Preparation And Properties Of Active And Passive Targeting DOX-loaded Polymeric Micelles

In recent years,cancer has been regarded as one of the major diseases threat to human life and health.Chemotherapy is one of the most common treatments,in which doxorubicin,camptothecin,paclitaxel and other anti-cancer drugs have been used to kill cancer cells and cure the cancer.However,due to the shortcomings for the common small molecule anti-cancer drugs,such as,fast metabolism in the body,short duration and weak selectivity,so that the use of anti-tumor drugs was limited in cancer chemotherapy.For these side effects,researchers have found that stimuli-responsive polymer micellar nanoparticles could be used as candidate for drug carrier.In the process of treatment,the anti-tumor drug was encapulated in the polymer micellar nanoparticles,and then released to desired pathological site and kill cancer cells.This method could improve the drug loading efficiency,prolong circulation time of the drug in vivo,reduce the toxicity of antitumor drugs,and achieve the controlled release of the drug in the tumor site.In view of this,in this paper,we designed different stimuli-responsive polymer micellar nanoparticles to load the doxorubicin,moreover,the structure and the vitro release effect of the polymer micellar nanoparticles have been studied deeply.1.Preparation and properties of redox and pH dual responsive triblock doxorubicin-loaded polymeric micelles.Amphiphilic triblock copolymers polyethylene glycol-SS-poly(?-caprolactone)Acetal-SS-polyethylene glycol(PEG-SS-PCL-Acetal-SS-PEG)with good biocompatibility and biodegradability were prepared by ring-opening polymerization.This polymer was mainly synthesized by functionalized PEG and functionalized PCL.During the main chain reaction process,redox responsed disulfide bond and an acid responsed acetal bond have been introduced.The structure of the block polymer was characterized by nuclear magnetic resonance(NMR).The size and morphology of micelles were characterized by dynamic light scattering(DLS),transmission electron microscopy(TEM)and scanning electron microscop(SEM),it was found that the block copolymer was self-assembled into nanosized micelles in aqueous solution with core-shell structure,with good dispersion and narrow particle size distribution and the mean hydrodynamic diameter around 180 nm.In addition,the micelle display the ability to response to external pH and redox stimuli.as DLS measurements indicated,the diameter of the micelles increased when the pH values is 5.0 and the DTT was existent at the room temperature,due to the disulfide/acetal bond of cleavage of micelles.Then adriamycin(DOX)was used as a model drug to incorporate into PEG-SS-PCL-Acetal-SS-PEG micelles,and the vitro release results of DOX-loaded PEG-SS-PCL-Acetal-SS-PEG micelles in pH values and DTT drug release was studied,it is indicated that 40.07%,92.05% and 95.36% of DOX were released from DOX-loaded PEG-SS-PCL-Acetal-SS-PEG micelles at pH 5.0,DTT/pH 7.4 and DTT/pH 5.0 in 24 h,respectively;However,only 25.17% of DOX were released from DOX-loaded PEG-SS-PCL-Acetal-SS-PEG micelles at pH 7.4 in24 h.Therefore,the DOX-loaded micelles showed redox and pH dual responsive drug release behavior.2.Preparation and properties of the active targeting P(MA-SS-TA)-b-PHPMA-b-PFA DOX-loaded polymeric mcellesA new active targeting and reduced respansive amphiphilic block copolymer poly(functionalized lipoic acid)-b-poly(N-(2-hydroxypropyl)methacrylamide)-b-poly(folic acid)[P(MA-SS-TA)-b-PHPMA-b-PFA ]was synthesized.Firstly,disulfide bonds and double bond functional groups were introduced into lipoic acid form functionalized lipoic acid(MA-SS-TA)monomer with a hydrophobic and a redox response.Secondly,The MA-SS-TA and HPMA monomer were initiated by RAFT polymerization to form amphiphilic block copolymer P(MA-SS-TA)-b-PHPMA.Finally,FA was initiated by polymerization forming copolymer(MA-SS-TA)-b-PHPMA-b-PFA with active targeting.The structure of the block polymer was characterized by NMR and Fourier Transform Infrared Spectrometer(FTIR).The size and morphology of micelles were characterized by DLS and TEM.The size changes of micelles were detected by DLS at DTT.The results showed that DOX-loaded micelles swelled,particle size became large and DOX was released fast due to disulfide bond of cleavage of copolymer micelles under conditions of containing DTT.In vitro release results(measured by UV/vis spectroscopy)showed that 79.12% of DOX released from DOX-loaded micelles at DTT/pH 7.4 in 48 h,However,only 16.47% of DOX were released from DOX-loaded micelles at pH 7.4 in 48 h.The result indicated that the copolymer micelles with redox stimuli-response can synergistically promote the release of DOX and have a synaptic effect at the tumor site.