Tumor targeting with polymeric molecules having extended conformation

• US 5,762,909 A
• Filed: 08/01/1996
• Issued: 06/09/1998
• Est. Priority Date: 08/31/1995
• Status: Expired due to Fees

• Current Assignee: General Electric Company
• Original Assignee: General Electric Company
• Inventors: Uzgiris, Egidijus Edward
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US08/691,164
• Time in Patent Office: 677 Days
• Field of Search: 424/1.11, 424/1.37, 424/1.65, 424/1.69, 424/9.1, 424/9.3, 424/9.34, 424/9.4, 424/9.5, 530/300, 530/324-330, 430/944, 544/313, 534/10-16, 424/9.6
• US Class Current: 424/9.34
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 49/146 the peptide being a polyamino acid, e.g. poly-lysine
• CPC Class Codes: G01N 33/574 for cancer

Abstract

Enhanced drug delivery to tumor tissue is obtained by attaching drug molecules to elongated polypeptide carrier molecules several orders of magnitude longer than wide. These are chosen to have a high net negative charge. The carrier molecules are created by unfolding long polypeptides by a large degree of substitution with steric hindrance molecules, such as diethylene triamine pentaacetic acid (DTPA) with at least 90% substitution. This causes the conformation to be worm-like as evidenced by a measure of persistence length, with a diameter small enough squeeze through the pore structures of tumor tissue but not so small as to pass through pores of vessels in normal tissue. The length is determined by optimizing two processes, blood circulation lifetime, and tumor uptake. The elongated conformation may cause the complex to become entwined with stroma in tumor interstitium and become trapped. The complex molecules provides increased therapeutic benefit in effecting tumor tissue destruction, or may be used in enhancing imaging contrast depending upon the active agent attached to the carrier molecules. The enhanced concentration and retention of the complex molecules within the tumor reduces side effects of the active agent in other tissues.

Claims

1. A method of concentrated delivery of an active agent to a tumor of a subject comprising the steps of:

a) selecting an optimum carrier molecule average length;

b) selecting a carrier molecule having the determined optimum average length, a diameter of between 30-50 Angstroms, a net negative charge, persistence length between 100-600 Angstroms;

c) combining the active agent with the carrier molecule to create a carrier/active agent (C/A) complex molecules; and

d) introducing the C/A complex molecules into a blood vessel of said subject to result in reptation and concentrated delivery of said active agent to said tumor of said subject.

2. The method of concentrated delivery of an active agent of claim 1 wherein the step of determining an optimum carrier molecule average length comprises the steps of:

a) acquiring plasma lifetime vs. average chain length data;

b) acquiring tumor uptake vs. average chain length data;

c) multiplying plasma lifetime data by tumor uptake data for corresponding average chain lengths to result in tumor accumulation data;

d) selecting a chain length substantially corresponding to a highest point of the tumor accumulation data.

3. The method of claim 1 wherein the active agent is selected to be an imaging agent.

4. The method of claim 1 wherein the active agent is selected to be a chemotherapy drug.

5. The method of claim 1 wherein the active agent is selected to be a radiotherapy agent.