ABSTRACT
Novel polyphosphoesters containing anthracene-derived aminophosphonate units, poly(oxyethylene aminophosphonate)s (4 and 5) and poly[oxyethylene(aminophosphonate-co-H-phosphonate)]s (6 and 7), were synthesized via an addition of poly(oxyethylene H-phosphonate)s to 9-anthrylidene-p-toluidine. The IR, NMR ((1)H, (13)C and (31)P) and fluorescence emission spectral data of the polymers are presented. The copolymers 6 and 7 were tested for in vitro antitumor activity on a panel of seven human epithelial cancer cell lines. Safety testing was performed both in vitro (3T3 NRU test) and in vivo on ICR mice for genotoxicity and antiproliferative activity. The copolymer 7 showed excellent antiproliferative activity to HBL-100, MDA-MB-231, MCF-7 and HepG2 cell lines. However, the in vitro safety testing revealed significant toxicity to Balb/c 3T3 mouse embryo cells. In contrast, the copolymer 6 showed complete absence of cytotoxicity to Balb/c 3T3 cells, but inhibited the growth of breast cancer cells, cervical carcinoma cells (HeLa) and hepatocellular carcinoma cell cultures after prolonged (72h) exposure. The polymers (4-6) exhibited low (4 and 6) to moderate (5) clastogenicity in vivo and slightly inhibited bone marrow cell division, compared to Mitomycin C. The subcellular distribution of the copolymers 6 and 7 were studied in model cell culture systems. The tested polyphosphoesters are expected to act in vivo as prodrugs of aminophosphonates and could be valuable as a new class of biodegradable polymer drug carriers.
Subject(s)
Anthracenes/chemistry , Antimitotic Agents/pharmacology , Antineoplastic Agents/pharmacology , Organophosphonates/pharmacology , Animals , Antimitotic Agents/administration & dosage , Antimitotic Agents/chemical synthesis , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , BALB 3T3 Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Hep G2 Cells , Humans , MCF-7 Cells , Male , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Mitosis/drug effects , Molecular Structure , Organophosphonates/administration & dosage , Organophosphonates/chemical synthesis , Structure-Activity RelationshipABSTRACT
Hydrogels, based on polyacrylic acid and various macrodiisocyanates that contain polyethylene glycol, polypropylene glycol or polytetramethylene glycol in the main chain are synthesized. The obtained hydrogels are studied as possible polymer carriers of drug substances. Etophylin was applied as a model drug. It is exposed that the etophylin release rate from the hydrogel depends on the way of drug comprise in the polymer net, from its density from the chemical nature of the crosslinking agent and from the pH of the environment. The carried out studies let us to conclude that the obtained hydrogels are possible materials as drug carriers.
