Dendrimer conjugates

• US 8,980,907 B2
• Filed: 12/16/2013
• Issued: 03/17/2015
• Est. Priority Date: 09/30/2008
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Baker, James R. Jr., Cheng, Xue-min, Van Der Spek, Abraham F. L., Huang, Baohua Mark, Thomas, Thommey P.
• Primary Examiner(s): Singh, Anoop
• Assistant Examiner(s): FALKOWITZ, ANNA R
• Application Number:
  US14/107,817
• Publication Number:
  US 20140128327A1
• Time in Patent Office: 456 Days
• Field of Search: 514/282, 514/237.2, 424/78.3, 546/46
• US Class Current: 514/282
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 47/595 Polyamides, e.g. nylon polyamino acids A61K47/62
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The present invention relates to novel therapeutic and diagnostic dendrimers. In particular, the present invention is directed to dendrimer-linker conjugates, methods of synthesizing the same, compositions comprising the conjugates, as well as systems and methods utilizing the conjugates (e.g., in diagnostic and/or therapeutic settings (e.g., for the delivery of therapeutics, imaging, and/or targeting agents (e.g., in disease (e.g., cancer) diagnosis and/or therapy, pain therapy, etc.)). Accordingly, dendrimer-linker conjugates of the present invention may further comprise one or more components for targeting, imaging, sensing, and/or providing a therapeutic or diagnostic material and/or monitoring response to therapy.

Claims

1. A method for simultaneously ameliorating pain and preventing respiratory depression in a subject, comprising

providing a composition comprising pain relief complexes and pain relief antagonist complexes;

wherein said pain relief complexes consist of dendrimers separately conjugated with

     1) a pain relief agent via an ester linkage agent, wherein said pain relief agent is morphine,

     2) a locking agent, wherein said locking agent is trigonelline, and

     3) a targeting agent, wherein said targeting agent is transferrin;

wherein said pain relief antagonist complexes consist of dendrimers separately conjugated with

     1) a pain relief agent antagonist via an indolequinone trigger agent, wherein said pain relief agent antagonist is naloxone,

     2) a locking agent, wherein said locking agent is trigonelline, and

     3) a targeting agent, wherein said targeting agent is transferrin;

wherein said dendrimers within said pain relief complexes and pain relief antagonist complexes are separate within said composition;

administering said composition to a subject experiencing pain such that said pain relief complexes and pain relief antagonist complexes cross the blood brain barrier and are locked within the central nervous system,

releasing said morphine from said pain relief complexes upon interaction between an endogenous esterase and said ester linkage agent, wherein said release of said morphine results in pain amelioration, and

releasing said naloxone from said pain relief antagonist complexes upon endogenous hypoxic conditions within said subject, wherein said release of said naloxone results in prevention of respiratory depression.

2. The method of claim 1, wherein said subject is a human subject.

3. The method of claim 1, wherein said dendrimers are selected from the group consisting of a polyamideamine (PAMAM) dendrimer, a polypropylamine (POPAM) dendrimer, and a PAMAM-POPAM dendrimer.

4. The method of claim 1, wherein the linkage agent comprises a spacer comprising between 1 and 8 straight or branched carbon chains, wherein said straight or branched chains are selected from the group consisting of i) unsubstituted, and ii) substituted with alkyls.

5. The method of claim 1, wherein said dendrimers are acetylated.