[Structure and antiviral activity of adamantane-containing polymer preparation]. / Struktura i antivirusnaia aktivnost' adamantansoderzhashchikh polimernykh preparatov.

New water-soluble antiviral chemical agents, containing 10 to 30% of adamantane derivatives (amino-, aminopropyl-adamantane-, aminomethyl- and rimantadine), which were conjugated with polycarboxylic matrixes of the divinyl ether and maleic anhydride copolymers (DIVEMA), were developed. The polymeric drugs exhibited a low cytotoxicity (4 to 10 times less than rimantadine) and a wide spectrum of antiviral activity against influenza viruses, including both the remantadine-resistant strains of A/PR/8/34 (H1N1) and the B/Saint-Petersburg strain/71/77 as well as against herpes viruses of type 1, parainfluenza viruses of types 1 and 3 and RS-virus. A reduction of the viral infection titer in their reproduction in sensitive cells' cultures was more than 2.0 Ig ID50. Complete inhibition of viral-specific syntheses, registered by immune-enzyme assay (IEA) and by hemagglutination test was observed at low infection doses ranging from 1 to 100 ID50. The efficiency of the antiviral effect depends on a drug's molecular weight and a structure of chemical bonds between the adamantane nucleus and the polymeric matrix.

[Antitumor activity of polyanion and its application for drug delivery system of antitumor drugs].

Polyanionid copolymer of divinyl ether and maleic anhydride (DIVEMA) with narrow molecular weight distribution was synthesized and tested of its antitumor activity. DIVEMA showed a significant antitumor activity against colon 26 adenocarcinoma and FSaI fibrosarcoma transplanted in syngenic mice. Furthermore, DIVEMA was used as a polymeric drug carrier of antitumor drugs to reduce side effects and enhance the antitumor activity of the drugs. Adriamycin and neocarzinostatin were attached covalently to DIVEMA and the polymeric conjugates showed higher antitumor activity than the corresponding mother drugs against P 388 leukemic mice.

Increased therapeutic efficacy and reduced toxicity of doxorubicin linked to pyran copolymer via the side chain of the drug.

Doxorubicin was covalently linked to divinyl ether-maleic anhydride copolymer (pyran copolymer) in its polycarboxylate form via the methylketone side chain through a nucleophilic substitution reaction of the 14-bromo derivative of the drug. The drug conjugated to the synthetic polyanionic polymer was tested for antitumor activity in a range of experimental murine tumor systems. When administered ip to mice bearing ip implanted tumors (P388 leukemia or macrophage tumor J774), the polymer-linked drug was superior to free doxorubicin and daunorubicin in increasing the life span of treated animals. Treatment with the conjugate also resulted in an improvement in survival time of mice bearing ascitic M50 tumor, although the effects of a single dose of free drug, in the range of maximum tolerated doses, were marginal. When given iv, the conjugate was more effective than free drug against systemic Gross leukemia. The therapeutic advantage of the polymer-linked doxorubicin over free drug was more marked when a multiple treatment schedule was used. Studies in vitro showed that the drug following covalent fixation to the polymer had only marginally decreased cytotoxicity against HeLa and P388 cells when compared with that of free anthracycline. This effect paralleled the lack of reduction in in vivo potency. Moreover, the covalent linkage of the drug to synthetic polymer reduced drug toxicity. This effect was more marked with the ip route of administration than with the iv route.