Brain tumor targeting peptides and methods

Abstract

A method of diagnosing and treating a human glioblastoma multiforme (GBM) brain tumor in a subject is disclosed. The method includes administering to the subject, an effective amount of composition having a peptide 12-20 amino acid residues in length and selected for its ability to bind preferentially to a subtype of human GBM cells identified as brain tumor initiating cells (BTICs) or highly invasive glioma cells (HIGCs).

1 . A peptide composition for targeting one of (i) a highly invasive glioma cell (HIGC) subtype of human glioblastoma multiforme (GBM) cells characterized by their ability to migrate from one brain hemisphere into which the cells are injected into the contralateral hemisphere, and (ii) a brain tumor initiating cell (BTIC) subtype of human GBM cells characterized by their stem-cell like properties of being able to self renew, generate spheres without the addition of exogenous mitogens and growth factors, and induce tumor formation in vivo when placed in the brains of immuno-compromised mice, comprising
 an isolated peptide having between 12-20 amino acids, and containing a sequence selected from the group consisting of SEQ ID NOS: 1-10, 13, and 17 for targeting HIGCs, and SEQ ID NOS: 11-16, for targeting BTICs.   
     
     
         2 . The peptide composition of  claim 1 , wherein the peptide is composed of L-amino acids, D-amino acids, a mixture of L- and D-amino acids, or a retro-inverso peptide formed of D-amino acids arranged in reverse order. 
     
     
         3 . The peptide composition of  claim 1 , for use in localizing of HIGCs or BTICs in a subject with a human GBM tumor, which further includes a contrast agent attached to the peptide. 
     
     
         4 . The peptide composition of  claim 1 , for use in inhibiting or killing HIGCs or BTICs in a subject with a human GBM tumor, which further includes an anti-tumor agent attached to the peptide. 
     
     
         5 . The peptide composition of  claim 1 , for use in targeting HIGCs, wherein the peptide contains a sequence selected from the group consisting of SEQ ID NOS: 7 (H10), 13 (E10) and 17 (modified H10); 
     
     
         6 . The peptide composition of  claim 1 , for use in targeting HIGCs, wherein the peptide contains the sequence identified by SEQ ID NOS: 17 (modified H10); 
     
     
         7 . The peptide of composition 1, for use in targeting BTICs, wherein the peptide contains a sequence selected from the group consisting SEQ ID NOS: 11 (7A), 13 (E10), 14 (3F) and 16 (3B). 
     
     
         8 . The peptide composition of  claim 7 , wherein the peptide has the sequence identified by SEQ ID NOS: 11 (7A). 
     
     
         9 . The peptide composition of  claim 1 , for use in delivery to a patient human GBM tumor across the blood-brain barrier, wherein the peptide is coupled to a carrier peptide having the sequence identified by SEQ ID NOS: 18 or 19. 
     
     
         10 . The peptide composition of  claim 1 , wherein the peptide is encapsulated within a nanoparticle formed of poly(lactide-co-glycolide) copolymer, a cyclodextrin, or cetyl alcohol/polysorbate. 
     
     
         11 . The peptide composition of  claim 1  which includes at least one peptide that binds preferentially to HGIC's and at least one peptide that binds preferentially to BTIC's. 
     
     
         12 . The use of the composition of  claim 1 , for detecting the presence of HIGC or BTIC subtypes of cells in a patient with GBM tumor, where the composition includes a detectable contrast agent coupled to the peptide. 
     
     
         13 . The use of the peptide composition of  claim 1 , for inhibiting or killing HIGC or BTIC subtypes of cells in a patient with GBM tumor, where the composition includes an anti-tumor agent coupled to the peptide. 
     
