Table 5.
Cancer-Targeting Peptides Selected by Panning in Vivo
| Tumor Typea | Peptide Sequenceb,c,d,e,f | Cellular Receptor |
Applications and Notes |
|---|---|---|---|
| Gastric (AZ-P7a) | SWKLPPS259 (g) (pIII, T) | α3β1 (suggested) | Therapeutic Applications: Peptide-liposomal doxorubicin killed AZ-P7a cells better than unconjugated liposomes in vitro. |
| Human gastric adenocarcinoma (propagated in mice) | CGNSNPKSC260 (GX1) (pIII, V) |
Therapeutic Applications: The free peptide fused to recombinant human tumor necrosis factor alpha (rmhTNFα) induced HUVEC apoptosis in vitro.261 This peptide-rmhTNFα fusion also inhibited SGC7901 tumor growth in mice.261 Imaging Applications: 99Tcm-peptide261,262 and 99Tcm-peptide-rmhTNFα261 successfully detected SGC7901 tumors by SPECT imaging. MicroPET imaging using 64Cu-DOTA-peptide detected U87MG tumors in mice.263 Near-infrared fluorescence imaging of Cy5.5-peptide in U87MG tumor-bearing mice demonstrated tumor targeting.264 |
|
| Lung (irradiated and SU11248 treated murine Lewis lung carcinoma) & Glioblastoma (GL261, murine) | HVGGSSV243 (h) (T7 phage, V) | TIP-1265,266 |
Therapeutic Applications: Peptide-nab-paclitaxel inhibited Lewis lung carcinoma and H460 tumor growth in mice in conjunction with irradiation.265 Lewis lung carcinoma and H460 tumor growth inhibition was observed when animals were treated with irradiation and peptide liposomal doxorubicin.267 Imaging applications: Near-infrared fluorescence imaging using dye labeled peptide has been performed for several tumor types and in various types of tumor-bearing mice treated with irradiation or TKI (tyrosine kinase inhibitors) or both.243,265–269 |
| Lung (CL1-5) | SVSVGMKPSPRP249 (pIII, V) |
Therapeutic Applications: Peptide liposomal doxorubicin inhibited CL1-5 tumor growth and increased survival in mice. Note: This peptide has been suggested to be a non-specific peptide that is isolated from the NEB 12-mer library most likely due to preferential propagation of this phage clone.207 |
|
| Lung (H460) | RCPLSHSLICY270 (pIII, T) | ||
| Oral (SAS) | SVSVGMKPSPRP249 (pIII, V) |
Therapeutic Applications: Peptide liposomal doxorubicin inhibited SAS tumor growth and increased survival in mice. Note: This peptide has been suggested to be a non-specific peptide that is isolated from the NEB 12-mer library most likely due to preferential propagation of this phage clone.207 |
|
| SNPFSKPYGLTV244 YPHYSLPGSSTL244 (pIII, V) |
Therapeutic Applications: Peptide-liposomal doxorubicin inhibited tumor growth and increased survival in mice with various tumor types compared to non-conjugated liposomal doxorubicin. Similar growth inhibition was observed for both peptides. | ||
| Nasopharyngeal Carcinoma (CNE-1) | EDIKPKTSLAFR271 (pIII, ND) | ||
| Prostate (PC-3) | IAGLATPGWSHWLAL272 (G1) (pIII, T) |
Imaging applications:
111In-DOTA-Gl peptide has been used for SPECT/CT imaging of PC-3 tumors in mice.273 Functional Peptide Activity: The peptide induced apoptosis of PC-3 cells in culture.273 |
|
| LKGDCTQRYVYCMKSK273 (H5) (pVIII hybrid, T) |
Imaging applications:
111In-DOTA-H5 peptide has been used for SPECT/CT imaging of PC-3 tumors in mice.273 Functional Peptide Activity: The peptide induced apoptosis of PC-3 cells in culture.273 |
||
| CRGDKGPDC274 (iRGD) (T7 phage, T/V) | αvβ3, αvβ5 then cleaved to CRGDK which binds NRP-1 |
Therapeutic Applications: Co-injection of the peptide with Nab-paclitaxel, trastuzumab, liposomal doxorubicin or doxorubicin inhibited BT474 or 22Rv1 orthotopic tumor growth in mice.275 CGKRK-d[KLAKLAK]2-iron oxide nanoworms systemically injected into mice with 005 tumors prolonged survival when co-injected with the peptide.276 Imaging applications: The peptide was conjugated to Cy7 for near-infrared imaging of tumors in mice bearing novo pancreatic ductal adenocarcinoma. MRI of 22Rv1 orthotopic xenografts in mice using peptide-linked SPIO nanoworms has been performed.276 Note: This peptide has been postulated to have a unique mode of action in which the peptide first binds the target integrin and is then cleaved to expose a NRP-1 binding peptide. The binding of NRP-1 increases penetration of cargo throughout the tumor. |
