Theranostic imaging agents and methods of use
The present invention provides targeted nanoplex molecules which carry multimodality imaging reporters together with target enzyme inhibitors such as siRNAs and target prodrug enzymes, that are useful for theranostic imaging of cells and diseases, including, for example, various cancers, and including metastatic prostate cancer. The nanoplex molecules of the present invention provide a platform technology toward many cancer subtypes and alternative therapeutic targets. Downregulation of specific pathways using targeted enzyme inhibitors further provides unique opportunities to target cancer cells selectively while sparing normal tissue. The nanoplex molecule platform described herein has the ability to deliver multiple siRNA enzyme inhibitors. Methods of diagnosis and treatment of various diseases are also included. The strategy described herein can be useful to down-regulate multi-drug resistance pathways, or repair enzymes with the goal of increasing the efficacy, safety, and efficiency of chemotherapeutic or irradiation therapies.
1. A nanoplex molecule comprising:
a) a prodrug enzyme portion;
b) a reporter portion;
c) an enzyme inhibitor portion; and
d) a targeting agent;
wherein,
the prodrug enzyme portion is the enzyme bacterial cytosine deaminase (bCD);
the reporter portion is a poly-L-lysine carrier linked to a Cy5.5 dye and a DOTA moiety labeled with 111 In or Gd 3+ linked to a polyethyleneimine (PEI):poly ethylene glycol (PEG) block co-polymer;
the enzyme inhibitor portion is at least one siRNA; and
the targeting agent comprises a prostate specific membrane antigen (PSMA) targeting moiety having the following formula:
2. The nanoplex composition of claim 1 , wherein the targeting agent is (2-(3-[1-carboxy-5-[7-(2,5 -dioxo-pyrrolidin-1-yloxycarbonyl)-heptanoylamino]-pentyl]-ureido)-pentanedioic acid.
3. The nanoplex composition of claim 1 , wherein the at least one siRNA is specific for the choline kinase (Chk) enzyme.
4. A pharmaceutical composition comprising one or more nanoplex compositions of claim 1 , and a pharmaceutically acceptable carrier.
5. A pharmaceutical composition comprising one or more nanoplex compositions of claim 1 , a pharmaceutically active compound, and a pharmaceutically acceptable carrier.
6. A method of modulating expression of a target gene in a host cell or population of cells, wherein the host cell or population of cells express prostate specific membrane antigen (PSMA), comprising administering to the cell or population of cells the nanoplex composition of claim 1 , or a pharmaceutical composition thereof, in an amount sufficient to modulate target gene expression with the host cell or population of cells.
7. The method of claim 6 , wherein the target gene is upregulated in a cancer cell when compared to a non-cancerous cell, wherein the cancer cell has an increased expression of prostate specific membrane antigen (PSMA) relative to the non-cancerous cell.
8. A method for treating a cancer in a subject in need of treatment thereof, the method comprising administering to the subject an effective amount of a nanoplex molecule of claim 1 , or a pharmaceutical composition thereof.
9. The method of claim 8 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
10. The method of claim 8 , wherein the pharmaceutical composition further comprises a second therapeutic agent.
11. The method of claim 8 , wherein the cancer is prostate cancer.
12. The method of claim 8 , further comprising imaging a target cell or population of cells, wherein the target cell or population of cells express prostate specific membrane antigen (PSMA).
13. The method of claim 12 , wherein the imaging is selected from the group consisting of SPECT imaging, PET imaging, MR imaging, and fluorescence imaging.