Construction And Application Of Polymer Hybrid For Tumor Microenvironment Triggered Drug Delivery System

Cancer has become one of the main diseases affecting human health due to high incidence and mortality.Based on the difference between tumor environment and physiological environment,nanocarriers have been reasonably designed to deliver anticancer drugs through the combination of nanotechnology and chemotherapy.Accordingly,a series of "all-in-one" multifunctional drug delivery systems(DDS)with remarkable stability,high drug loading capacity(DLC)/encapsulation efficiency(DEE),pH/glutathione(GSH)responsiveness,excellent biocompatibility,biodegradability and enhanced acid/GSH-activated magnetic resonance imaging(MRI)were developed to deliver antitumor drugs.In vitro and in vivo investigations were utilized to evaluate the influence of these drug delivery systems on tumor growth.Research contents are as follows:A simple and effective method for self-assembly of water-soluble triblock copolymers(PAA68-b-PEG86-b-PAA68)in an aqueous phase was used to prepare polymer vesicles with controllable morphology and high stability,which were utilized in the efficient delivery of anti-tumor drugs.To achieve self-assembly of PAA68-bPEG86-b-PAA68 in the aqueous phase,manganese oxide(MnO2)was first generated to drive phase separation of the PAA block to form the PAA68-b-PEG86-bPAA68/MnO2 polymeric hybrid with a stable structure in a physiological medium,which exhibited vesicular morphology with a diameter of approximately 30 nm and high doxorubicin(DOX)loading capacity of approximately 0.94 mg mg-1.The transformation of MnO2 to Mn2+under endogenous GSH facilitated the disassembly of PAA6s-b-PEG86-b-PAA68/MnO2 to enable precise drug delivery at tumor sites.The toxicity of DOX-loaded PAA68-b-PEG86-b-PAA68/MnO2 to tumor cells has been verified both in vitro and in vivo.Notably,drug-loaded polymeric vesicles have been demonstrated,especially in in vivo studies,for its ability to overcome the cardiotoxicity caused by DOX.Based on the above results,two metallic oxides(MnO2 and zinc oxide(ZnO))are displayed herein to demonstrate a novel self-assembly mechanism in an aqueous phase for diblock copolymers(CH3O-PEG108-WPAA116)and verify its universal applicability.By in situ generation of metallic oxides,self-assembly of block copolymers was induced to result in polymeric hybrid micelles(CH3O-PEG108-bPAA116/ZnO and CH3O-PEG108-b-PAA116/MnO2)with tunable stability in aqueous solution.The metallic oxide nanoparticles possessed excellent dispersibility due to the hydrophilic feature of both PEG and PAA.It was observed through transmission electron microscope(TEM)that ZnO nanoparticles with a diameter of approximately 2 nm were uniformly dispersed in polymeric hybrid micelles.These CH3O-PEG108b-PAA116/ZnO micelles exhibited a high DLC of 0.41 mg mg-1 toward DOX,whereas DOX-loaded CH3O-PEG108-b-PAA116/ZnO micelles could be broken down into Zn2+and polymer scraps,which facilitated drug release in tumor microenvironments.Both in vitro and in vivo investigations showed that the drug-loaded ZnO-crosslinked polymeric micelles effectively suppressed tumor growth.In order to improve the tumor microenvironment-responsiveness of polydopamine(PDA)-based drug delivery system,a novel hollow PDA-based hybrid sphere(DOX@(hPDA/MnO2)-PEG)was designed herein to deliver therapeutic agents by responding to tumor microenvironments.To overcome the limited stimuli-responsiveness in PDA platform,MnO2 nanoparticles were employed to cap the surface of hollow PDA spheres as they displayed potent responsiveness to endogenous GSH in tumor microenvironments.MnO2 nano-caps with virtue of the excellent stability can prevent drug leakage of DOX@(hPDA/MnO2)-PEG in physiological medium.Meanwhile,the GSH-sensitive MnO2 nano-caps were removaled promotes precise delivery and controlled release of loaded drugs and further improves the anti-tumor effect in the tumor microenvironment.In addition,the outer surface of the hollow PDA hybrid sphere can be integrated with biocompatible polymers such as amino polyethylene glycol(NH2-PEG),which facilitates the use of the novel hollow sphere in drug delivery for cancer therapy.In vitro and in vivo investigations shown that DOX@(HPDA/MnO2)-PEG has good biological safety and can significantly inhibit cell and tumor growth.To explore more design possibilities for drug delivery systems,smart poly(methacrylic acid-co-N,N-bis(acryloyl)cystamine)/DOX/MnO2-2/polyethylene glycol theranostic nanohybrids(PMAABACy/DOX/MnO2-2/PEG TNs)were rationally fabricated in this work using in-situ generation of amorphous MnO2 by taking advantage of the spatial confinement effect of PMAABACy nanohydrogels as well as its PEGylation accomplished through Mn-N coordinate bonding.The amorphous MnO2 of PMAABACy/DOX/MnO2-2/PEG TNs was synthesized through the chelation between Mn2+ions and carboxyl groups of PMAA chains,and served as a gatekeeper to prevent the premature leakage of DOX during blood circulation.In the presence of intracellular acidic and GSH,Mn2+ions were released from amorphous MnO2 as dual T1/T2 contrast agents,endowing the nanohybrids with enhanced acid/GSH-activated magnetic resonance imaging(MRI).Notably,the site-specific release of DOX was also promoted due to the disintegration of both amorphous MnO2 and PMAABACy in response to the biological endogenous stimulus such as slightly acidic pH and increased GSH level in tumor cells.In conclusion,the newly as-synthesized nanohybrids exhibit some excellent characteristics,including reduced premature release,enhanced stability under physiological conditions,excellent T1/T2 MRI performances,remarkable biodegradability,and efficient site-specific release of DOX.Our findings indicate that such polymer/amorphous MnO2-based biodegradable nanohybrids can facilitate the development of DDS with reduced premature release for real-time MRI-guided cancer therapy.