WO2003103717A1 - Therapeutic conjugate consisting of a mek inhibitor and a targeting agent - Google Patents
Therapeutic conjugate consisting of a mek inhibitor and a targeting agent Download PDFInfo
- Publication number
- WO2003103717A1 WO2003103717A1 PCT/GB2003/002501 GB0302501W WO03103717A1 WO 2003103717 A1 WO2003103717 A1 WO 2003103717A1 GB 0302501 W GB0302501 W GB 0302501W WO 03103717 A1 WO03103717 A1 WO 03103717A1
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- Prior art keywords
- targeting agent
- mek inhibitor
- conjugate according
- pain
- conjugate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
Definitions
- This invention relates to a conjugate for use in therapy, and in particular for use in the treatment of pain.
- MEK inhibitors One class of compounds that can be used for the treatment of pain comprises MEK inhibitors.
- MEK enzymes are dual- specificity kinases involved in, for example, immunomodulation, inflammation and proliferative diseases such as cancer and restenosis .
- MEK inhibitors may reduce chronic pain as the MEK pathway is 'upregulated in dorsal horn neurons in persistent pain (Journal of Neuroscience, January 15, 2002, 22(2): 478-485).
- MEK inhibitors and their uses are described in, for example, WO 01/05390, WO 01/05391, WO 01/05392 and WO 01/05393 (these publications, and also publications identified therein, are incorporated herein by reference) .
- the present invention is based on the realisation that the utility of MEK inhibitors as agents for the treatment of a condition such as arthritis, cancer or pain can be enhanced by conjugation with a suitable targeting agent.
- the targeting agent should be capable of delivering the MEK inhibitor to the locus of the condition.
- the MEK inhibitor may be targeted to those neurons actually malfunctioning in neuropathic pain, i.e. c-fibres and dorsal horn neurons .
- MEK inhibitors are known.
- therapeutic endpoints, including pain that may be treated with MEK inhibitors are known.
- a conjugate of the MEK inhibitor and a targeting agent is provided.
- conjugate for use in the treatment of a condition such as arthritis, cancer or pain, comprising a MEK inhibitor and a targeting agent, wherein the targeting agent can deliver the MEK inhibitor to the locus of a condition.
- the MEK inhibitor may be any compound that reduces or blocks MEK activity, particularly the ability of MEK to activate MAP kinase, specifically the ERK kinase.
- Known MEK inhibitors are described in WO 01/05390, WO 01/05391, WO 01/05392, and WO 01/05393, and the publications cited therein.
- Preferred MEK inhibitors include U0126 (MEKl/2 inhibitor from Cell Signaling Technology) : and PD98059 (MEK1 inhibitor from Cell Signaling Technology) :
- the targeting agent may also be known.
- suitable targeting agents include monoclonal antibodies and axonal transport facilitators .
- Compounds such as NGF receptor and the IB4 lectin binding site can be used as c- fibre recognition structures.
- Such compounds, their preparation and means for their conjugation to drugs, are known.
- a hydrolysable linker may be used.
- the targeting agent should be capable of binding to the locus of the condition to allow- the MEK inhibitor to act.
- the locus of the condition includes any site- at which delivery of a MEK inhibitor will allow the MEK inhibitor to exert a beneficial therapeutic effect in relation to the condition.
- the targeting agent may comprise any binding partner of a component at the locus .
- the targeting agent may comprise an antibody (or fragment or derivative thereof) , . preferably a monoclonal antibody.
- the antibody, fragment, or derivative is directed to a cell surface molecule.
- the targeting agent can bind to sensory neurons .
- Targeting of a MEK inhibitor to sensory neurons is expected to provide relief against pain, particularly ' chronic pain such as neuropathic or inflammatory pain.
- the chronic pain may be associated with cancer or arthritis .
- the targeting agent can bind to c-fibres or A fibres (in particular A ⁇ fibres) .
- the targeting agent may comprise an antibody (or fragment or derivative thereof) , NGF (or a derivative thereof which binds the NGF receptor) , lectin (or a derivative thereof which binds the IB4 lectin binding site) , or any ligand that binds to receptors expressed on c-fibres.
- MEK inhibitors are also known to have anti-cancer activity.
