Etoposide and doxorubicin conjugates for drug delivery
Inventors
Demeule, Michel • Che, Christian • Gabathuler, Reinhard • Yang, Gaoqiang
Assignees
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Publication Number
US-8828925-B2
Publication Date
2014-09-09
Expiration Date
Abstract
The invention relates to improvements in the field of drug delivery. More particularly, the invention relates to polypeptides having a hydrolyzable covalent bond to a therapeutic agent that includes, etoposide, etoposide 4′-dimethylglycine or doxorubicin. These polypeptide conjugates can be used as vectors to transport the podophyllotoxin derivative across the blood brain barrier (BBB) or into particular cell types such as ovary, liver, lung, or kidney. The invention also relates to pharmaceutical compositions that include the compounds of the invention and to uses thereof in methods of treatment.
Core Innovation
The invention relates to compounds and pharmaceutically acceptable salts having a structure as recited in the patent. The disclosure describes structural modification of etoposide and related podophyllotoxin derivatives by replacing the phenolic —OH with a phosphate substituent or with acyloxy groups, and further includes generalized structural definitions for podophyllotoxin derivatives with variable substituents.
The invention defines general Formula (I) for podophyllotoxin derivatives, including a hydrolyzable linker Y at positions R1–R6 and covalent attachment via hydrolyzable covalent linkers to amino acids within polypeptides. Example polypeptide-related components include Angiopep-2 (SEQ ID NO:97), and the disclosure ties specific attachment positions to described hydroxyl sites, including etoposide 2''-hydroxyl/3''-hydroxyl attachment options.
Beyond etoposide and podophyllotoxin derivatives, the framework is extended to doxorubicin, epirubicin, and generalized Formula (II)/(II-A). Hydrolyzable linker attachment via a hydrolyzable linker Y is again included, along with described conjugation positions such as the doxorubicin 14-hydroxyl group, and the conjugates are associated with improved physicochemical and pharmacologic properties and improved water solubility.
Claims Coverage
The claim coverage centers on one structure-defined compound or pharmaceutically acceptable salt and method refinements for treating cancer by administering a therapeutically effective amount to a patient. The inventive features emphasized across the provided claims include Angiopep-2 (SEQ ID NO:97) conjugation to an anticancer agent, selection of paclitaxel, and a second therapeutic agent identified as ANG1005 with a specified structure.
Structure-defined compound or pharmaceutically acceptable salt
A compound having the structure recited in the claim, or a pharmaceutically acceptable salt thereof.
Cancer treatment by administering a therapeutically effective amount
A method of treating cancer by administering a therapeutically effective amount of a compound according to claim 1 to a patient.
Angiopep-2 (SEQ ID NO:97) polypeptide conjugated to an anticancer agent
The second therapeutic agent is the polypeptide Angiopep-2 (SEQ ID NO:97) conjugated to an anticancer agent.
Paclitaxel as the anticancer agent
The anticancer agent used is paclitaxel.
ANG1005 as the second therapeutic agent with specified structure
The method is carried out using a second therapeutic agent identified as ANG1005 having a specified structure.
The claim coverage is directed to a structure-defined compound or salt, with therapeutic use in cancer treatment by administering a therapeutically effective amount. The main inventive refinements identify Angiopep-2 (SEQ ID NO:97) as a conjugated targeting component to an anticancer agent, including paclitaxel and ANG1005.
Stated Advantages
Improved solubility.
Enhanced targeting.
Altered accumulation and transport characteristics.
Reduced toxicity with subtherapeutic dosing.
Potential for supertherapeutic dosing.
Improved physicochemical and pharmacologic properties.
Increased targeting to organs.
Improved water solubility is stated for replacing the phenolic —OH with phosphate substituents or with acyloxy groups.
Documented Applications
Delivery and targeting to the brain and selected tissues or cell types including ovary, liver, lung, and kidney.
Method of treating cancer by administering a therapeutically effective amount of the compound to a patient.
Use of Angiopep-2 (SEQ ID NO:97) conjugated to an anticancer agent, including paclitaxel and a second therapeutic agent identified as ANG1005.
Oral/solid dosage formulations for the compound, including tablet coatings for sustained or enteric release and capsule/tablet forms.
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