Smart Nanocarrier System To Overcome Multiple Anticancer Drug Delivery Barriers

Nanomedicine provides a novel metholodegy for cancer treatment.Compared with small molecular anticancer drugs,currenttly clinical nanomedicine exhibited significantly lower systemic toxicity and increased tumor targeting.Although more than 200 nanomedicine products have been either approved or are under clinical investigation,the final overall therapeutic efficacy has not shown great advantages compared with corresponding small molecular drugs.The already approved nanomedicine increased the blood circulation and tumor accumulation via the well-known EPR effect due to the presence of surface PEG and suitable size.While the tissue penetration,cellular uptake and drug release have not been improved significantly,which may cause the limited final therapeutic efficacy as well as hinder their clinical translation.To solve these problems,smart nanomedicine which can overcome multiple drug delivery barriers may provide a very promising technology to improve the therapeutic efficacy.Thus,we proposed 2 stratgies,including,tumor stimuli-responsive active targeting and tumor microenvironment remodelling to improve the performance of nanomedicine.Based on such 2 stratgies,this dissertation includes 5 chapters.1st Chapter:Modular Design and Facile Synthesis of Enzyme-Responsive Peptide-Linked Block Copolymers for Efficient Delivery of Doxorubicin.We design well-defined enzyme-responsive peptide-linked block copolymer,PEG-GPLGVRGDG-P(BLA-co-Asp)with modular functionality for efficient delivery of DOX.Upon the stimulus of tumor over-expressed matrix metalloproteinase-2(MMP-2),the dePEGylation would happen at the surface of micelles with the retaintion of RGD ligands.Against HT1080 cells overexpressing MMP-2,DOX-loaded micelles showed approximately 4-fold increase of the cellular internalization amount as compared with free DOX and half maximal inhibitory concentration(IC50)value of DOX-loaded P3 micelles was determined to be 0.38 ?g/mL compared with 0.66?g/mL of free DOX.Binding and penetration evaluation againist HT1080 multicellular tumor spheroids(MCTs)confirmed high affinity and deep penetration of P3 micelles in tumor tissues.This modular design of enzyme-responsive block copolymers represents an effective strategy to construct intelligent drug delivery vehicles for addressing PEG dilemma.2nd Chapter:Matrix Metalloproteinase-Responsive Multifunctional Peptide-Linked Amphiphilic Block Copolymers for Intelligent Systemic Anticancer Drug Delivery.Biodegradable amphiphilic block copolymer,poly(ethylene glycol)-b-poly(D,L-lactide)(PEG-PDLLA)has been approved for clinical applications as a paclitaxel(PTX)nanocarrier.We introduced a matrix metalloproteinase(MMP)-responsive peptide GPLGVRGDG into the block copolymer via efficient click chemistry and ring-opening polymerization to prepare PEG-GPLGVRGDG-PDLLA.Furthermore,this polymer could self-assembly into micellar nanoparticles(NPs)to load PTX.In the presence of MMP-2,the cytotoxicity of PTX loaded in NPs against 4T1 cells is significantly enhanced as compared with free PTX or PTX-loaded PEG-GPLGVRG-PDLLA and PEG-PDLLA NPs.In vivo studies confirmed that PTX-loaded P1 NPs show prolonged blood circulation and more efficient tumor accumulation.Ultimately,PTX-loaded NPs display statistically significant improvement of antitumor activity against tumor-bearing mice via systemic administration.3rd Chapter:A Robust Strategy for Preparation of Sequential Stimuli-responsive Block Copolymer Prodrugs via Thiolactone Chemistry to Overcome Multiple Anticancer Drug Delivery Barriers.Herein,we report a robust and facile strategy based on thiolactone chemistry to fabricate well-defined block copolymer prodrugs(BCPs),which can self-assemble into micellar nanoparticles in aqueous solution with a small size(?40 nm).After reaching tumor site via EPR effect,the tumor microenvironment pH(?6.5)would induce the change transiton from neutral to positive which significantly promoted tumor penetration and cellular internalization.Disulfide bonds can be cleaved by intracellular glutathione(GSH)of cancer cells,which accelerate the release of active PTX drug inside cells.Finally,highly aggressive murine breast cancer 4T1 tumor and hypopermeable human pancreatic adenocarcinoma BxPC3 tumor were completely ablated after treatment by PTX BCP nanoparticles.4th Chapter:Integrated Block Copolymer Prodrug Nanoparticles for Combination of Tumor Oxidative Stress Amplification and ROS-responsive Drug Release.Tumor reactive oxygen species(ROS)have been frequently explored as the specific stimulus to trigger drug release.However,the low intrinsic ROS concentration and heterogeneous distribution in tumor tissues hinder the applications as the stimulus for drug delivery.Herein,we developed integrated nanoparticles to remold tumor microenvironment via specific amplification of the tumor oxidative stress and simultaneously realize ROS-responsive drug release.The amphiphilic block copolymer prodrugs composed of poly(ethylene glycol)and polymerized methacrylate monomer containing thioketal-linked camptothecin(CPT)were synthesized and self-assembled to form core-shell micelles for encapsulation of ?-lapachone(Lapa@NPs).After tumor accumulation and internalization into tumor cells post systemic administration of Lapa@NPs,Lapa can selectively induce remarkable ROS level increase which would trigger the cleavage of thioketal linkers to release drug.The released CPT together with high ROS level achieved a synergistic therapy to suppress tumor growth.5th Chapter:Therapeutic Polymersome Nanoreactors with Tumor-Specific Activable Cascade Reactions for Cooperative Cancer Therapy.Herein,we demonstrate a polymersome nanoreactor with tumor acidity-responsive membrane permeability to activate cascade reactions for orchestrated cooperative cancer treatment.The nanoreactors are constructed from responsive polyprodrug polymersomes incorporating ultrasmall iron oxide nanoparticles and glucose oxidase in the membranes and inner aqueous cavities,respectively.The cascade reactions including glucose consumption to generate H2O2,accelerated iron ion release,Fenton reaction between H2O2 and iron ion to produce hydroxyl radicals(·OH),and·OH-triggered rapid release of parent drugs can be specifically activated by the tumor acidity-responsive membrane permeability.During this process,starving therapy,chemodynamic therapy,and chemotherapy are realized for high-efficiency tumor suppression.