# US 8,785,371 B2 · Drug delivery of temozolomide for systemic based treatment of cancer

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- Number: US 8,785,371 B2
- Document ID: US8785371B2
- Status: Granted
- Kind: B2
- Application number: 13/513,145
- Filed: 2010-12-10
- Published: 2012-12-27
- Granted: 2014-07-22
- Earliest claimed: 2009-12-10
- Assignees: Cedars-Sinai Medical Center
- Applicants: Rameshwar Patil; Eggehard Holler; Keith L. Black; Julia Y. Ljubimova
- Inventors: Rameshwar Patil; Eggehard Holler; Keith L. Black; Julia Y. Ljubimova
- Web page: https://patentgrep.com/patent/US8785371B2

## CPC

- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/425: Thiazoles
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/593: {Polyesters, e.g. PLGA or polylactide-co-glycolide}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6865: {the tumour determinant being from skin, nerves or brain cancer cell}
- A61K 47/6877: {the antibody being an immunoglobulin containing regions, domains or residues from different species}
- A61K 47/6883: {Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61K 47/6898: {using avidin- or biotin-conjugated antibodies}
- A61P 35/00: Antineoplastic agents
- C07K 16/2881: {against CD71}
- C07K 16/3015: {Breast}
- C07K 16/3053: {Skin, nerves, brain}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/77: Internalization into the cell
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention relates to methods of drug delivery for the treatment of a condition or disease, such as cancer. In one embodiment, the invention provides a method of preparing a multifunctional nanoconjugate of temozolomide (TMZ) by conjugating TMZ in its hydrazide form to a polymalic acid platform. In another embodiment, the polymalic acid platform is conjugated to a monoclonal antibody to transferrin receptor, a trileucine (LLL) moiety, and/or a polyethylene glycol (PEG) moiety. The present invention relates to methods of drug delivery for the treatment of a condition or disease, such as cancer. In one embodiment, the invention provides a method of preparing a multifunctional nanoconjugate of temozolomide (TMZ) by conjugating TMZ in its hydrazide form to a polymalic acid platform. In another embodiment, the polymalic acid platform is conjugated to a monoclonal antibody to transferrin receptor, a trileucine (LLL) moiety, and/or a polyethylene glycol (PEG) moiety.

## Claims

### Claim 1

A pharmaceutical composition, comprising:
a therapeutically effective amount of a polymalic acid-based nanoconjugate of temozolomide (TMZ), wherein the polymalic acid-based nanoconjugate of TMZ is a compound of the formula:
or a derivative thereof, wherein the derivative is an imidazotetrazine compound having antitumor activity; and
a pharmaceutically acceptable carrier.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the polymalic-acid based nanoconjugate of TMZ is a compound of the formula:
or a derivative thereof, wherein the derivative is an imidazotetrazine compound having antitumor activity.