Camptothecin conjugates

Details Camptothecin conjugates Camptothecin conjugates

2000-03-31

2003-10-07

Milano, Michael J. (Department: 3731)

Prosthesis (i.e., artificial body members), parts thereof, or ai

Arterial prosthesis

Drug delivery

Reexamination Certificate

active

06629995

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to improved formulations for the administration of certain camptothecin conjugates.
2. Description of Related Art
20(S)-camptothecin (CPT), a plant alkaloid, was found to have anticancer activity in the late 1950's. Wall, M. et al.,
Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata
, J. Am. Chem. Soc. 88: 3888-3890, (1966); Monroe E. Wall et al.,
Camptothecin: Discovery to Clinic,
803 Annals of the New York Academy of Sciences 1 (1996). These documents, and all documents (articles, patents, etc.) cited to herein, are incorporated by reference into the specification as if reproduced fully below. The chemical formula of camptothecin was determined to be C
20
H
16
N
2
O
4
.
CPT itself is insoluble in water. However, during the sixties and seventies the sodium salt of CPT was derived from CPT through opening of the lactone ring using a mild base. Clinical trials were then conducted using this hydrosoluble, sodium salt derivative of CPT (CPT Na+), which was administered intravenously. The studies were later abandoned because of the high toxicity and low potency of CPT Na+. Gottlieb, J. A., et al.,
Preliminary pharmacological and clinical evaluation of camptothecin sodium salt
(
NSC
100880), Cancer Chemother. Rep. 54:461-470 (1979); Muggia, F. M., et al.,
Phase I clinical trials of weekly and daily treatment with camptothecin
(
NSC
100880):
Correlation with clinical studies
, Cancer Chemother. Rep. 56:515-521 (1972); Gottlieb, J. A. et al.,
Treatment of malignant melanoma with camptothecin
(
NSC
100880), Cancer Chemother. Rep. 56:103-105 (1972); and Moertel, C. G., et al.,
Phase II study of camptothecin
(
NSC
100880)
in the treatment of advanced gastrointestinal cancer
, Cancer Chemother Rep. 56:95-101 (1972).
Despite its potential, interest in CPT as a therapeutic remained at a low ebb until the mid-1980's. By that time, drug therapies were being evaluated for treating human cancer using human cancer xenograft lines. During these evaluations, human tumors are serially heterotransplanted into immunodeficient, so-called “nude” mice, and the mice then tested for their responsiveness to a specific drug. (Giovanella, B. C., et al.,
Cancer
52(7): 1146 (198
3
)). The data obtained in these studies strongly support the validity of heterotransplanted human tumors into immunodeficient mammals, such as nude mice, as a predictive model for testing the effectiveness of anticancer agents.
CPT, and later some of its substituted forms, elicited differential responses in the cell cycle of nontumorigenic and tumorigenic human cells in vitro. Although it is not yet understood why CPT and some of its substituted forms are cytostatic for nontumorigenic cells and cytotoxic for tumorigenic cells, the selective toxicity of the compounds against tumorigenic cells in vitro and in vivo was an especially interesting feature of these drugs.
Investigators began to experiment with various substituted forms of CPT. Good activity was found when various substitutions were made to the CPT scaffold. For example, 9-Amino-20(S)-Camptothecin (9AC) and 10,11-Methylendioxy-20(S)-Camptothecin (10,11 MD) are capable of having high anticancer activity against human colon cancer xenografts. Giovanella, B. C., et al.,
Highly effective topoisomerase
-
I targeted chemotherapy of human colon cancer in xenografts
, Science 246:1046-1048 (1989).
Additionally, 9-nitrocamptothecin (9NC) has shown high activity against human tumor xenograft models. 9NC has a nine position hydrogen substituted with a nitro moiety. 9NC has inhibited the growth of human tumor xenografts in immunodeficient nude mice and has induced regression of human tumors established as xenografts in nude mice with little or no appearance of any measurable toxicity. D. Chatterjee et al.,
Induction of Apoptosis in Malignant and Camptothecin
