Preparation, Characterization And Biological Evaluation Of BC Whisker/P (NiPAAm-co-BMA) Nanogel Complex For Interventional Therapy Of Hepatocellular Carcinoma

Currently, transcatheter arterial embolization (TAE) is the first choice of thetreatments for intermediate or advanced stage hepatocellular carcinoma. Embolizationagents are of great importance to this treatment. Bacterial cellulose (BC), produced byAcetobacter xylinum, consists of ribbon-shaped nano-fibers in web-like structures. Poly(N-isopropylacrylamide-co-butylmethacrylate)(PNB) nanogel dispersion exhibitedreversible thermosensitive sol-gel phase behaviors and it could be used as a new materialfor interventional therapy. In this paper, BC whiskers were nanosized and then utilized toprepare BC whisker/PNB nanogel complex, which could enhance thebloodvessel-embolization property of PNB nanogel. Main contents and results are asfollows:(1) BC whiskers were first nanosized by microfluidization method under thepressure of2000bar. The nanosized and lyophilized BC whiskers were dispersed inaqueous, and via soap-free emulsion polymerization, BC whisker/PNB nanogel complexwas prepared by the addition of NiPAAm and BMA. The morphology, average size andsize distribution of the nanogel complex were characterized by transmission electronmicroscope (TEM) and dynamic light scattering (DLS). The complex had an average ofsize of400±50nm and uniform size distribution. Independent BC whiskers with a lengthof approximately600nm and diameters between40nm and60nm were clearly observed.DLS and TEM characterization revealed that BC whiskers were well combined with PNBnanogel particles. It can be seem that results from the DLS measurements and from TEMwere basically consistent.(2) The vial inverting with visual method was utilized to study the thermosensitivebehaviors of concentrated BC whisker/PNB nanogel complex dispersion. The dispersionusually underwent four phases when temperature increased: semitranslucent swollen gel,semitranslucent fluid, cloud suspension and white shrunken gel. The gels of complexnanogels having the more content of BC have the stronger gelation strength, indicatingthat the addition of BC in PNB nanogel can enhance the gelation strength on themacroscopy, and more BC in nanogel, stronger gelation intensity it has. And the result makes sense for the use of BC/PNB complex nanogel as an embolizing agent forinterventional therapy of HCC, because the embolizing agents with higher gelationstrength are harder to be cleaned up, which is just the expected effect.(3) The kinetics of the thermosensitive volume phase transitions of pNiPAAm/BMAnanogel particles were evaluated by measuring the relative turbidity of nanogel aqueousdispersions under varying temperature. The viscosity of nanogel dispersions was affect bytemperature, shear rate and the concentration of the nanogels. Temperature, shear rate andthe concentration of the complex have heavily influence on the viscosity of BCwhisker/PNB nanogel complex. The concentrated dispersion showed good shear thinningbehavior, which play a key role on the interventional therapy for hepatocellular carcinoma.Meanwhile, the enriched blood supply and slow blood velocity in tumor could increase theviscosity of the complex dispersion, followed by gelation of the complex. With an increaseof temperature, the rheological parameters (G’, G’’) first decrease and then increaseremarkably. The phase transition temperatures of the nanogel dispersions respectively are29.7℃,28.1℃,27℃and26.8℃. The rheological results are generally accordant with theDSC results.(4) Cytotoxicity test (MTT) showed that BC whisker/PNB Nanogel complexes haslittle cytotoxicity at low concentrations (<0.01wt/v%), unexpectedly, it can promote thepropagation of HUVEC cells at high concentration (0.1~0.5wt/v%), and the higher theconcentration the more obvious effect the promotion. Meanwhile, the promotion effect isclosely related to the BC whiskers content.In summary, BC whiskers/PNB nanogel dispersion has the sol-gel phase transitionbehavior as the temperature changes, and it has higher gelation strength and betterbiocompatibility compared to the previous PNB nanogels, can be used as a new type oftemperature-sensitive material.