     
         14 . A method of characterizing a glioblastoma multiforme (GBM) tumor in a patient, comprising
 (a) generating an image of the patient's brain tumor after administering to the patient a peptide composition containing (i) a first peptide having between 12-20 amino acids in length that has been selected for its preferential binding to a highly invasive glioma cell (HIGC) subtype of human GBM cells characterized by their ability to migrate from one brain hemisphere into which the cells are injected into the contralateral hemisphere, and coupled to first peptide, a first contrast agent that allows the first peptide, when bound to cells in the patient tumor region, to be imaged in vivo;   (b) generating an image of the patient's brain tumor after administering to the patient a peptide composition containing (i) second peptide having between 12-20 amino acids in length that has been selected for its preferential binding to a brain tumor initiating cell (BTIC) subtype of human GBM cells characterized by their stem-cell like properties of being able to self renew, generate spheres without the addition of exogenous mitogens and growth factors, and induce tumor formation in vivo when placed in the brains of immunocompromised mice, and coupled to the second peptide, a second contrast agent that allows the second peptide, when bound to cells in the patient tumor region, to be imagined in vivo;   (c) determining, from the distribution of the first and second peptides and their associated contrast observed in the image(s) generated in steps (a) and (b), at least one of:   (ci) the boundaries of the tumor, for purposes of surgical resection of the tumor,   (cii) the boundaries of the tumor for purposes of radiation therapy of the tumor,   (ciii) the expression profiles of different tumor-cell phenotypes within the tumor, for purposes of tailoring a chemotherapeutic regimen for treating the tumor; and   (civ) the change in the distribution of the first and second peptides and their associated contrast agents over a given time course in which steps (a) and (b) are repeated over time.   
     
     
         15 . The method of  claim 14 , wherein steps (a) and (b) are carried out by one of:
 (i) MRI, wherein the contrast agent is selected from the group consisting of a gadolinium-based contrast agent, an iron oxide contrast agent, and a manganese contrast agent;   (ii) positron emission tomography (PET) or scintigraphy, wherein the contrast agent is selected from the group consisting of  64 Cu diacetyl-bis(N 4 -methylthiosemicarbazone),  18 F-fluorodeoxyglucose,  18 F-fluoride, 3′-deoxy-3′-[ 18 F]fluorothymidine (FLT),  18 F-fluoromisonidazole, gallium, Technetium-99m, and thallium; and   (iii) x-ray imaging, where the contrast agent is selected from the group consisting of barium, gastrografin, and iodine contrast agents.   
     
     
         16 . The method of  claim 14 , wherein steps (a) and (b) are carried out together and the first and second contrast agents allow the distributions of bound first and second peptides to be independently determined. 
     
     
         17 . The method of  claim 14 , wherein steps (a) and (b) are carried sequentially. 
     
     
         18 . The method of  claim 14 , wherein the first peptide contains a sequence selected from the group consisting of SEQ ID NOS: 7 (H10), 13 (E10) and 17 (modified H10); 
     
     
         19 . The method of  claim 14 , wherein the second peptide contains a sequence selected from the group consisting SEQ ID NOS: 11 (7A), 13 (E10), 14 (3F) and 16 (3B). 
     
     
         20 . The method of  claim 14 , wherein said peptide compositions are administered intravenously. 
     
     
         21 . A method of characterizing the gene expression profiles of cellular phenotypes in a human glioblastoma multiforme (GBM) tumor in a patient, comprising
 (a) identifying cells in the tumor corresponding to one of (i) a differentiated GBM tumor cell, (ii) a highly invasive glioma cell (HIGC) subtype of human glioblastoma multiforme (GBM) cells characterized by their ability to migrate from one brain hemisphere into which the cells are injected into the contralateral hemisphere, and (iii) a brain tumor initiating cell (BTIC) subtype of human GBM cells characterized by their stem-cell like properties of being able to self renew, generate spheres without the addition of exogenous mitogens and growth factors, and induce tumor formation in vivo when placed in the brains of immuno-compromised mice, and   (b) correlating the identified cell type with the known gene expression pattern of that cell type.