Heparin-paclitaxel conjugates using mixed anhydride as intermediate: synthesis, influence of polymer structure on drug release, anticoagulant activity and in vitro efficiency.
OBJECTIVE
The heparin-paclitaxel conjugates using amino acid as linker (HD2), with low anticoagulant activity, the similar anticancer activity as paclitaxel, offer great potential for further investigation.


METHODS
Two types of heparin-paclitaxel conjugates (HD) have been developed, in which O-acetylated heparin as carrier conjugates with paclitaxel by direct ester bond (HD1) and by inserting different amino acids as spacers, including valine, leucine, and phenylalanine (HD2a, HD2b, and HD2c), respectively. Specifically, mixed anhydride groups of carrier as activating intermediates mediate the synthesis of prodrugs. The HD conjugates are characterized by (1)H NMR, FT-IR and GPC. The percentage weight of drug and hydrolysis rate for HD are detected by UV and HPLC. The anticoagulant activity and cell cycle of MCF-7 of HD are measured by APTT and FCM, respectively.


RESULTS
HD2 conjugates show better solubility and faster hydrolysis rates than those of HD1. Meanwhile, the anticoagulant activity of HD is reduced and FCM analysis show that MCF-7 cells treated with HD are arrested in the G2/M phase of cell cycle.


CONCLUSIONS
Amino acids as linkers between paclitaxel and carrier are appropriate to facilitate the release of paclitaxel from carrier. Mixed anhydrides mediate the synthesis of prodrugs and HD2 conjugates are expected to further investigate in vivo experiment.
Wang
Ying
Y
Biomedical Engineering Center, Hunan University, Changsha, 410082, China.
Xin
Dingcheng
D
Liu
Kaijian
K
Xiang
Jiannan
J
D000107:Acetylation; D000812:Anhydrides / Q000737:chemistry*; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004339:Drug Compounding; D015195:Drug Design; D005260:Female; D006493:Heparin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D010314:Partial Thromboplastin Time; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods
D000812:Anhydrides; D000925:Anticoagulants; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D011355:Prodrugs; D006493:Heparin; D017239:Paclitaxel