UTMD-Promoted Co-Delivery Of Gemcitabine And MiR-21 Inhibitor By Dendrimer-Entrapped Gold Nanoparticles For Pancreatic Cancer Therapy

Objective:Conventional chemotherapy of pancreatic cancer(Pa Ca)suffers the problems of low drug permeability and inherent or acquired drug resistance.Development of new strategies for enhanced therapy still remains a great challenge.Herein,we report a new ultrasound-targeted microbubble destruction(UTMD)-promoted delivery system based on dendrimer-entrapped gold nanoparticles(Au DENPs)for co-delivery of gemcitabine(Gem)and mi R-21 inhibitor(mi R-21i).Methods:In this study,Gem-Au DENPs/mi R-21i was designed and synthesized.The designed polyplexes were characterized via transmission electron microscopy(TEM)and dynamic light scattering(DLS)and so on.Then,the optimum exposure parameters were examined by an ultrasound exposure platform with different ultrasound power.The cellular uptake,cytotoxicity and anticancer effects in vitro were analyzed by confocal laser microscopy,CCK-8,flow cytometry and so on.In vivo,subcutaneous implantation in nude mice were established and divided into four groups:Control group,Free Gem,Gem-Au DENPs/mi R-21i and Gem-Au DENPs/mi R-21i+U.After different treatments,the anticancer effects were evaluated by B-mode ultrasound,TUNEL staining,hematoxylin and eosin(HE)staining and comparison of tumor volume.We further investigated the fluorescence bio-distribution and the pharmacokinetic profile of free Gem and nanoparticles loaded Gem,as well as Gem accumulation in tumor.Lastly,the contrast enhanced ultrasound(CEUS)was also used to evaluate the intra-tumoral perfusion.Results:Gem-Au DENPs/mi R-21i polyplexes were successfully synthesized?The results revealed that the mean hydrodynamic size of the polyplexes was in a range of154-276 nm.The results showed that the Gem-Au DENPs/mi R-21i can be uptake by cancer cells and the cellular uptake was further facilitated by UTMD with an ultrasound power of 0.4 W/cm~2 to enhance the cell permeability.Further,the co-delivery of Gem and mi R-21i with or without UTMD treatment displayed 82-fold and 13-fold lower IC50 values than the free Gem,respectively.The UTMD-promoted co-delivery of Gem and mi R-21i was further validated by in vivo treatment and showed that the accumulation time of Gem-Au DENPs/mi R-21i complex was longer than that in the control group.These results showed that UTMD effectively increased the chemotherapeutic effect of nanoparticle and prolonged the survival rate of the nude mice.The CEUS images also showed an increased in blood perfusion of pancreatic tumor after Gem-Au DENPs/mi R-21i+U treatment with a significant tumor volume reduction.It also provided further evidence for the reasons for the synergistic effect of chemotherapy,Conclusion:The co-delivery of Gem and mi R-21i using Au DENPs can be significantly promoted by UTMD technology,hence providing a promising strategy for effective pancreatic cancer treatments.