| Cancer is one of the diseases with the characteristics of high morbidity and high mortality,which seriously affects human life and health.Therefore,the diagnosis and treatment of cancer is still one of the issues to be solved.in the past decades,nanocarriers with different physicochemical properties(e.g.,size,shape,stiffness and surface chemistry)have been developed,which have effectively reduced the toxic side effect of anticancer drugs.However,the low bioavailability of anticancer drugs limits their applications.Therefore,improving the bioavailability of anticancer drugs is the main development direction for the next generation of anticancer drug carriers.We designed and fabricated a series of polymer nanoparticles(NPs)by self-assembly and sono-polymerization strategies,based on the characteristics of biological barriers and tumor microenvironment.The bio-nano interactions of the obtained polymer NPs as well as their application in cancer diagnosis and therapy were systematically investigated.The contents of this dissertation include the following five chapters.:Chapter I is a comprehensive introduction of the research background.Based on the development history of drug carriers,the characteristics of drug carriers at different stages in past few decades are introduced.Different types of drug carriers are summarized based on the properties of the carrier materials.The bio-interfaces and biological barriers are introduced to guide the engineering of drug carriers.Perspectives for designing drug carriers to overcome biological bar:rier and improving delivery efficiency are also reviewed based on the characteristics of bio-nano interaction.Finally,the applications of nanocarriers in tumor diagnosis,treatment,and cancer theranostics are summarized.In chapter Ⅱ,we report the synthesis and assembly of dual-responsive supramolecular polymer brushes based on the host-guest interaction between β-cyclodextrin(P-CD)on star-like side chains and azobenzene groups on a polymer backbone.The fraction of the hydrophilic-hydrophobic units can be easily controlled via changing the ratio of host and guest molecules.The supramolecular polymer brushes can self-assemble into unimolecular micelles,multi-molecular micelles,and vesicles with tunable sizes from 30 to 300 nm in water,respectively,with the decrease of β-CD side chains.The assemblies of micelles or vesicles can be disassembled by the trigger of UV light irradiation due to the responsive azobenzene groups.in addition,the micelles or vesicles can further assemble into strawberry superstructures by increasing the temperature.Our work provides a platform for the generation of assemblies across a wide range of scales,from polymer brushes to micelles or vesicles and superstructuresIn chapter Ⅲ,theranostic polymer NPs are fabricated via the assembly of an amphiphilic paramagnetic block copolymers(PCL-b-PIEtMn),in which IR-780 and doxorubicin(DOX)were co-encapsulated for magnetic resonance(MR)and near infrared fluorescence(NIRF)imaging as well as photo thermal therapy(PTT)-enhanced chemotherapy.The synthesized amphiphilic paramagnetic block copolymers demonstrated high relaxivity(r1=7.05 mM-1 s-1).The encapsulated DOX could be released by the trigger with near infrared(NIR)light.in vivo imaging confirmed that the paramagnetic NPs could be accumulated effectively at tumor sites.Upon NIR laser irradiation,tumor growth was inhibited by PTT-enhanced chemotherapy.The advantages of the reported system lie in the one-step convergence of multiple functions(e.g.,imaging and therapy agents)into one delivery vehicle and the dual mode imaging-guided synergistic PTT and chemotherapy.This study represents a new drug delivery vehicle of paramagnetic NPs for visualized theranostics.In chapter Ⅳ,poly(L-lysine)(PLL)and poly(L-glutamic acid)(PGA)were chosen as building blocks for the fabrication of polypeptide NPs based on electrostatic interaction in aqueous medium.The size and surface charge of polypeptide NPs can be controlled by adjusting the ratio of positively and negatively charged polypeptides and the molecular weight of the polypeptides.Charged functional molecules(e.g.,drugs)and NPs could be encapsulated in this polypeptide NPs during the self-assembly process.in addition,the redundant amine groups on the NP surface can be used for surface modification.(1)in the first part,we report the one step assembly of polypeptide vehicles encapsulated with anticancer drug and Fe3O4 nanoparticles(Pt&Fe3O4@PP)for T2-weighted MRI and combination therapy of chemotherapy and ferroptosis therapy.The surface modification with poly(ethylene glycol)can prolong the blood circulation time.The number of Fe3O4 NPs in a single polypeptide vehicle is controlled by adding different amount of Fe3O4 NPs.Pt drug and Fe2/3+ions are released in the reduction and acidic environments(e.g.,endosome and lysosome).respectively,which could induce the intracellular cascade reactions to generate sufficient.OH for ferroptosis.Meanwhile,the released Pt drug can result in apoptosis of cancer cells.in addition,the encapsulated Fe3O4 can also be used for T2-weighted MRI to monitor the distribution of carrers in tumor.in vitro and in vivo results indicate that the reported polypeptide carriers can efficiently inhibit cancer cell growth without causing significant systemic toxicity.This study combines bio-imaging,chemotherapy and ferroptosis therapy based on self-assembled polypeptide vehicles for cancer theranostics,which has great potential in biomedical applications.(2)in the second part,we report the assembly of dual-responsive polypeptide drug carrier with pH-sheddable PEGylation to overcome biological barriers and enhance therapeutic efficiency.The polypeptide core composed of PLL and PGA was fabricated by electrostatic self-assembly method and modified with pH-sheddable PEG shell.Reduction-sensitive cisplatin prodrug can be encapsulated into the polypeptide carriers via amide bond.The PEG shell is cleavable at the acidic tumor microenvironment,which results in the surface charge reversal and size reduction that therefore enhances cellular uptake.in addition,the GSH in cancer cells induce the Pt drug release from the polypeptide nanocarriers.As a result,the pH-responsive polypeptide nanocarrier induces higher cytotoxicity to cancer cells than the non-responsive nanocarriers.This process highlights the engineering of transformable polypeptide drug carriers,which provide a promising way for enhanced drug delivery efficacy.In chapter Ⅴ,we report a targeted PEG-based chemotherapy system synthesized via a catalyst-free sono-polymerization process for drug delivery.The polymerization process was fast(20 min),and different monomers were able to be polymerized to form NPs in a one-pot process.GSH-responsive platinum prodrugs and cyclic peptides containing Arg-Gly-Asp(RGD)could be modified in NPs and on the surface of NPs,respectively.We demonstrated that the low-fouling and targeted properties of NPs at the cellular level.More importantly,these PEG-based NPs can be freeze-dried into a powder form and re-dispersed in an aqueous solution without aggregation,which may facilitate the storage and transportation of nanomedicine.This study establishes a green and efficient method to engineer targeted drug carriers for drug delivery. |
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