PTX-mPEG-PLGA-PLL-antiCA19-9 Combined With UTMD Enhances Chemotherapy In Pancreatic Cancer

Objective: To investigate the effectiveness of PTX-mPEG-PLGA-PLL-antiCA19-9 and UTMD in enhancing the chemotherapy of pancreatic cancer,and explore the dynamic transporting mechanism of PTX in vitro and in vivo under the driving of nanoparticles and UTMD,to reveal the underlying principle of nanoparticles and UTMD enhancing chemotherapy in pancreatic cancer.Methods: We synthesized the PTX loaded mPEG-PLGA-PLL nanoparticles by emulsion-evaporation method,modify antiCA19-9 antibody on their surface,and further characterize the properties of the nanoparticles including the size,encapsulation efficiency and drug release,et al.We selected pancreatic cancer cell line which had highCA19-9 expression and established subcutaneous implantation in nude mice.The UTMD parameters were optimized in vitro and in vivo.We have seven groups: Control,free PTX(PTX),PTXNP(PN),PTX-NP-antiCA19-9(PN-Ab),PTX-NP-antiCA19-9+antiCA19-9(PN-Ab+Ab),PTX-NP+UTMD(PN+U),PTX-NP-antiCA19-9+UTMD(PN-Ab+U).In order to study the therapy effect of the seven groups,we conducted CCK8,Tunel staining,cell cycle and cell apoptosis after 24 h and 48 h in vitro.we also observe the cellular uptake of fluorescence over time in all groups to see the dynamic change under targeted nanoparticles and UTMD.In vivo,we recorded the tumor growth,survival and Tunel staining in all groups;detected the serum markers of heart,liver and kidney.We further investigated the pharmacokinetic profile of free PTX and nanoparticles loaded PTX,as well as PTX accumulation in tumor.The organ fluorescence distribution over time was shown in the small animal imaging,which revealed the dynamic change caused by the targeted nanoparticles and UTMD.Results: PTX-mPEG-PLGA-PLL-antiCA19-9 nanoparticles were synthesized with mean size of 184 nm and displayed a controlled release manner of the loading PTX.In vitro,the results of CCK8,IC50,Tunel staining,cell cycle and cell apoptosis demonstrated that the order of therapy effect was as follows: PN-Ab+Ab<PN-Ab,PN<PN-Ab<PN-Ab+U,PN<PN+U.Cellular uptake of fluorescence over time shown that the nanoparticles could help to resist the cell metabolism and keep the peak at a high level,UTMD made the peak ahead and increased.In vivo,the results of tumor growth curve and survival revealed that the order of therapy effect was as follows: PN-Ab+Ab<PN-Ab,PN<PN-Ab<PN-Ab+U,PN<PN+U.The pharmacokinetic analysis confirmed the function of anti-metabolism of nanoparticles,the half time of the loading PTX was evidently prolonged.The targeted nanoparticles and UTMD significantly enhanced the PTX concentration and fluorescence intensity of the tumor.Conclusion: The combination of PTX-mPEG-PLGA-PLL-antiCA19-9 and UTMD largely increased the chemotherapy effect of PTX in pancreatic cancer,offered a promising new method in pancreatic cancer treatment.