- a conjugate can be used in the treatment of cancer.
- the targeting agent can bind to a tumour cell.
- the targeting agent may be an antibody (preferably a monoclonal antibody) against a tumour cell.
- MEK inhibitors are also known to have anti-inflammatory activity in arthritis.
- a conjugate can be used in the treatment of arthritis .
- the targeting agent can bind to a site of inflammation in arthritis.
- the targeting agent may be covalently or non-covalently conjugated to the MEK inhibitor.
- the conjugate binds to a cell, it is thought that the conjugate is internalised, and the MEK inhibitor released from the targeting agent so that it can inhibit MEK.
- Preferred covalent linkages comprise bonds that are likely to be broken in vivo after the conjugate has been delivered to the cell and internalised. Suitable covalent linkages comprise an ester, peptide, or disulphide bond.
- a method of making a conjugate of the invention which comprises conjugating a MEK inhibitor to a targeting agent which can deliver the MEK inhibitor to the locus of a condition.
- a method of preventing, treating or ameliorating arthritis, cancer or pain which comprises administering a conjugate of the invention to a subject in need of such prevention, treatment, or amelioration.
- Preferred methods of the invention are for the prevention, treatment, or amelioration of chronic pain, such as neuropathic or inflammatory pain.
- a conjugate may be formulated with any suitable carrier, excipient or diluent.
- a composition of the invention may be in any suitable form, of which examples are tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories and liquid preparations such as oral and/or sterile . parenteral solutions or suspensions .
- the compound may be formulated for administration by any suitable route, depending on the site of the condition to be treated. Suitable routes of administration are oral, rectal, topical, parenteral and pulmonary. Parenteral administration may be by subcutaneous, intravenous, intramuscular or intrasternal injection.
- the amount of • the active agent to be administered can be determined depending on the usual factors, such as the potency of the active agent, the nature and severity of the condition to be treated, and the condition, age and other characteristics of the patient .
- a suitable dosage can be determined by one skilled in the art, or can be based on existing data for MEK inhibitors, allowing for the fact that targeted administration will generally require less of the active agent to be administered.
- Coupling of drugs to specific carriers e.g. antibodies, NGF, lectins or other specific recognition processes enables the drug to be selectively administered to c- fibres which may also transport the said drug and deliver it to the dorsal horn neurons . This may dramatically reduce the dose required and avoid (or reduce) the side- effects seen with most MEK inhibitors.
- Figure 1 shows Western blot analysis of ERKl/2 and pERKl/2 activity in rat DRGs (L4-L6) following carrageenan injection into the hind paw;
- Figure 2 shows the effect of MEK inhibitor on paw withdrawal latency (PWL) in carrageenan induced thermal hyperalgesia (CITH) .
- MEK activity was assessed in the dorsal root ganglion (DRG) by measuring the phosphorylation of ERK1 and ERK2 using Western blotting.
- Figure 1 shows Western blot analysis of ⁇ RKl/2 and pERKl/2 activity in rat dorsal root ganglions (DRGs) (L4-L6) following carrageenan injection into the hind paw.
- the intensity of the bands is proportional to the level of protein.
- Administration of carrageenan into the right paw (Ipsi) produced an increase in the level of pERKl/2 but not ERKl/2 when compared with the control paw (Con) .
- the increase in staining intensity indicates an increase in MEK activity on the treated side but not the untreated side.
- the MEK inhibitor U0126 (2mg/kg, i.p.) was administered 30 minutes prior to injection of carrageenan into the hind paw
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- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Conjugates for use in the treatment of pain, particularly chronic pain are described. The conjugates comprise a MEK inhibitor and a targeting agent. The targeting agent targets the MEK inhibitor to sensory neurons, thereby reducing the dosage of MEK inhibitor required to treat chronic pain. Methods of treating chronic pain using the conjugates are also described.
Description
THERAPEUTIC CONJUGATE CONSISTING OF A MEK INHIBITOR AND A TARGETING AGENT
Field of the Invention
This invention relates to a conjugate for use in therapy, and in particular for use in the treatment of pain.
Background of the Invention
The effective treatment of pain remains an elusive aim. While many drugs are known for this purpose, whether for acute or chronic pain, nociceptive or neurogenic pain, the use of those drugs that are relatively potent is generally associated with undesirable side-effects.
