Construction Of Bombyx Mori Silk Fibroin/zif-8 Composite Nanocarrier And Its Performance In Tumor Therapy

Bombyx mori(B.mori)silk fibroin(SF)is a natural biopolymer material.SF-based drug carriers have been widely studied owing to its good biocompatibility,low immunogenicity,degradability,easy processing and modification.It plays an important role in delivering multiple types of drugs,including small molecules,enzymes,and nucleic acids.However,how to reduce drug loss and enhance tumor-targeting ability to enrich drugs at tumor sites are still problems need to be solved for SF-based drug carriers.Owing to its abundant amino acids and self-assembly properties,SF has been considered as a good bio-template to induce the self-assembly of inorganic materials,such as gold nanoparticles and silica.Zeolitic imidazolate framework-8(ZIF-8)is one of the emerging metal-organic framework family.It combines some advantages from organic and inorganic materials,such as porous structure,high porosity,adjustable pore size and sensitive p H responsiveness.Thus,it has also been regarded as one of the ideal candidates for drug delivery.Therefore,this study explored the use of SF as biotemplate to induce the formation of SF/ZIF-8 nanoparticles.This complex can be a promising drug delivery carrier with good biocompatibility,high drug encapsulation efficiency,high p H sensitivity and tumor-targeting ability.Firstly,we used doxorubicin(DOX)-loaded SF nanoparticles(DSF-NPs)as templates to induce formation of SF/ZIF-8 composite nanoparticles(DSF@Z-NPs)in situ with core-shell structures.The p H-responsive drug release and anti-tumor properties of DSF@Z-NPs were verified through in vitro/vivo experiments.On this basis,the regulatory effect of SF on ZIF-8 was further investigated.The composite nanocarriers co-loading the DOX and indocyanine green(ICG)by one-pot method not only had sensitive p H responsiveness,but also realized the high efficient loading capacity.And then tumor-targeting peptide obtained by phage biopanning was introduced to improve the tumor-targeting ability.The peptide-modified composite nanoparticles were used for tumor chemistry,photothermal and photodynamic synergistic targeted therapy.The results obtained are as follows:(1)Taking DOX-loaded SF-NPs(DSF-NPs)as bio-templates,core-shell(core:DSF-NPs,shell: ZIF-8)composite nanoparticles were constructed for MCF-7breast cancer in situ chemotherapy.Constructed by freezing-thawing method,SF-NPs in about 200 nm size had good dispersion and then DOX was loaded into SF-NPs(termed as DSF-NPs).DSF-NPs were applied as bio-templates and core structures,over which a 20 nm-thickness-ZIF-8 shell was induced.Compared with DSF-NPs,DSF@Z-NPs significantly improved the p H-responsiveness.DOX loss reduced under neutral condition,and DOX was slowly released with the degradation of ZIF-8 shell in an acidic tumor microenvironment.DSF@Z-NPs had sufficient biological safety without significant effect on the serum biochemical indicators and morphologies of important tissues and organs from mice.Therefore,DSF@Z-NPs was a safe and efficient p H-responsive nano-drug carrier for tumor therapy.(2)Self-assembly of ZIF-8 was regulated through SF to construct SF/ZIF-8composite nanoparticles with efficient co-loading of DOX and ICG by one-pot synthesis.The size of SF/ZIF-8 composite nanoparticles(ZS NPs)decreased with the increasement of SF concentrations.When the SF concentration reached to 10 mg/m L,the obtained ZS NPs had good dispersion in about 100 nm diameter.The encapsulation rates of DOX and ICG added by one-pot method were as high as 99.07% and 96.18%,respectively.The efficacies were higher than other conventional nano-drug delivery systems,laying the foundation for realizing synergistic treatment of tumors.(3)MCF-7 tumor-targeting peptides were modified on the surface of ZS/ID NPs,which were used for breast cancer-targeted chemistry,photothermal and photodynamics synergistic therapy under imaging guidance.Aiming to improve the targeting ability to MCF-7 tumor,AR(AREYGTRFSLIGGYR)peptide obtained from in vivo biopanning was introduced to the surface of PEI-modified ZS/ID NPs(termed as AR-ZS/ID-P NPs).Except for still having the sensitive p H responsiveness,AR-ZS/ID-P NPs also had dual targeting capabilities from enhanced permeability and retention(EPR)effect and AR peptide affinity.It can realize tumor chemistry,photothermal and photodynamics synergistic therapy under the guidance of near-infrared fluorescence imaging and thermal imaging.This study confirmed that ZIF-8 nanocrystals can be induced in situ using DSFNPs as bio-templates.Core-shell SF/ZIF-8 composite carrier had good biocompatibility and sensitive p H responsiveness.On this basis,SF fully played the role in regulating ZIF-8 nucleation and growth.SF/ZIF-8 composite nanoparticles high efficiently coloaded ICG and DOX.And then,MCF-7 tumor-targeting peptide was introduced to help realize synergistic targeted tumor therapy.The construction of SF/ZIF-8composites not only broaden the application of SF in the field of drug delivery,but also provided a basis for the integration of tumor imaging diagnosis and synergistic therapy.