaneous logistic fitting with a shared transition-width parameter yielded half-maximal release pressures (P50) of 0.71 MPa for afatinib and 0.63 MPa for doxorubicin. Together, these findings establish a platform for localized, ultrasound-mediated release of highly hydrophobic antineoplastics and provide a foundation for future translational development toward targeted chemotherapy.