Design And Development Of Reactive Oxygen Species Responsive Nanocarriers For Chemotherapeutic Delivery

Nanodrug carriers,including polymer-drug conjugates,liposomes,polymeric micelles,dendrimers,and nanoparticles have been extensively investigated in anticancer drug delivery.Drug delivery for cancer chemotherapy is a process using nanocarriers with appropriate sizes and stealth properties to preferentially ship drugs into tumor tissues via active or passive targeting.However,despite the improved pharmacokinetic properties and the reduced adverse effects,currently cancer drug delivery has not achieved satisfied therapeutic efficacy in clinical trials.Thus,the design of nanocarriers with more efficient drug delivery and thus higher therapeutic efficacy is still in insistent demand,to which tumor-targeted drug delivery and specificity-responsive drug release are undoubtedly an effective solution.Using tumor abnormal structure and metabolism to design smart nanocarriers,thus accelerating targeted tumor accumulation and promoting stimuli-responsive drug release,has become a hotspot in the field of tumor treatment.In this paper,we designed and developed several intelligent nanodrug delivery systems,enhanced tumor-homing capability and facilitated specific release at tumor site,thus achieving good therapeutic effect.In this thesis,we first designed an oxidation-responsive poly(ethylene glycol)-paclitaxel conjugate(PEG-B-PTX).Tumor tissues are featured with an enhanced level of reactive oxygen radicals(ROS)due to its abnormal physiological characteristics,among which hydrogen peroxide(H2O2)is the most important form.PEG-B-PTX,containing a ROS-labile spacer between hydrophilic polyethylene glycol(PEG)and hydrophobic paclitaxel(PTX),could self-assemble into nanomicelles with a diameter of 50 nm and slightly negatively-charged surface.Different from the conventional PEG-PTX conjugates with uncontrolled release properties,PEG-B-PTX nanomicelles released very slowly in normal physiological conditions.But once inside the cell,boronic esters could be oxidized by intracellular H2O2 and the subsequent 1,4-elimination triggered fast release of paclitaxel succinate,which could be rapidly hydrolyzed into free PTX.In addition,PEG-B-PTX nanomicelles exhibited long blood circulation,effectively accumulated in tumor areas,successfully triggered intracellular PTX release to kill tumorous cells,and thus produced significantly better tumor growth suppression and lower adverse effects than Taxol in MCF-7 human breast xenografted tumor model.In the second part of this thesis,we designed a novel tumor-ROS-labile linkage-bridged block polymer(PEG-B-PCL)as a nanodrug carrier to package doxorubicin(DOX)into nanoparticles(B/DOX-M)with a diameter of around 60 nm.Upon the oxidation of H2O2,the block polymer disintegrated and the PEG corona on the surface were shedded,leading to dissociation of the nanoparticles and thus quick release of DOX.Compared with the nonresponsive control,the H2O2-triggered dePEGylation of B/DOX-M promoted more effective intracellular drug release,showing much stronger in vitro and in vivo tumor cell killing ability."Shell removal" strategy upon oxidative response was proved to be an effective method for controlled drug release.Thus,this tumor specific biodegradable nanomicelles has great potential application prospect for chemotherapeutic drug delivery.In the third part,a tumor-homing cascade amplified drug release system(AP-BNPLap)was successfully established by encapsulation of ?-lapachone with a redox responsive amphiphilic polymeric prodrug PEG-PBPTX.A sequential release manner of the two drugs was observed and utilized to realize discriminatory drug release strategy and distinguish malignant and healthy cells,based on their diversified expression of NQO1.Mediated by the up-regulated NQO1 in cancer cells,lapachone could induce an enhanced level of ROS which triggered a cascade PTX release process and then synergistically killed cancer cells,after AP-BNPLap was uptook through specific interaction between AP-1 peptide and the interleukin-4 receptors overexpressed on the surface of human breast cancer cells.In the last part,two novel ROS-responsive linkers with multiple functional groups were designed and synthesized successfully.Conjugated with 7-ethyl-10-hydroxycamptothecin(SN38)through an ether bond,the oxidation-sensitive prodrugs BSN38-1 and BSN38-2 were obtained and then coupled to the block polymer PEG-PAZMA through CuAAC strategy to produce two kinds of stimuli-responsive nanodrugs BNPLap-1 and BNPLap-2.Both small molecular prodrugs were very sensitive to H2O2,and quickly transformed into free SN38 at a very low concentration of H2O2.Due to the strong crystallization tendency of SN38,the formed nanoparticles had very stable micellar kernel,thus showing suppressed but continuous drug release properties.Both BNPLap-1 and BNPLap-2 showed synergistic killing ability to tumor cells in vitro.