Compositions and methods for treatment and imaging using nanoparticles
The present invention encompasses compositions comprising two spectrally distinct radionuclides separated by a site susceptible to cleavage. Compositions of the invention may be used to detect enzyme activity and/or image diseases associated with said enzyme activity.
1. A composition comprising:
(a) a peptide comprising a Tyr residue and a -Lys-Gly-Cys- group, wherein the Tyr residue is separated from the -Lys-Gly-Cys- group by a caspase-3 sensitive site, wherein the caspase-3 sensitive site comprises the amino acid sequence SEQ ID NO:2 (Asp-Glu-Val-Asp); and,
(b) two radionuclides, wherein the spectrally differentiated radionuclides are 125 I and 99 mTc,
wherein the radionuclides are attached to the peptide at positions separated by the caspase-3 sensitive site, which is susceptible to cleavage by caspase-3, within the peptide.
2. A method of detecting enzyme activity in a subject, the method comprising:
a) administering to the subject an effective amount of a composition of claim 1 :
wherein cleavage at a caspase-3 sensitive site within the peptide results in a radiative hydrophobic peptide fragment and a radiative hydrophilic peptide fragment;
b) imaging the subject for a signal corresponding to a radionuclide radiative hydrophobic peptide fragment and a radionuclide radiative hydrophilic peptide fragment to determine a biodistribution for the radiative hydrophobic peptide fragment and the radiative hydrophilic peptide fragment;
c) comparing the biodistribution of the radionuclide radiative hydrophobic peptide fragment to the biodistribution of the radionuclide radiative hydrophilic peptide fragment,
wherein when the biodistribution for the radionuclide radiative hydrophobic peptide fragment differs from the biodistribution for the radionuclide radiative hydrophilic peptide, enzyme activity is detected.
3. The method of claim 2 , wherein the subject is imaged about 4 to about 48 hours after administration.
4. The method of claim 2 , wherein the subject is imaged using single photon emission computed tomography (SPECT).
5. A method of detecting enzyme activity in a subject, the method comprising:
a) administering to the subject an effective amount of a composition of claim 1 ;
b) imaging the subject for a signal corresponding to the 125 I and 99 mTc to determine a biodistribution for 125 I and 99 MTc; and,
c) comparing the biodistribution of 125 I to the biodistribution of 99 mTc,
wherein when the biodistribution for the 125 I differs from the biodistribution for the 99 mTc-enzyme activity is detected.
6. The method of claim 5 , wherein the subject is imaged about 4 to about 48 hours after administration.
7. The method of claim 5 , wherein the subject is imaged using single photon emission computed tomography (SPECT).
8. The composition of claim 1 , wherein one of the radionuclides is conjugated to the Tyr residue found in the peptide.
9. The composition of claim 8 , wherein the radionuclide is 125 I.
10. The composition of claim 1 , wherein one of the radionuclides is conjugated to the -Lys-Gly-Cys-group found in the peptide.
11. The composition of claim 10 , wherein the radionuclide is 99m Tc.
12. The composition of claim 1 , wherein the peptide comprises SEQ ID NO:5 (Ahx-Tyr-Ahx-Asp-Glu-Val-Asp-Gly-Lys-Cys) and Ahx is 6-aminocaproic acid.