Study On Tumor-targeting Delivery Of Folate Receptor Mediated Drug/gene-loaded Albumin Biomimetic Nanoparticles

In this study,a folate-modified albumin nanocarrier was synthesized to respond to the pH microenvironment of tumor.Based on this nanocarrier,a folate receptor mediated pH/reduction-sensitive albumin nanoparticle was designed for the in vivo delivery of anticancer drugs.Furthermore,given the lack of tumor-targeting of nanoparticles,a delivery strategy combined upregulated folate receptor with the delivery of folate-modified albumin nanoparticles was proposed for enhancing the drug/gene targeting step by step,which is expected to enhance the anti-tumor effect of drug/gene.The first chapter:It mainly summarizes the current situation of tumor therapy,the advantages,disadvantages and applications of albumin nanoparticles in tumor targeted therapy were discussed,from the aspects of in vivo targeting,intracellular release and development prospects based on the research background at home and abroad.Based on this,the idea of the subject was put forward.The second chapter:How to overcome the cell membrane barriers and achieve release payloads efficiently in the cytoplasm have been major challenges for anticancer drug delivery and therapeutic effects with nanosystems.In this study,bovine serum albumin(BSA)was modified with folate acid(FA)and histamine(His),which was then used as the nanocarrier for the antitumor agent doxorubicin(DOX).The DOX-loaded nanoparticles(DOX/FBH-NPs)were prepared via a crosslinking method,and the release of DOX from these nanoparticles(NPs)exhibited pH/reduction-responsive behaviors in vitro.These NPs interacted with the folate receptor(FR)overexpressed on the cell membrane of 4T1 cells and achieved enhanced endocytosis.Afterwards,these NPs exhibited pH-responsiveness within endo-lysosomes and escaped from endosomes due to the "proton sponge" effect due to the graft of His,and then completed release of DOX was triggered by high concentration of glutathione(GSH)in cytoplasm.Thus,DOX/FBH-NPs exhibited excellent cytotoxicity against 4T1 cells in vitro.Benefited from the enhanced permeability and retention(EPR)effect and FR-mediated endocytosis,these NPs gained satisfied tumor-targeting effects in vivo and efficient delivery of DOX to tumor tissues.As a result,these NPs exhibited excellent antitumor effects and decreased adverse effects in vivo.In conclusion,these dully modified BSA-based NPs showed enhanced tumor-targeting effects in vivo and intracellular pH/reduction-responsive behaviors,providing a promising strategy for the efficient delivery of antitumor agents.The third chapter:Acute myeloid leukemia(AML)is the most universal type of hematological malignancy,despite bone marrow transplantations and chemotherapy with poor therapy.Folate receptor ?(FR?)has high affinity to folate acid(FA),which was often found to be aberrantly expressed on hematological linage cell lines such as KG-1 cells(AML cells).Benefited from the narrow tissue specificity of FR? expression,NPs modified with FA has been widely applied in FR-targeted therapies to AML.Besides,small interfering RNA(siRNA)technique would offer an effective tumor therapy for its advantages of high specificity and high therapeutic efficacy.Given the defect of siRNA in the delivery in vivo,such as negative charge,unable to across cell membrane due to large molecular weight or water solubility,a safe and effective delivery system was predominantly under consideration.Thus,the siRNA-loaded nanoparticles mediated by FR(Lip-S@FBH)were conducted by cationic liposomes with high transduction efficiency and BSA modifier as previously synthesized.However,how to further enhance the tumor-targeting and cellular uptake of NPs have been great challenges of cancer therapy.It was reported that FR? could be selectively augmented by all trans retinoid acid(ATRA).Herein,the treatment could be achieved by FR expression enhanced by ATRA NPs,the subsequent promoted endocytosis of FA modified biomimetic albumin NPs and the tumor inhibition mediated by siRNA.The strategy combined the FR amplification effect with the effective delivery of siRNA,was mostly desirable for the AML-targeting therapy.