Nanoparticle peg modification with h-phosphonates
AssigneeMallinckrodt Inc.
InventorThomas E. Rogers
Life of this patent
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Abstract
The present invention provides phosphonate conjugates and methods of preparing the phosphonate conjugates so as to allow, for example, improved methods and compounds for modifying the surface of a nanoparticle to increase in vivo circulation times and targeted delivery performance.
Claims27
1-20. (canceled)
A method of preparing a phosphonate conjugate, the method comprising:
- combining a primary amine compound having the formula:
- H2N(L1)-(R1),
- a carbonyl compound having the formula:
- O═C[(L2)-(R2)]n, and
- a H-phosphonate compound having the formula:
- under conditions sufficient to form the phosphonate conjugate having the formula:
- wherein
- each L1, L2, L3 and L4 is independently selected from the group consisting of a bond and a linking group;
- R1 is selected from the group consisting of a nanoparticle, an attachment component, a targeting agent, a diagnostic agent, a stealth agent, and a tetrapodal presentation component;
- each R2 is independently selected from the group consisting of a stealth agent, C1-C10 alkyl, a carboxylic acid or ester, a phosphonic acid or ester, a sulfonic acid or ester, and a hydroxy;
- each R3 and R4 is independently selected from the group consisting of H, an attachment component, a targeting agent, a diagnostic agent, and a stealth agent, wherein at least one of R3 or R4 is other than H;
- and
- n is an integer from 0 to 2, wherein when n is 0 or 1 the carbonyl compound is an aldehyde.
A compound of the formula:
- wherein
- each L1, L2, L3 and L4 is independently selected from the group consisting of a bond and a linking group;
- R1 is selected from the group consisting of a nanoparticle, an attachment component, a targeting agent, a diagnostic agent and a stealth agent;
- R2 is independently selected from the group consisting of a stealth agent, C1-C10 alkyl, a carboxylic acid or ester, a phosphonic acid or ester, a sulfonic acid or ester, and a hydroxy;
- each R3 and R4 is independently selected from the group consisting of H, a nanoparticle, an attachment component, a targeting agent, a diagnostic agent, and stealth agent, wherein at least one of R3 or R4 is other than H;
- R9 is a C1-C10 alkyl group;
- and
- n is an integer from 0 to 2.
A method of preparing a phosphonate conjugate, the method comprising:
- combining a secondary amine compound having the formula:
- HN[(L1)-(R1)](R9), a carbonyl compound having the formula:
- O═C[(L2)-(R2)]n, and a H-phosphonate compound having the formula:
- under conditions sufficient to form the phosphonate conjugate having the formula:
- wherein
- each L1, L2, L3 and L4 is independently selected from the group consisting of a bond and a linking group;
- R1 is selected from the group consisting of a nanoparticle, an attachment component, a targeting agent, a diagnostic agent and a stealth agent;
- R2 is independently selected from the group consisting of a stealth agent, C1-C10 alkyl, a carboxylic acid or ester, a phosphonic acid or ester, a sulfonic acid or ester, and a hydroxy;
- each R3 and R4 is independently selected from the group consisting of H, an attachment component, a targeting agent, a diagnostic agent, and a stealth agent, wherein at least one of R3 or R4 is other than H;
- R9 is selected from the group consisting of a C1-C10 alkyl group;
- and
- n is an integer from 0 to 2, wherein when n is 0 the carbonyl compound is a formaldehyde.
(canceled)
The targeted delivery composition of claim 41, wherein the nanoparticle is a liposome and each of R3 and R4 is associated with a bilayer of the liposome and independently selected from the group consisting of a lipid and cholesterol.
(canceled)
The targeted delivery composition of claim 42, wherein the nanoparticle is a liposome, and R1 is associated with a bilayer of the liposome and independently selected from the group consisting of a lipid and cholesterol.
A method for treating or diagnosing a cancerous condition in a subject, comprising administering to the subject a targeted delivery composition of claim 41, wherein the composition comprises a therapeutic or a diagnostic agent that is sufficient to treat or diagnose the condition, and wherein at least one of R1, R3 and R4 is a targeting agent.
A method of determining the suitability of a subject for a targeted therapeutic treatment, comprising administering to the subject a targeted delivery composition of claim 41, wherein at least one of R1, R3 and R4 is a targeting agent and the nanoparticle comprises a diagnostic agent, and imaging the subject to detect the diagnostic agent.
Dependencies are inferred from the claim text.