| Cancer is believed to be the major threat to the globe human health, and could threat the life quality of human and limit the social economic development for the present and coming decades. DTX, as one of the most effective first-line chemotherapy regimen for breast cancer and lung cancer, processes very high biological antitumor activity and has been used in clinical treatment widely. However, its poor water solubility, high affinity to P-gp and plasma protein, low bioavailability and severe side effects inhibit DTX to achieve its best pharmacological action. It’s necessary to develop a new DTX delivery system to improve the solubility, antitumor efficacy, pharmacokinetic characteristics and safety for its clinical use.1 DTX-CD solid complexes were prepared on the basis of CD’s capabilities to solubilize and encapsulate DTX. Many chemicals were studied for screening out the best CCF to form cocrystal with DTX, and the DTX-NA cocrystal was made successfully for the first time. The DTX-CD solid complexes and DTX-NA cocrystal were confirmed by FT-IR, Powder X-Ray, DSC et al. Study results showed both DTX-CD solid complexes and DTX-NA cocrystal could increase the DTX solubility effectively.2 The optimum formulations and ionic cross-linked gelation method were surveyed to prepared DTX-CD CS NPs, DTX-NA CS NPs, DTX-CD BB CS NPs and DTX-NA BB CS NPs. The diameters of these CS NPs were 202.2±21.9nm, 197.8±16.9nm,230.1±19.1nm and 219.8±19.3nm; the PDI values were all less than 0.28; Zeta potential values were between 25mv and 32mv; the encapsulated percents of DTX were more than 80% and the encapsulated percents of BB were more than 78%; the yields of all CS NPs were above 60%. The CS NPs images by TEM showed the spherical particles with uniform size. All the data indicated all the four kinds of CS NPs could be made properly and repetitively, the CS NPs’ characters were satisfied and in order.3 Cell biology research data indicated the antitumor effect of DTX was elevated remarkably by DTX-CD CS NPs, DTX-NA CS NPs, DTX-CD BB CS NPs and DTX-NA BB CS NPs. The IC50 values of MCF-7 cells by the four kinds of CS NPs were 59.21±5.51ng/mL,52.44±4.67ng/mL,51.64±2.36ng/mL and 45.09±3.36ng/mL, which were less than that (71.85±4.19ng/mL) by pure DTX formulation. Quantitative detection and laser scanning confocal fluorescence microscope verified that MCF-7 cells could endocytose NPs efficiently; cell uptake demonstrated concentration and time linear positive dependency relationship with all CS NPs; when the concentration of DTX was lOμg/mL, the four kinds of DTX CS NPs amount by cell uptake in 4h were 34.76±5.69ng/mL,76.28±9.34 ng/mL,65.59±6.73 ng/mL and 91.34±11.73ng/mL. Meanwhile, all CS NPs were able to induce MCF-7 cell apoptosis intensively and block the cell cycle at G2/M. The expression of survivin mRNA was inhibited significantly by all CS NPs; when the concentration of DTX was 10μg/mL, the expression of survivin mRNA in MCF-7 cells treated by the four kinds of DTX CS NPs for 24h were 62±7%,51±8%,48±5% and 42±4%。 All the results revealed DTX-NA BB CS NPs owed the greatest antitumor efficiency.4 All the CS NPs could promote the amount of DTX absorbed and inhibit the amount of DTX excreted by rat intestine in transport experiment in vitro, which might be relevant with CS NPs’ ability to suppress the activity of P-gp on the intestinal cell membrane. Pharmacokinetics data indicated that all CS NPs had raised Cmax,Tmax, AUCo't and Frel of DTX remarkably after oral administration to rats, the clearance was also reduced and DTX fitted the two-compartment model. The AUCo't(h·ng/mL) of pure DTX was 216.96±10.47, and the AUCo't(h·ng/mL) of DTX-CD CS NPs, DTX-NA CS NPs, DTX-CD BB CS NPs and DTX-NA BB CS NPs were 3140.56±105.72,3760.14±111.78,4850.67±189.22 and 5277±209.14; the oral Frel(%) of these CS NPs compared with the pure DTX were 1447.53,1733.58、2235.84 and 2432.25. All data showed that the pharmacokinetics characters of DTX were improved extremely the most by DTX-NA BB CS NPs.In conclusion, DTX/SBE-β-CD (DTX-CD) inclusion complexes and DTX-niacinamide (DTX-NA) cocrystal were made in this research, and two new kinds of dual-drug loading CS NPs, DTX-CD BB CS NPs and DTX-NA BB CS NPs, were prepared successfully for the first time in this research. The cell biology, anti-tumor efficiency and pharmacokinetics properties of the two kinds of CS NPs were investigated, analyzed and compared emphatically. DTX-NA BB CS NPs had the unique advantage, potential and prospect as new oral carrier for drug delivery, which were not possessed by other CS NPs. The exploration and study for DTX cocrystal were rare in pharmaceutical field for now, and results in this research provided confirmed experimental evidence, theoretical basis and enlightenment for the design and development of new delivery carrier and cocrystal of DTX for the future. |
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