PH-Sensitive Nanogels Based On Hyaluronic Acid For Drug Delivery

Compared with the normal tissues,tumor micro-environment has a slight acid environment,which needs pH responsive drug carriers to enhance drug treatment effect and reduce drug side effects.Furthermore,nanogels with network construction as drug carrier possess many advantages,such as high drug loading efficiency,high water content.And hyaluronic acid(HA)is an anionic natural biodegradable polymer and can be modified hydroxyl and carboxyl functional groups,which widely used to drug carrier material.Therefore,novel pH responsive hyaluronic acid nanogels used as drug carriers has great significance.This text mainly contains the two parts,more details are as follows:1.Preparation and pH-sensitive property of bortezomib loading hyaluronic acid nanogelsBy modifying the hydroxyl of HA with methacrylic anhydride,the methacrylated HA(MAHA)was obtained.Then MAHA was selected as the monomers,the pH-sensitive methyl methacrylate with ketal was selected as cross-linker(DMAEP)of polymerization reaction to prepare HA-based nanogel by a one-pot.The size of nanogels are within 75-160 nm by control the proportion of cross-linker and the negative charge under-15 mV on the surface of nanogels.The morphology of nanogels,observed by atomic force microscopy,have a spherical structure and uniform distribution.Used the poorly soluble doxorubicin(DOX)as the model drug for the p H-sensitive nanogels,the drug-loading content was closely related to the content of cross-linker,and which reached up to 12.15%.The experiment of in vitro release shows that drug release behavior of pH-sensitive drug-loading nanogels present pH-dependent behavior,the cumulative release content of doxorubicin was approximately 35% in 72 h under pH 7.4 condition,and which was approximately 83.34% in 72 h under pH 5.0 condition.The in vitro cytotoxicity experiment proved that the nanogels was safe and non-toxic,and pH-sensitive drug-loading nanogels for tumor cells have stronger cytotoxicity than non-pH-sensitive drug-loading nanogels.In the end,in vivo anti-tumor test also showed that the antitumor effect of pH-sensitive drug-loading nanogels is better than nanogels which don’t contain ketal and free DOX.2.Hyaluronic acid nanogels modified by dopamine for bortezomib deliveryIt was used dopamine(DOPA)modified the carboxyl of the methacrylated HA(MAHA)to get the dopamine(DOPA)modified MAHA(DOPA-MAHA).Then the nanogels(NGs)was synthesized via a one-pot free radical polymerization using ethylene glycol dimethacrylate(EGDMA)as a cross-linker.The size of nanogels was measured by DLS,which revealed the formation of the particles with diameters of approximately 100-200 nm,and its surface carry with the negative charge.The spherical morphology of the nanogels was characterized by AFM.Bortezomib(BTZ)with boric acid group as the model drug,it can covalent binding with catechol group of DOPA in alkaline condition to form pH-sensitive borate ester bonding.The crystal state of BTZ,nanogels,physical mixture of BTZ and nanogels and BTZ-loaded nanogels were determined by X-ray powder diffraction(XRD)and the result showed that BTZ and physical mixture has higher crystallinity,but BTZ-loaded nanogels and nanogels are amorphous state.In vitro drug release shows that the drugs released from nanogels reached 76.06% in 24 h at pH 5.0 environment,which is higher 3.4 times than in pH 7.4 environment.MTT assay was revealed that NGs has favorable biocompatibility,and the cytotoxicity of drug-loading nanogels for tumor cells have dose-dependent property.The in vivo antitumor activities of the NGs-BTZ has better than free BTZ.