ABSTRACT
INTRODUCTION: Although a great many strategies have been proposed for tumor-targeted chemotherapy, current delivery methods of anticancer drugs present limited success with inevitable systemic toxicity. The aim of this study was to develop a new kind of theranostic carrier for targeted tumor therapy. METHODS: Prior to prepare CHC-PFP-DOX, carboxymethyl-hexanoyl chitosan (CHC) was synthesized by acylation of carboxymethyl chitosan. To develop CHC-PFP, perfluoropentane (PFP), an ultrasound gas precursor, was simultaneously encapsulated into the hydrophobic inner cores of pre-formulated CHC micelle in aqueous phase via using the oil in water (O/W) emulsion method. The size distribution and surface charges of these nanodroplets were measured and the morphology was observed by transmission electron microscopy (TEM). For ultrasound imaging application, in vitro model was established to evaluate the imaging of CHC-PFP-DOX under different concentration and mechanical index. After that, the anti-tumor effect of ultrasound combined with CHC-PFPDOX on ovarian cancer cells was investigated. RESULTS: The resulting CHC-PFP-DOX had a nano-sized particle structure, with hydrophobic anticancer DOX/PFP inner cores and a hydrophilic carboxymethyl chitosan polymer outer shell. The favorable nano-scaled size offers the potential to extravagate from veins and accumulate in tumor tissues via enhanced permeation and retention (EPR) effect. Additionally, CHC-PFP-DOX showed the ability to serve as ultrasound imaging agent at body temperature. Notably, it exhibited an ultrasound-triggered drug release profile through the external ultrasound irradiation. Further study demonstrated that ultrasound combined with CHC-PFP-DOX can improve the killing effect of chemotherapy for tumor. CONCLUSION: CHC-PFP-DOX holds great promise in simultaneous cancer-targeting ultrasound imaging and ultrasound- mediated delivery for cancer chemotherapy.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Chitosan/analogs & derivatives , Doxorubicin/pharmacology , Drug Delivery Systems , Nanoparticles/chemistry , Ovarian Neoplasms/drug therapy , Ultrasonography , Antibiotics, Antineoplastic/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Chitosan/chemistry , Doxorubicin/chemistry , Drug Screening Assays, Antitumor , Female , Humans , Micelles , Ovarian Neoplasms/pathology , Particle Size , Surface PropertiesABSTRACT
Objective To evaluate the inhibitory effect of phase change doxorubicin loaded carboxymethyl hexanoyl chitosan nanodroplet on ovarian cancer cells,and the effect of its ultrasound image in vitro.Methods The carboxymethyl hexanoyl chitosan synthesized through the acylationreaction with carboxymethyl chitosan and hexanoic anhydride.The drug loaded carboxymethyl hexanoyl chitosan nanodroplets were prepared by ultrasonic emulsification.The surface morphology,particle diameter and electric potential were characterized.Ultrasound imaging of the nanodroplet was evaluated in vitro.The encapsulation efficiency was determined by ultraviolet spectrophotometry.The survival rate of ovarian cancer cell was detected using CCK-8 reagent.The statistical analysis was performed.Results The drug loaded carboxymethyl hexanoyl chitosan nanodroplet was successfully prepared which showed regular morphology in microscope,the mean diameter of (458.33± 43.50)nm.The encapsulation efficiency was (52.06 ± 10.14)％.The nanodroplet could enhance ultrasonic imaging.The survival rate of ultrasound combined with drug loaded nanodroplet group ([62.54± 3.60]％) was lower than those of the free drug group ([75.55±7.21]％) and drug loaded nanodroplet group ([76.18±4.94]％),ultrasound group ([89.90±0.83]％;P＜0.05).Conclusion Ultrasound-mediated drug loaded nanodroplet can inhibit ovarian cancer cells,and has the potential for application in the clinical diagnosis and treatment.
