Biotin Modifed Cholesteryl Pullulan As A Novel Drug Nanocarrier: Synthesis、Characterization And Preliminary Safety Evaluation

Cholesterol-modified pullulan (CHSP), as an anticancer drug nano-carrier using passivetarget tumors, has the property of amphiphilic and self-aggregation in water. To improve thetherapeutic index and decrease its toxic effects, we synthesized biotin grafted CHSPcopolymers (Bio-CHSP), made further characterization and preliminary safety evaluation.The main contents are as follows:Biotin grafted Cholesterol-modified pullulan (Bio-CHSP) conjugate was synthesized andcharacterized by fourier transform infrared (FT-IR), proton nuclear magnetic resonance (1H-NMR), and X-ray diffraction (XRD). The degree of substitution (DS) of biotin moietydetermined by1H-NMR ranged from20.1to38.9biotin groups per hundred glucose units.Various physicochemical properties of Bio-CHSP self-assembled nanoparticels werecharacterized by dynamic laser light scattering (DLS)、 fuorescence spectroscopy andtransmission electron microscopy (TEM). The Bio-CHSP NPs had a homogeneously sphericalshape with the diameter from100to180nm. With the DS of biotin moiety increased, thecritical aggregation concentration (cac) and diameter of the Bio-CHSP NPs decreased.Mitoxantrone, as a model drug, was loaded into Bio-CHSP NPs by dialysis method. Thediameter of the drug-loaded Bio-CHSP NPs was decreased with the DS of biotin increased.There was no significant impact on the diameter, which has the same DS and certaindrug/carrier ratio, and the drug loading content (LC) was enhanced with the weight of carrierincreased, whereas, the loading content(LC) and loading efficiency (LE) had relationship withthe content of Bio-CHSP carrier. The release behavior of MTO from Bio-CHSP-29.2NPs wasstudied in different PBS in vitro, MTO release rate increased with the pH value decreased.Compared with the free drug, the drug-loaded Bio-CHSP NPs exhibited a biphasic release,which showed sustained release.The toxicity study in vivo was performed to establish the safety of the blank Bio-CHSPNPs after i.v. administration in kunming mice. The result showed that Bio-CHSP NPs werewell tolerated at the dose of200mg/kg and there was no significant diffe rence between theexperimental group and control group, including weight, food intake and the pathologicalchanges, such as heart、liver、spleen、lung、kidney. Therefore, the Bio-CHSP has thepreliminary bio-safety, and could be used as a novel drug nanocarrier in the future.