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Pharmaceutical compositions contg. anti-body-enzyme conjugates in combination with prodrugs

A technology of prodrugs and conjugates, applied in drug combinations, medical preparations containing active ingredients, nano-drugs, etc., can solve optimization difficulties, difficulties in enzyme expression duration and reproducibility, and lack of specificity in enzyme expression And other issues

Inactive Publication Date: 2000-07-12
SCHOOL OF PHARMACY UNIV OF LONDON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the case of VDEPT, there are inherent dangers associated with viral vectors, potential lack of specificity of enzyme expression in tumors due to problems delivering genes specifically to cancer cells, and assessment of enzyme expression duration and reproducibility on a patient basis. Sexual difficulties lead to difficulties in optimizing subsequent prodrug schedules

Method used

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  • Pharmaceutical compositions contg. anti-body-enzyme conjugates in combination with prodrugs
  • Pharmaceutical compositions contg. anti-body-enzyme conjugates in combination with prodrugs
  • Pharmaceutical compositions contg. anti-body-enzyme conjugates in combination with prodrugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Invention with reference to the accompanying drawings figure 2 etc. are further illustrated in the following examples. Example 1: HPMA-β-lactamase conjugates

[0082] β-lactamase (Sigma; ~29kDa) reacts with the polymer carrier N-(2-hydroxypropyl)methacrylamide-glycine-glycine-P - Nitrophenol (HPMA-Gly-Gly-ONp; Polymer Laboratories; ~30 kDa) bound. react in figure 2 Indicated. The following steps were performed:

[0083] Dissolve the polymer with side chain P-nitrophenol (ONp) group in double distilled water (4mg / ml) and dissolve the β-lactamase in 0.05M phosphate buffer at pH 7.2 (2mg / ml), and this solution was added to the polymer solution at 4°C with stirring.

[0084] The reaction mixture was stirred at pH 7.2 for 30 minutes in the dark. The pH was carefully raised to 8.5 over 4 hours (to prevent enzyme denaturation) by the addition of saturated sodium tetraborate buffer, and the reaction mixture was stirred for an additional 4 hours. The reaction was termi...

Embodiment 2

[0101] Cathepsin B (Sigma, ~28 kDa) was bound to the polymeric carrier (HPMA-Gly-Gly-ONp; ~30 kDa) by nonspecific aminolysis of the ONp group at controlled pH. react in figure 2 Indicated. The same procedure as in Example was carried out except that the polymer was dissolved in double distilled water at 1 mg / ml and cathepsin B was used instead of β-lactamase.

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Abstract

Prodrugs which can be activated by enzymes, are formulated for sequential administration, with enzyme conjugates. Either or each component comprises a polymeric carrier which allows it to be directed preferentially to the target tissue. A new polymer-prodrug conjugate is cleavable by Cathepsin B or other thiol-dependent protease. The invention is of particular utility for targeting solid tumours.

Description

[0001] The pharmaceutical composition of the conjugate Field of invention: [0002] The present invention relates to compositions and kits for enzyme-prodrug therapy wherein the enzyme is coupled to a carrier. Background of the invention: [0003] Chemotherapy of neoplastic diseases is often hampered by adverse systemic toxicities that limit the administered dose or limited by the emergence of multidrug resistance. Several strategies have been employed to improve drug targeting and increase drug concentrations in tumors to levels that overcome clinically relevant resistance to several drugs. [0004] Prodrugs have been used in medicine for many years for the treatment of various disorders. They can provide improved solubility, improved pharmacokinetics and tissue distribution, avoidance of adverse metabolism, selective organ effects and specific tumor toxicity. For a prodrug to be useful as an anticancer agent, the tumor must have high levels of an enzyme that activates th...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K47/48A61P35/00
CPCA61K47/48361A61K47/48176B82Y5/00A61K47/58A61K47/67A61P35/00A61K47/00
Inventor R·敦肯R·萨奇
Owner SCHOOL OF PHARMACY UNIV OF LONDON
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