Tumor Microenvironment(TME)-Responsive Nanoplatform For Targeted Saporin Delivery And Breast Cancer Therapy

Proteins play vital roles in various cellular processes(e.g,signaling transduction,metabolism,and gene regulation)and their dysfunction is widely involved in the development and progression of various diseases,including cancer.Therefore,protein therapy has shown great potential for cancer therapy with the advantages of high selectivity,strong activity,and low toxicity.However,due to their intrinsically vulnerable structure and susceptibility to enzymatic degradation,most therapeutic proteins(e.g,enzymes,growth factors,and cytokines)suffer from poor physicochemical/biological stability and potential immunogenicity.With the rapid development of nanotechnology,nanocarriers have been widely used for drug delivery to improve their anti-cancer efficacy.In particular,compared to normal cells,cancer cells show hypoxic environment and abnormal metabolism,which induces the different physiological microenvironment in the tumor tissues,including weakly acidic and hypoxic microenvironment,over-expression of special chemicals(e.g,glutathione,etc.)and enzymes(e.g,matrix metalloproteases,etc.).Based on the distinct physiological microenvironment,development of TME-responsive nanocarriers has become a research focus in the drug delivery field.Thses TME-responsive nanocarriers are stable during blood circulation and in the normal tissues.After arriving the tumor tissues,the TME-responsive nanocarriers can respond to a TME signal(e.g.,acidic p H,overexpressed enzymes,and hypoxia)to change their physicochemical properties including size,zeta potential,and hydrophilic-hydrophobic balance,thereby leading to enhanced diffusion,cellular uptake,and/or intracellular cargo release.Currently,TME-responsive nanocarriers have been widely used to improve the anti-cancer efficacy of chemotherapeutic drugs.However,the application of these nanocarriers for systemic protein drug delivery and cancer therapy is still in infancy.In this thesis,considering that the advantages of TME-responsive nanocarriers may address the issues of protein drugs for cancer therapy,we designed and developed a new long-circulating and TME p H-responsive polymeric nanocarrier for targeted delivery of cytotoxic protein saproin and effective breast cancer therapy.This thesis contains the following two chapters.In Chapter 1,we reviewed the preparation and application of TME-responsive nanocarriers for drug delivery in recent years.These TME-responive nanocarriers mainly include p H,hypoxia,enzyme,ROS,and reduction-responsive nanocarriers.In this chapter,the responsive mechanism of TME-responsive nanocarriers is systematically described.Based on the advantages and disadvantages of TME-responsive nanocarriers,we also summarized the main purpose of this thesis.In chapter 2,we designed and developed a robust nanocarrier made with a TME p H-responsive Meo-PEG-b-PPMEMA polymer and a cationic lipid-like compound G0-C14 for targeted delivery of cytotoxic saporin and breast cancer therapy.After intravenous injection of this saporin-loaded nanoparticles,they show long blood circulation that could enhance tumor accumulation via the enhanced permeability and retention(EPR)effect.After arriving the tumor tissues,this nanoplatform could respond to a TME p H to rapidly release saporin/G0–C14 complexes.Subsequently,the cationic characteristic of G0-C14 could induce endosomal swelling through the ‘‘proton sponge’’ effect and thus improve endosomal escape of the internalized protein,thereby leading to an effective inhibition of tumor growth.