One class of compounds that can be used for the treatment of pain comprises MEK inhibitors. MEK enzymes are dual- specificity kinases involved in, for example, immunomodulation, inflammation and proliferative diseases such as cancer and restenosis . MEK inhibitors may reduce chronic pain as the MEK pathway is 'upregulated in dorsal horn neurons in persistent pain (Journal of Neuroscience, January 15, 2002, 22(2): 478-485). MEK inhibitors and their uses are described in, for example, WO 01/05390, WO 01/05391, WO 01/05392 and WO 01/05393 (these publications, and also publications identified therein, are incorporated herein by reference) .
While MEK inhibitors are effective, they are non-specific. Their practical utility is severely limited by central side-effects .
Summary of the Invention
The present invention is based on the realisation that the utility of MEK inhibitors as agents for the treatment of a condition such as arthritis, cancer or pain can be enhanced by conjugation with a suitable targeting agent. The targeting agent should be capable of delivering the MEK inhibitor to the locus of the condition. For example, the MEK inhibitor may be targeted to those neurons actually malfunctioning in neuropathic pain, i.e. c-fibres and dorsal horn neurons .
Description of the Invention
As indicated above, MEK inhibitors are known. Again, as indicated above, therapeutic endpoints, including pain, that may be treated with MEK inhibitors are known. For the purposes of this invention, and typically for the treatment of pain, a conjugate of the MEK inhibitor and a targeting agent is provided.
There is also provided according to the invention a conjugate for use in the treatment of a condition such as arthritis, cancer or pain, comprising a MEK inhibitor and a targeting agent, wherein the targeting agent can deliver the MEK inhibitor to the locus of a condition.
The MEK inhibitor may be any compound that reduces or blocks MEK activity, particularly the ability of MEK to activate MAP kinase, specifically the ERK kinase. Known MEK inhibitors are described in WO 01/05390, WO 01/05391, WO 01/05392, and WO 01/05393, and the publications cited therein. Preferred MEK inhibitors include U0126 (MEKl/2 inhibitor from Cell Signaling Technology) :
and PD98059 (MEK1 inhibitor from Cell Signaling Technology) :
The targeting agent may also be known. Examples of suitable targeting agents include monoclonal antibodies and axonal transport facilitators . Compounds such as NGF receptor and the IB4 lectin binding site can be used as c- fibre recognition structures. Such compounds, their preparation and means for their conjugation to drugs, are known. For example, a hydrolysable linker may be used.
The targeting agent should be capable of binding to the locus of the condition to allow- the MEK inhibitor to act. The locus of the condition includes any site- at which delivery of a MEK inhibitor will allow the MEK inhibitor to exert a beneficial therapeutic effect in relation to the condition.
The targeting agent may comprise any binding partner of a component at the locus . For. example the targeting agent may comprise an antibody (or fragment or derivative thereof) , .preferably a monoclonal antibody. Preferably the
antibody, fragment, or derivative is directed to a cell surface molecule.
In preferred embodiments the targeting agent can bind to sensory neurons . Targeting of a MEK inhibitor to sensory neurons is expected to provide relief against pain, particularly ' chronic pain such as neuropathic or inflammatory pain. The chronic pain may be associated with cancer or arthritis .
Preferably the targeting agent can bind to c-fibres or A fibres (in particular Aδ fibres) . . To target the MEK inhibitor to c-fibres, the targeting agent may comprise an antibody (or fragment or derivative thereof) , NGF (or a derivative thereof which binds the NGF receptor) , lectin (or a derivative thereof which binds the IB4 lectin binding site) , or any ligand that binds to receptors expressed on c-fibres.
MEK inhibitors are also known to have anti-cancer activity. Thus, in other embodiments of the invention a conjugate can be used in the treatment of cancer. In such embodiments the targeting agent can bind to a tumour cell. For' example, the targeting agent may be an antibody (preferably a monoclonal antibody) against a tumour cell.
MEK inhibitors are also known to have anti-inflammatory activity in arthritis. Thus, in further embodiments of the invention a conjugate can be used in the treatment of arthritis . In such embodiments the targeting agent can bind to a site of inflammation in arthritis.
