Multifunctional Nanocarriers For Controlled Drug Delivery And Cancer Starvation Therapy

Traditional chemotherapy and radiotherapy still face the difficulties in distinguishing tumor from normal tissues,probably causing serious side effects and sequelae during cancer therapy process.Nanomaterials are considered to have small size,controllable morphology,easy-to-modify surface and good biocompatibility.The multifunctional nanocarriers based on nanomaterials can realize the controlled delivery and the stimuli-responsive release of the drug,improve the drug delivery efficiency and minimize the side effects to normal tissues.Glucose oxidase(GOx)can consume intratumoral oxygen and glucose and starve the tumors eventually.This unique chemical property makes it an ideal drug for cancer starvation therapy.However,the continuous supply of oxygen and nutrients to the tumor site and the low catalytic efficiency of GOx in tumor hypoxic microenvironment make it difficult to eliminate the tumor by GOx alone.Therefore,it is very urgent to develop new GOx synergistic therapeutic strategies.This thesis is devoted to constructing intelligent stimuli-responsive nanocarriers and developing synergistic therapeutic strategies based on cancer starvation therapy,which can improve the therapeutic efficiency and minimize the side effects to normal tissues.The main contents are as follows:1.Cascaded Aptamers-Governed Multistage Drug Delivery System Based on Biodegradable Envelope-Type Nanovehicle for Targeted Therapy of HER2-Overexpressing Breast CancerConstructing nanovehicles by nanomaterials is a novel drug delivery system(DDS)construction strategy.However,most of the reported nanovehicles are considered to be poorly targeted and the premature drug leakage during delivery process may cause serious side effects.Capitalizing on the recognition capability and biocompatibility of aptamers,we designed a cascaded aptamers-governed multistage drug delivery system based on biodegradable envelope-type nanovehicle for targeted delivery and the stimuli-responsive release of the drug.The nanovehicle was constructed by HER2 and ATP-specific aptamers.The outmost HB5 aptamer can specifically target HER2 protein overexpressed on cancer cells,while the ternary complex core(TC)constructed by ATP aptamer can gradually disintegrate under high concentration of ATP in cancer cells and accelerate the release of anticancer drug(-)-epigallocatechin gallate(EGCG).Nanostructured lipid carriers(NLC)were constructed to wrap and stabilize the loosely bounded TC,minimizing the toxic side effects of the nanovehicle caused by premature drug leakage during delivery process.The nanovehicle was completely constructed by drugs and biomolecules approved by the FDA,which have extraordinary biocompatibility and biodegradability.The nanovehicle possesses the dual-targeted recognition capabilities conferred by HB5 and ATP aptamers and all composition monomers are stable and non-toxic.It provides a novel nanovehicle construction strategy for designing more drug delivery platforms with high targeting efficiency,high therapeutic efficiency and negligible side effects.2.Promoting Oxidative Stress in Cancer Starvation Therapy by Site-Specific Startup of Hyaluronic Acid-Enveloped Dual-Catalytic NanoreactorsCutting off the glucose supply by GOx has been regarded as an emerging strategy in cancer starvation therapy.However,the standalone GOx delivery suffered suboptimal potency for tumor elimination and potential risks of damaging vasculatures and normal organs during transportation.To enhance therapeutic efficacy and tumor specificity,a site-specific activated dual-catalytic nanoreactor was herein constructed by embedding GOx and ferrocene in hyaluronic acid(HA)-enveloped dendritic mesoporous silica nanoparticles(DMSNs)to promote intratumoral oxidative stress in cancer cells and improve the therapeutic efficiency of cancer starvation therapy.In this nanoreactor,the encapsulated GOx served as the primary catalyst that accelerated oxidation of glucose and generation of H2O2,while the covalently linked ferrocene worked as the secondary catalyst for converting the upstream H2O2 to more toxic hydroxyl radicals(·OH)via a classic Fenton reaction.The outmost HA shell not only offered a shielding layer for preventing blood glucose from oxidation during nanoreactor transportation,thus minimizing the probable oxidative damage to normal tissues,but also imparted the nanoreactor with targeting ability for facilitating its internalization into CD44-overexpressing tumor cells.After the nanoreactor was endocytosed by target cells,the HA shell underwent hyaluronidase(HAase)-triggered degradation in lysosomes and switched on the cascade catalytic reaction mediated by GOx and ferrocene.The resultant glucose exhaustion and ·OH accumulation would effectively kill cancer cells and suppress tumor growth via combination of starvation and oxidative stress enhancement.The nanoreactor improves the therapeutic efficiency by cascade catalytic reaction and minimizes the side effects by targeting and shielding abilities of the HA shell.Our study provides a novel construction strategy for designing more nanoreactors with high synergistic therapeutic efficiency and negligible side effects in the future.