Real-Time Imaging Tracking Of Engineered Macrophages As Ultrasound-Triggered Cell Bombs For Cancer Treatment

BACKGROUND:Cell-based drug delivery systems are a promising platform for tumor-targeted therapy.Compared with traditional drug delivery systems,cell-based drug delivery systems have excellent biocompatibility,low immunogenicity,inherent targeting abilities,long circulation time and half-life period.Besides,these systems could deliver drugs outside the vasculature.However,the real-time tracking of these carrier cells and controlled release of the encapsulated drugs are still challenging.OBJECTIVE:In order provide an accurate approach to cancer treatment,this study develop cell bombs(DPH-RAWs)with great tumor-homing abilities.Especially,their migration can be tracked in real time using ultrasound.After accumulation at the tumor site,the vaporization of perfluoropentane(PFP)can be triggered by a short-pulsed high intensity focused ultrasound(HIFU)sonication,resulting in the generation of several large microbubbles,which destroys DPH-RAWs and allows drug release out of these cells.METHODS:Hollow mesoporous organosilica nanoparticles(HMONs)are synthesized using Stober method and structural difference-based selective etching strategy.Ultrasound activatable cell bombs are developed by encapsulating doxorubicin(DOX)and phase transformable PFP into HMONs to prepare DOX/PFP-loaded HMONs(DPHs),followed by internalization into macrophages(RAW 264.7 cells)to prepare DPH-RAWs.Cell and animal experiments are done to evaluate the tumor-targeting capability of DPH-RAWs in vitro and in vivo.To determine the stability,phase-change capability and ultrasound tracking capability,4T1 tumor-bearing mice were used to image by using high-frequency ultrasound imaging system.DPH-RAWs are destroyed by short-pulsed HIFU sonication at suitable acoustic pressure and release drugs out of cells.Finally,the antitumor efficacy and biosafety are further assessed by in vivo antitumor experiment.RESULTS:DPHs with uniform morphology(623 nm)and DPH-RAWs with great stability are fabricated.DPH-RAWs can be tracked in real time using ultrasound due to the vaporization of a small portion of PFP during cell incubation at 37?.DPH-RAWs have excellent tumor-homing capability in vitro and in vivo.After intravenously injected with DPH-RAWs,the accumulation and migration of DPH-RAWs from tumor vessels to tumor parenchyma are tracked by ultrasound contrast imaging.Scattered contrast-enhanced ultrasound signal is seen in the tumors at 24 h,which can be enhanced by a short-pulsed HIFU sonication.Besides,the further vaporization of remaining PFP can be triggered by a short-pulsed HIFU sonication,resulting in the generation of several large microbubbles,which destroys DPH-RAWs and allows drug release out of these cells.The cumulative amount of DOX released from the irradiated and control cells within 24 h was 93%and 43%,respectively.The DPH-RAWs combined with short-pulsed HIFU sonication significantly inhibit tumor growth and prolong survival of tumor-bearing mice.CONCLUSION:This study develops cell bombs with excellent tumor-homing capability and ultrasound triggered controlled release of the encapsulated drugs,which provides a new approach to cell-based drug delivery systems for real-time tracking of their migration and precise targeted cancer treatment.