-
resistant Human Cells,
803 Annals of the New York Academy of Sciences 143 (1996).
U.S. Pat. No. 5,552,154 to Giovanella et al. disclosed methods of treating specific forms of cancer with water-insoluble 20(S)-camptothecin and derivatives thereof, having the closed-lactone ring intact. In particular, transdermal, oral and intramuscular methods of administration using solutions of water-insoluble 20(S)-camptothecin were disclosed.
Other substituted CPT compounds that have shown promise include 7-ethyl-10-hydroxy CPT, and other 7, 9, 10, 11-substituted compounds.
However, another problem arose when testing began to be done in an in vivo environment. CPT compounds contain an &agr;-hydroxy-&dgr;-lactone ring functionality that may hydrolyze under physiological conditions. The lactone moiety may open up easily to yield the carboxylate form, particularly in the presence of human serum albumin (HSA), where 97% of 9NC has been observed as converting to the open lactone form. Thomas G. Burke,
Chemistry of the Camptothecins in the Bloodstream: Drug Stabilization and Optimization of Activity,
803 Annals of the New York Academy of Sciences 29 (1996). As noted above, the biological activity of the closed lactone ring form is far greater than the activity of the open lactone ring, carboxylated form. In addition, some researchers have concluded that a closed lactone ring also may play a role in enhancing passive diffusion of the CPT molecule into cancer cells. Id.
There have been some attempts to overcome the problems associated with opening of the lactone ring. For example, Published PCT Application WO 97/28165 discloses substituted derivatives of camptothecin that are acylated with linear or cyclo alkyl or epoxy moieties at the 20 position hydroxyl moiety. A stated objective of the acylation is to retain the lactone ring and the 20 position hydroxyl group intact. However, the class of molecules disclosed suffers from the problem that the pharmacokinetics of release of the active entity, 9-substituted camptothecin, are suboptimal. No teaching or suggestion is present in the WO 97/28165 Application of how to adjust the pharmacokinetics.
There is therefore a need for a compound, compositions, methods, apparatus, and kits that combine the desirable properties of CPT and its substituted forms with the ability to maintain a closed lactone ring structure.
SUMMARY OF THE INVENTION
The invention is related to compounds comprising a camptothecin conjugated to a lactone ring protecting moiety.
DETAILED DESCRIPTION OF THE INVENTION
In an aspect, the invention is directed to compounds comprising a camptothecin conjugated to a lactone ring protecting moiety. In another aspect, the invention is directed to the compound, wherein the camptothecin is a substituted camptothecin. In another aspect, the invention is directed to the compound, wherein the substituted camptothecin is 9-nitrocamptothecin, 9-aminocamptothecin, 10,11-methylendioxy-20(S)-camptothecin, topotecan, irinotecan, 7-ethyl-10-hydroxy camptothecin, or another substituted camptothecin that is substituted at least one of the 7, 9, 10, 11, or 12 positions. In yet another aspect, the invention is directed to the compound, wherein the substituted camptothecin is 9-nitrocamptothecin, or 9-aminocamptothecin.
In still another aspect, the invention is directed to the compound, wherein the lactone ring protecting moiety is a polyalkylene oxide, dextran, polyvinyl alcohol, carbohydrate polymer, an antibody, streptozoticin or derivatives or mixtures thereof. In an aspect, the invention is directed to the compound, wherein the polyalkylene oxide is a polyethylene glycol. In another aspect, the invention is directed to the compound, wherein the antibody is a monoclonal or polyclonal antibody. In yet another aspect, the invention is directed to the compound, wherein the lactone ring protecting moiety is streptozoticin.
In an aspect, the invention is directed to the compound, wherein a bond connecting the camptothecin and the lactone ring protecting moiety, thus forming the conjugate, is atta

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