A Novel Anticancer Drug Delivery System Based On Poly(A) Functionalized Nanoparticles

Poly adenine (poly(A)) is widespread in biosystems, and is closely relatedto several life activities, such as the transcription and translation of DNA.Meanwhile, the end of mRNA come from most of the cancer cells has anoverexpression of poly(A). Therefore, to obtain the antitumor effect, poly(A)which exists on the end of mRNA has been uesd as the target spot in manydrug designs, in order to suppress the mRNA via the specific combination ofHydrogen bonding between poly(A) and mRNA. Previous research hasshown that the binding force of hydrogen bonding stands between that ofcovalent binding and electrostatic interaction. And on some particularconditions(such as low pH, increasing temperature), the binding forcedeclines. A novel kind of anti-tumor drug carrier is expected by takingadvantage of the characteristic of the interaction between poly(A) and drugs.Meantime, with the development of nanotechnology, nanomaterials havebeen extensively used in biomedical field for their high specific surfacearea, easy modification and other unique functions. It will make greatsignificance for anti-cancer strategies to develop a kind of nano-drug-loaded carrier with the advantages of facile preparation, goodbiocompatibility and controlled release which can improve the ability oftargeting and reduce the dose of drug as well as the toxic and side effect.Aiming to construct a new anti-tumor nanoparticles drug delivery system,this essay carried out the research of anti-tumor drug carrier based on thepoly(A) functionalized nanoparticle. Our work was mainly composed of thefollowing two parts:1.pH controlled release anticancer drug delivery based on poly(A)/SiO2nanoparticlesIn this work, a pH controlled release anticancer drug delivery based onpoly(A)/silica nanoparticles has been developed by taking advantage of theweak interaction of isoquinoline alkaloid and adenine at acidic environment.In this design, the poly(A) was firstly modified on the surface of the silicananoparticles through the EDC/NHS crosslinking. The coralyne was selectedas a model drug. Through the adenine-coralyne-adenine binding, the coralyne then can be loaded onto the poly(A)/silica nanoparticles to formcoralyne-poly(A)/silica nanoparticles complex. The properties ofpoly(A)/silica nanoparticles and coralyne-poly(A)/silica nanoparticlescomplex were characterized by agarose gel electrophoresis, transmissionelectron microscopy (TEM) and fluorescence spectroscopy. The stability ofthe coralyne-poly(A)/silica nanoparticles complex and the effect of drugrelease at different pH buffer were investigated. In addition, theintracellular behavior of coralyne-poly(A)/silica nanoparticles in Hela cellswas further studied by using laser confocal scanning microscopy and MTTassay. The results showed that the coralyne-poly(A)/silica nanoparticlesexhibited a good stability at neutral pH buffer. At acidic environment(pH<6), the coralyne was released easily from the nanoparticles complexbecause the hydrogen bonds interaction between coralyne and adenine wasgetting weak. Therefore, the release of coralyne could be controlled bychanging pH. The further cells experiments demonstrated that the coralyne-poly(A)/silica nanoparticles could be endocysised by the Hela cells anddemonstrated highly efficient operation at lysosomal pH, while thepoly(A)/silica nanoparticles was relative biocompatible and suitable to useas drug carriers. This research provided a new way for the isoquinolinealkaloid drug delivery system.2.pH and light controlled release anticancer drug delivery based onpoly(A)/gold rods.On the basis of the previous work, the specific combination betweenpoly(A) and coralyne and the unique spectrum of gold rods were used todevelop a novel drug delivery system, in which the release controlled byboth the pH and light. This multifunctional system realized doubleresponsed release, photothermic therapy and chemotherapy simultaneously.In this system, poly(A) was modified on the surface of gold rods throughthe Au/Sulfhydryl crosslinking to load coralyne. The loading efficiencydecreased for the photothermal effect caused by the near infrared lightabsorbtion of gold rods. UV-Vis spectrophotometer, fluorescencespectrophotometer, transmission electron microscopy (TEM) and zeta-sizeparticle sizer were used to characterize the gold rods and their complexs.Then ultraviolet-visible spectrophotometry and confocal laser scanningmicroscope (CLSM) were used to investigate the drug release in solutions and intracellular. In addition, MTT experiments were utilized to determinethe cytotoxicity. The results showed this system had an ideal response toboth pH and light stimulis, and the model improved the efficiency of drugcontrolled release significantly. With coralyne releasing, the fluorescencesignal quenched by the gold rods recovered gradually, which indicated thedrug intracellular release. MTT experiment showed that the system itselfhad good biocompatibility while it realized the drug therapy after theloading of coralyne and photothermic therapy after the irradiation of nearinfrared light simultaneously. This research further expanded the applicationof functional nano-materials in the therapy of anti-tumor.