Tumor Acidity Sensitive Cell Nuclear Targeting Nanocarriers For Drug Delivery

Chemotherapy is one of the most important methods for tumor therapy,but it has been long suffered from severe side effect and low therapeutic efficiency.To solve these problems scientists have developed many drug delivery systems to transport drugs targeted to tumor tissue.Except for the EPR effect of nano-sized carriers,actively conjugating target ligands to nanoparticles could effectively improve the tumor targeting effect,and the stimuli responsive drug delivery systems that utilizing the specific tumor microenvironment is another nice targeting strategy.The charge reversal drug delivery systems that respond to the slightly acidic tumor microenvironment and change their surface charge from negative to positive are powerful and smart tumor targeting method.On the other hand,the cell nuclei are the heart of the cells and the final location of many therapeutic agents,and targeted delivering drugs to cell nuclei might greatly improve the therapeutic efficacy while bypass some hard obstacles.However,nuclei targeted drug delivery has long been ignored and there are little studies,which is also quite a challenge.In view of these,this dissertation focus on the the chemical modification of nuclear localization signal peptides to combine the nuclear target function with charge reversal strategy to construct a series of tumor and cellular nuclei dual-target drug delivery systems.In chapter 1,the tumor target strategies,especially the tumor acidity triggered charge reversal drug delivery systems are summarized.Then the development of nuclear targeted drug delivery is introduced.In chapter 2,a polypeptide micelle PLLeu-PLL(DMA)-Tat(SA)that could stepwise respond to tumor acidity and endosome acidity to eventually realize the tumor targeted cellular uptake and cell nuclear target delivery is constructed.Amphiphilic diblock copolymer PLL-PLLeu was synthesized by ring opening polymerization to assemble into positively charged micelles.Then a Tat peptide amidated by succinyl chloride was conjugated via click reaction.Afterward,the lysine amino residues of the polylysine were amidated by 2,3-dimethylmaleic anhydride(DMA).The DMA and SA amides could be hydrolyzed at pH 6.5 and 5.0,respectively,which result in the tumor acidity triggered charge reversal and improved nuclear drug delivery.In chapter 3,due to the critical size restriction for nanoparticles to enter the cell nuclei,the mesoporous silica nanoparticles(MSN)which could friendly control their size were used to construct an effective nuclear targeting drug delivery system.The most classical nuclear localization peptide NLS was used and modified with DMA(MSN-NLS(DMA)to realize the tumor target at the same time.The physiochemical characterization and the cell experiments proved that the MSN-NLS(DMA)could reverse its charge and then be selectively internalized by cells at pH 6.5.What’s more,MSN-NLS(DMA)could strongly target to cell nuclei and delivery DOX directly to nuclei and improve the therapeutic efficiency.In chapter 4,in view of the biodegradability and the biological safety of the nanocarriers,a series of NLS peptide micelles was constructed to realize the nuclear target effect.The self-assemble behavior and size distribution of the peptide micelles were studied and the smallest micelle was selected.The NLS peptide was again modified with DMA to endow the peptide micelle the charge reversal and tumor targeting ability.The cell experiments proved that the smallest NLS peptide micelle could be selectively internalized by cells at pH 6.5 and effectively target to cell nuclei.