Platinum complex conjugated to cyclotriphosphazene, its...

Details Platinum complex conjugated to cyclotriphosphazene, its... Platinum complex conjugated to cyclotriphosphazene, its...

2000-03-02

2001-04-24

Nazario-Gonzalez, Porfirio (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heavy metal containing doai

C556S020000, C556S137000

Reexamination Certificate

active

06221906

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to an anticancer platinum complex conjugated to cyclotriphosphazene represented by Formula 1, which has a prominent anticancer activity when administered via injection, and a preparation method thereof.
(wherein N
3
P
3
is a cyclotriphosphazene backbone
R is a solubilizing agent selected from the group consisting of methylamine, methoxy and amino acid;
A is monodentate neutral ligand, ammonia (NH
3
) or as
represents a bidentate chelating diamine selected from the group consisting of ethylenediamine (NH
2
CH
2
CH
2
NH
2
)(en), 2,2-dimethyl-1,3-propanediamine (NH
2
CH
2
CH(CH
3
)
2
CH
2
NH
2
)(dmpda), 2,2-bisaminomethylpropanediol (NH
2
CH
2
C(CH
2
OH)
2
CH
2
NH
2
)(bampd), and trans-(±)-1,2-diaminocyclohexane
n is the number defining the kind of anionic amino carboxylic acids and is an integer from 0 to 2; wherein 0 for amino malonic acid derivatives, 1 for aspartic acid derivatives and 2 for glutamic acid derivatives; and x is a value between 0 and 3).
The present inventors have found that the platinum complex conjugated to cyclotriphosphazene as represented by the above Formula 1 is a novel compound that has superior anticancer activities especially having a controlled-releasing property when administered via injection.
Since the anticancer activity of cisplatin, cis-(NH
3
)
2
PtCl
2
, was reported by B. Rosenberg of USA (Nature 205, 698(1965)), it has been officially proven as one of the most efficient anticancer drugs for many types of carcinomas including testicular, ovarian, bladder, and head and neck cancers. However, its use is limited due to its high toxicity(LD
50
=13 mg/kg, M. J. Cleare, Biochimie 60, 835(1978)). On the other hand, a second generation anticancer agent, carboplatin(cis-(NH
3
)
2
Pt(CBDCA) (CBDCA=1,1-cyclobutane dicarboxylate), which was approved by the FDA in 1989, has much lower toxicity(LD
50
=180 mg/kg, M. J. Cleare, Biochimie 60, 835(1978)) than cisplatin, but is not widely used because carboplatin is more expensive and has lower anticancer activity than cisplatin. Therefore, researches, too numerous to mention, are being performed worldwide without much success to find a third generation anticancer drug that has a higher anticancer activity and a lower toxicity than cisplatin. Also the third generation anticancer drug should not have any cross-resistance to cisplatin or carboplatin, and must be water-soluble as well as chemically stable. Because of such many requirements, the third generation anticancer drug has not been commercialized yet, although there are more than 10 candidate compounds that are currently under clinical trials.
The mechanism of anticancer activity and toxicity of cisplatin has not been fully understood up to date. To summarize the research findings, even though some of the cisplatin molecules are partially hydrolyzed, most of them remain as neutral molecules due to the high chloride concentration(>100 mM) in the plasma, and therefore easily diffuse through cell membrane. Inside the cell, the chlorine ion is dissociated from the cisplatin molecule by hydrolysis since the chloride concentration is low (4 mM) in the cytoplasm. The cells are killed because DNA replication is prohibited as a result of complex formation between (diamine)platinum cation and DNA. The cytotoxicity of the platinum complex is exhibited since the drug molecules cannot distinguish between cancer cells and normal cells. The relationship, however, between the molecular structure of the platinum complex and the in vivo anticancer activity is not fully understood. The present inventors have developed a polymeric platinum complex by conjugating the active platinum (II) moiety to a biodegradable polyphosphazene bearing a solubilizing agent, which exhibited outstanding anticancer activity with lower toxicity. However, the polymeric platinum complex has been found to response positively to the anaphylaxis test, and therefore, could not be commercialized.
SUMMARY OF THE INVENTION
To develop a new third generation anticancer drug with higher anticancer activity and lower toxicity than cisplatin and without anaphylactic reaction, the present inventors have synthesized an oligomeric platinum complex by substitution reaction of hexachlorocyclotriphosphazene with a solubilizing agent and a dicarboxylic amino acid derivative as a spacer for the platinum complex. The newly formed oligomeric platinum complex has a lower toxicity(mouse LD
50
=125~250 mg/kg) compared to cisplatin (LD
50
=13 mg/kg) and higher anticancer activity (ILS(%)≧500). Moreover, this novel compound has a great advantage of wider spectrum of activity because it shows a high anticancer activity to non-small cell lung cancer that is not cured by cisplatin based regimens. Furthermore, this oligomeric new compound also dose not exhibit anaphylactic reaction unlike the polymeric platinum complex anticancer agent developed previously by the present inventors. When drugs are administered by injection, some bioincompatible drugs may rapidly bind to proteins resulting in anaphylaxis. Most polyphosphazene-platinum conjugates have been found to show positive anaphylactic reaction. On the other hand, platinum complex conjugated to oligomeric cyclotriphosphazene has been found to show good biocompatibility without anaphylactic reaction and the polymer backbone was found to degrade slowly in the body with controlled release of the antitumor platinum moiety so as to maintain the optimal effective concentration for outstanding antitumor activity.


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Harrison et al., 1980 “An Efficient Route for the Preparation of Highly Soluble Platinum (II) Antitumour Agents” Inorganica Chemica Acta. 46: L15-L16.
Rosenberg et al., 1965 “Inhibition of Cell Division in Escherichja Coli by Electrolysis Products from a Platinum Electrode” Nature 205: 698-699.
Sherman et al., 1987 “Structural Aspects of Platinum Anticancer Drug Interactions with DNA” Chem. Rev. 87: 1153-1181.

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