Abstract��OBJECTIVE To prepare heparan sulfate-vitamin E succinate (HDV) amphipathic copolymers and explore the pharmaceutical properties of doxorubicin (DOX)-loaded HDV copolymer micelles (DOX/HDV). METHODS HDV copolymers were prepared by amide reaction and its structure was confirmed by 1H-NMR. DOX/HDV micelles were prepared by ultrasonic method. The particle size, morphology, Zeta potential, drug loading, entrapment efficiency, and in vitro drug release and cytotoxicity were evaluated. RESULTS HDV amphipathic copolymers were synthesized successfully. The particle size, PDI value and Zeta potential of drug-loaded micelles were (105.0��7.3) nm, (0.239��0.484) and (-21.4��2.6) mV, respectively. The encapsulation and drug loading rate were (76.22��0.76)% and (9.53�� 0.58)%, respectively. The results of drug release test in vitro showed that DOX was released slowly from the micelles. Cytotoxicity experiments indicated that blank micelles had no apparent toxicity against both tumor cells and normal cells. However, DOX/HDV micelles could inhibit the tumor cells growth obviously. CONCLUSION HDV copolymers can effectively load DOX with properties of drug sustained release and enhanced cytotoxicity against tumor cells in vitro, which indicates that HDV may be a potential candidate for cancer therapy.
YANG S D, ZHANG X D. New polymer micelles and its application in cancer therapy[J]. Chin Pharm J (�й�ҩѧ��־), 2015, 50(12): 1006-1011.
CAPILA I, LINHARDT R J. Heparin-protein interactions[J]. Angew Chem Int Ed, 2002, 41(3): 390-412.
WANG Y, XIN D, LIU K, et al. Heparin paclitaxel conjugates as drug delivery system:synthesis, self-assembly property, drug release, and antitumor activity[J]. Bioconjug Chem, 2009, 20(12): 2214-2221.
PARK K, LEE G Y, KIM Y S, et al. Heparin-deoxycholic acid chemical conjugate as an anticancer drug carrier and its antitumor activity[J]. J Controlled Release, 2006,114(3): 300-306.
RABENSTEIN D L. Heparin and heparan sulfate: structure and function[J]. Nat Prod Rep, 2002, 19(3): 312-331.
ZHANG Z H, MA X L, ZHANG P, et al. Preparation and structural sequence analysis of heparan sulfate dodecasaccharide[J]. Chin Pharm J (�й�ҩѧ��־), 2014, 49(9): 781-785.
KNELSON E H, NEE J C, BLOBE G C. Heparan sulfate signaling in cancer[J]. Trends Biochem Sci, 2014, 39(6): 277-288.
BORSIG L. Heparin as an inhibitor of cancer progression[J]. Prog Mol Biol Trans Sci, 2010, 93: 335-349.
LIU H, WEI W, JIANG Z, et al. Inhibitory effects of heparan sulfate proteoglycan on mice transplanted tumors[J]. Chin Pharmacol Bull (�й�ҩ��ѧͨ��),2008,24(6):744-748.
TURLEY J M, FUNAKOSHI S, RUSCETTI F W, et al. Growth inhibition and apoptosis of RL human B lymphoma cells by vitamin E succinate and retinoic acid: role for transforming growth factor B[J]. Cell Growth Differ,1995, 6(6): 655-664.
ANGULO-MOLINA A, REYES-LEYVA J, L�SPEZ-MALO A, et al. The role of alpha tocopheryl succinate (��-TOS) as a potential anticancer agent[J]. Nutr Cancer, 2014, 66(2):167-176.
ZHU J, ZHENG L, WEN S, et al. Targeted cancer theranostics using alpha-tocopheryl succinate-conjugated multifunctional dendrimer-entrapped gold nanoparticles[J]. Biomaterials, 2014, 35(26): 7635-7646.
TAO Y, HAN J, WANG X, et al. Nano-formulation of paclitaxel by vitamin E succinate functionalized pluronic micelles for enhanced encapsulation, stability and cytotoxicity[J]. Colloids Surf B: Biointerfaces, 2013, 102: 604-610.
ANGULO-MOLINA A, M�FNDEZ-ROJAS M ��, PALACIOS-HERN��NDEZ T, et al. Magnetite nanoparticles functionalized with ��-tocopheryl succinate (��-TOS) promote selective cervical cancer cell death[J]. J Nanoparticle Res, 2014, 16(8): 1-12.
MALLICK A, MORE P, GHOSH S, et al. Dual drug conjugated nanoparticle for simultaneous targeting of mitochondria and nucleus in cancer cells[J]. ACS Applied Materials Interfaces, 2015, 7(14): 7584-7598.
LIANG N, SUN S, LI X, et al. ��-Tocopherol succinate-modified chitosan as a micellar delivery system for paclitaxel: Preparation, characterization and in vitro/in vivo evaluations[J]. Int J Pharm, 2012, 423(2): 480-488.
ZHANG Z, TAN S, FENG S S. Vitamin E TPGS as a molecular biomaterial for drug delivery[J]. Biomaterials, 2012, 33(19): 4889-4906.