The targeting agent may be covalently or non-covalently conjugated to the MEK inhibitor.
For those embodiments in which the conjugate binds to a cell, it is thought that the conjugate is internalised, and the MEK inhibitor released from the targeting agent so that it can inhibit MEK. Preferred covalent linkages comprise bonds that are likely to be broken in vivo after the conjugate has been delivered to the cell and internalised. Suitable covalent linkages comprise an ester, peptide, or disulphide bond.
There is also provided according to the invention a method of making a conjugate of the invention which comprises conjugating a MEK inhibitor to a targeting agent which can deliver the MEK inhibitor to the locus of a condition.
According to the invention • there is further provided a method of preventing, treating or ameliorating arthritis, cancer or pain, which comprises administering a conjugate of the invention to a subject in need of such prevention, treatment, or amelioration.
Preferred methods of the invention are for the prevention, treatment, or amelioration of chronic pain, such as neuropathic or inflammatory pain.
For use in the invention, a conjugate may be formulated with any suitable carrier, excipient or diluent. A composition of the invention may be in any suitable form, of which examples are tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories and liquid preparations such as oral and/or sterile . parenteral solutions or suspensions . The compound may be formulated for administration by any suitable route, depending on the site of the condition to be treated. Suitable routes of administration are oral, rectal, topical, parenteral and
pulmonary. Parenteral administration may be by subcutaneous, intravenous, intramuscular or intrasternal injection.
The amount of • the active agent to be administered can be determined depending on the usual factors, such as the potency of the active agent, the nature and severity of the condition to be treated, and the condition, age and other characteristics of the patient . A suitable dosage can be determined by one skilled in the art, or can be based on existing data for MEK inhibitors, allowing for the fact that targeted administration will generally require less of the active agent to be administered.
Coupling of drugs to specific carriers, e.g. antibodies, NGF, lectins or other specific recognition processes enables the drug to be selectively administered to c- fibres which may also transport the said drug and deliver it to the dorsal horn neurons . This may dramatically reduce the dose required and avoid (or reduce) the side- effects seen with most MEK inhibitors.
Experiments which form the basis of the invention are described below, with reference to the accompanying drawings in which:
Figure 1 shows Western blot analysis of ERKl/2 and pERKl/2 activity in rat DRGs (L4-L6) following carrageenan injection into the hind paw; and
Figure 2 shows the effect of MEK inhibitor on paw withdrawal latency (PWL) in carrageenan induced thermal hyperalgesia (CITH) .
Example
Evidence that MEK activity contributes to hyperalgesia
Following induction of inflammatory pain by injection of carrageenan into the hind paw of a rat, MEK activity was assessed in the dorsal root ganglion (DRG) by measuring the phosphorylation of ERK1 and ERK2 using Western blotting.
Figure 1 shows Western blot analysis of ΞRKl/2 and pERKl/2 activity in rat dorsal root ganglions (DRGs) (L4-L6) following carrageenan injection into the hind paw. The intensity of the bands is proportional to the level of protein. Administration of carrageenan into the right paw (Ipsi) produced an increase in the level of pERKl/2 but not ERKl/2 when compared with the control paw (Con) .
As can be seen from Figure 1 the increase in staining intensity indicates an increase in MEK activity on the treated side but not the untreated side.
To test whether or not this increase in enzyme activity contributes to the development of hyperalgesia, the MEK inhibitor U0126 (2mg/kg, i.p.) was administered 30 minutes prior to injection of carrageenan into the hind paw
(Figure 2) . This increased the paw withdrawal latency
(PWL) of the carrageenan-injected paw (Ipsi) but had no effect on the control paw (Con) , indicating an anti- hyperalgesic effect.
Claims
1. A conjugate comprising a MEK inhibitor and a targeting agent, wherein the targeting agent can deliver the MEK inhibitor to the locus of a condition such as arthritis, cancer or pain.
2. A conjugate according to claim 1, wherein the targeting agent can deliver the MEK inhibitor to sensory neurons .
3. A conjugate according to claim 1 or 2 , wherein the targeting agent can deliver the MEK inhibitor to those neurons malfunctioning in neuropathic pain.
4. A conjugate according to claim 2 or 3 , wherein the neurones are c-fibres, A fibres (preferably Aδ fibres) , or dorsal horn neurons .
5. A conjugate according to claim 4, wherein the targeting agent comprises NGF (or a derivative thereof which binds the NGF receptor) , or lectin (or a derivative thereof which binds the IB4 lectin binding site) .
6. A conjugate according to any of claims 1 to 4, wherein the targeting agent is a monoclonal antibody.
7. A conjugate according to any of claims 1 to 4, wherein the targeting agent is an axonal transport facilitator.
8. A conjugate according to any preceding claim, wherein the MEK inhibitor is U0126 or PD98059.
9. A conjugate according to any preceding claim, wherein the MEK inhibitor is conjugated to the targeting agent by means of a covalent linkage which can be broken in vivo after the conjugate has been delivered to the locus of the condition.
10. A conjugate according to claim 9, wherein the covalent linkage comprises an ester, peptide, or disulphide bond.
11. A conjugate according to any preceding claim for use as a medicament .
12. A conjugate according to any of claims 1 to 10 for use in the treatment of a 'condition such as arthritis, cancer or pain.
13. Use of a conjugate according to any of claims 1 to 10 in the manufacture of a medicament for the prevention, treatment, or amelioration of arthritis, cancer or pain.
14. Use according to claim 13 for the prevention, treatment, or amelioration of chronic pain, such as neuropathic or inflammatory pain.
15. A pharmaceutical composition comprising a conjugate according to any of claims 1 to 10 and a pharmaceutically acceptable carrier, excipient, or diluent.
16. A method of preventing, treating or ameliorating arthritis, cancer or pain, which comprises administering a conjugate according to any of claims 1 to 10 to a subject in need of such prevention, treatment, or amelioration.
17. A method according to claim 16 for preventing, treating, or ameliorating chronic pain, such as neuropathic or inflammatory pain.
18. A method of making a conjugate according to any of claims 1 to 10, which comprises conjugating a MEK inhibitor to a targeting agent which can deliver the MEK inhibitor to the locus of a condition.
19. A method according to claim 18, , wherein the MEK inhibitor is conjugated to the targeting agent by means of a hydrolysable linker.
20. A conjugate produced by a method according to claim 19.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003240080A AU2003240080A1 (en) | 2002-06-11 | 2003-06-11 | Therapeutic conjugate consisting of a mek inhibitor and a targeting agent |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0213383.3A GB0213383D0 (en) | 2002-06-11 | 2002-06-11 | Therapeutic conditions |
| GB0213383.3 | 2002-06-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2003103717A1 true WO2003103717A1 (en) | 2003-12-18 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2003/002501 Ceased WO2003103717A1 (en) | 2002-06-11 | 2003-06-11 | Therapeutic conjugate consisting of a mek inhibitor and a targeting agent |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2003240080A1 (en) |
| GB (1) | GB0213383D0 (en) |
| WO (1) | WO2003103717A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114788867A (en) * | 2022-04-24 | 2022-07-26 | 天津医科大学总医院 | Application of Map2k1 as a therapeutic target for post-chemotherapy neuralgia |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994023752A1 (en) * | 1993-04-16 | 1994-10-27 | University Of Portsmouth Enterprise Limited | Drug delivery system |
| WO1999017806A1 (en) * | 1997-10-08 | 1999-04-15 | The Speywood Laboratory Limited | Conjugates of galactose-binding lectins and clostridial neurotoxins as analgesics |
| WO2000056725A1 (en) * | 1999-03-19 | 2000-09-28 | Du Pont Pharmaceuticals Company | N-adamant-1-yl-n'-[4-chlorobenzothiazol-2-yl] urea useful in the treatment of inflammation and as an anticancer radiosensitizing agent |
| WO2000056706A1 (en) * | 1999-03-19 | 2000-09-28 | Du Pont Pharmaceuticals Company | Amino-thio-acrylonitriles as mek inhibitors |
| WO2000057897A1 (en) * | 1999-03-31 | 2000-10-05 | Microbiological Research Authority | Use of a lectin or conjugates for modulation of c-fibre activity |
| WO2001005390A2 (en) * | 1999-07-16 | 2001-01-25 | Warner-Lambert Company | Method for treating chronic pain using mek inhibitors |
| WO2002017952A2 (en) * | 2000-09-01 | 2002-03-07 | Van Andel Institute | Inhibition of mitogen-activated protein kinase (mapk) pathway: a selective therapeutic strategy against melanoma |
-
2002
- 2002-06-11 GB GBGB0213383.3A patent/GB0213383D0/en not_active Ceased
-
2003
- 2003-06-11 AU AU2003240080A patent/AU2003240080A1/en not_active Abandoned
- 2003-06-11 WO PCT/GB2003/002501 patent/WO2003103717A1/en not_active Ceased
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994023752A1 (en) * | 1993-04-16 | 1994-10-27 | University Of Portsmouth Enterprise Limited | Drug delivery system |
| WO1999017806A1 (en) * | 1997-10-08 | 1999-04-15 | The Speywood Laboratory Limited | Conjugates of galactose-binding lectins and clostridial neurotoxins as analgesics |
| WO2000056725A1 (en) * | 1999-03-19 | 2000-09-28 | Du Pont Pharmaceuticals Company | N-adamant-1-yl-n'-[4-chlorobenzothiazol-2-yl] urea useful in the treatment of inflammation and as an anticancer radiosensitizing agent |
| WO2000056706A1 (en) * | 1999-03-19 | 2000-09-28 | Du Pont Pharmaceuticals Company | Amino-thio-acrylonitriles as mek inhibitors |
| WO2000057897A1 (en) * | 1999-03-31 | 2000-10-05 | Microbiological Research Authority | Use of a lectin or conjugates for modulation of c-fibre activity |
| WO2001005390A2 (en) * | 1999-07-16 | 2001-01-25 | Warner-Lambert Company | Method for treating chronic pain using mek inhibitors |
| WO2002017952A2 (en) * | 2000-09-01 | 2002-03-07 | Van Andel Institute | Inhibition of mitogen-activated protein kinase (mapk) pathway: a selective therapeutic strategy against melanoma |
| US20020054869A1 (en) * | 2000-09-01 | 2002-05-09 | Han-Mo Koo | Inhibition of mitogen-activated protein kinase (MAPK) pathway: a selective therapeutic strategy against melanoma |
Non-Patent Citations (5)
| Title |
|---|
| DUNCIA J V ET AL: "MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 20, 20 October 1998 (1998-10-20), pages 2839 - 2844, XP004139571, ISSN: 0960-894X * |
| RU-RONG JI ET AL: "NOCICEPTIVE-SPECIFIC ACTIVATION OF ERK IN SPINAL NEURONS CONTRIBUTES TO PAIN HYPERSENSITIVITY", NATURE NEUROSCIENCE, NATURE AMERICA, INC, US, vol. 2, no. 12, December 1999 (1999-12-01), pages 1114 - 1119, XP000978586, ISSN: 1097-6256 * |
| SEBOLT-LEOPOLD J.S.: "Development of anticancer drugs targeting the MAP kinase pathway", ONCOGENE, vol. 19, no. 56, 27 December 2000 (2000-12-27), pages 6594 - 6599, XP002250479 * |
| SEZAKI H ET AL: "MACROMOLECULE-DRUG CONJUGATES IN TARGETED CANCER CHEMOTHERAPY", CRITICAL REVIEWS IN THERAPEUTIC DRUG CARRIER SYSTEMS, XX, XX, vol. 1, 1984, pages 1 - 38, XP002037405, ISSN: 0743-4863 * |
| TAKAKURA Y ET AL: "MACROMOLECULAR CARRIER SYSTEMS FOR TARGETED DRUG DELIVERY: PHARMACOKINETIC CONSIDERATIONS ON BIODISTRIBUTION", PHARMACEUTICAL RESEARCH, NEW YORK, NY, US, vol. 13, no. 6, June 1996 (1996-06-01), pages 820 - 831, XP001006101, ISSN: 0724-8741 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114788867A (en) * | 2022-04-24 | 2022-07-26 | 天津医科大学总医院 | Application of Map2k1 as a therapeutic target for post-chemotherapy neuralgia |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003240080A1 (en) | 2003-12-22 |
| GB0213383D0 (en) | 2002-07-24 |
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