|
| Prostate (TRAMP mice) | CREAGRKAC257 (REA) (i) (T7 phage, L) | Therapeutic Applications: Peptide-D(KLAKLAK)2 conjugate reduced PPC1 orthotopic tumor lymphatic vessels in mice. | |
| Prostate (DU145) | YRCTLNSPFFWEDMTHECHA277 (pIII, T) | CRKL | Therapeutic Applications: Peptide-proapoptotic peptideD(KLAKLAK)2 is cytotoxic to DU145 cells in vitro and inhibits DU145 tumor growth in mice. |
| Prostate (PPC-1)i | RPARPAR278 (T7 phage, T) | Neuropilin-1 (NRP-1)278,279 | |
| Breast (MDA-MB-435) | CNGRCVSGCAGRC112,280 (NGR)j (pIII, V) | Amino-peptidase N (CD13)281 | Therapeutic Applications: A NGR peptide-doxorubicin conjugate inhibited MDA-MB-435 tumor growth & prolonged survival in mice.112 Peptide-liposomal doxorubicin inhibited growth of orthotopic neuroblastoma xenografts in mice282 and increased survival in mouse lung, ovarian, and neuroblastoma xenografts.283 NRG peptide-TNF (tumor necrosis factor α) inhibited tumor growth284 and synergistically increased the effects of various chemotherapy drugs on tumor inhibition in mice (for various tumor types).285–289 Human interferon alpha (hIFN-α2a)-peptide conjugate290 and recombinant hIFN-α2a-peptide291 inhibited tumor growth in mice when injected i.p. in various tumor models. A conjugate of the NRG peptide with a Tum-5-peptide (derived from tumstatin) inhibited S180 tumor growth in mice.292 |
| Breast (MDA-MB-435) | CDCRGDCFC112 (RGD-4C)j (pIII, T/V) | αvβ3,αvβ5,α5β1 |
Therapeutic Applications: A RGD-4C-doxorubicin conjugate inhibited MDA-MB-435 tumor growth and prolonged survival in mice112 and inhibited MH134 orthotopic tumor growth in mice.293 A conjugate of RGD-4C-tumor necrosis factor-α (TNF) inhibited MDA-MB-435 orthotopic tumor growth.136 Conjugation of RGD-4C to adeno-associated virus phage vector (AAVP) allowed for delivery of the HSVtk gene. Treatment of DU145, KS1767, and UC3 xenografts in mice and EF43-FGF4 mouse mammary tumors with RGD-4C-AAVP- HSVtk and gancilovir inhibited tumor growth.294 RGD-4C-Delta-24 adenovirus (an adenovirus with anticancer activity) is cytotoxic to a variety of cancer cell lines.295 Intratumoral injection of RGD-4C-Delta-24 adenovirus into orthotopic U-87 MG tumors in mice increased survival.295 This conjugate has recently begun Phase I clinical trials. Imaging applications: Scintigraphic imaging of DU145 tumors in mice using 99mTc(CO3)-RGD-4C and 99mTc(CO3)-HPMA polymer-RGD-4C has been performed; the polymer conjugate was also imaged in PC-3 tumors.296 MicroPET imaging using 64Cu-DOTA-RGD-4C-TNF-α was able to detect U87MG and MDA-MG-435 tumors in mice.136 Oligonucleotide Delivery: Conjugation of RGD-4C to AAVP resulted in delivery of GFP to KS1767 xenografts in mice & delivery of luciferase to DU145 xenografts as evidenced by bioluminescent imaging.294 RGD-4C-AAVP delivered the HSVtk gene to DU145 xenografts as evidenced by PET imaging with [18F]FEAU.294 |
| CGNKRTRGC255 (LyP-1)i (T7 phage, T/L/M) | p32/gC1qR297 |
Therapeutic Applications: LyP-1 conjugated to liposomes containing doxorubicin are no more effective in reducing tumor growth than non-targeted liposomes.298 However, doxorubicin loaded LyP-1 liposomes injected after gold nanorod-mediated heating of tumors caused tumor regression in mice with MDA-MB-435 tumors.299 Peptide-doxorubicin liposomes killed cells with or without heat treatment in vitro. Peptide coupled to microbubbles containing paclitaxel killed cells when treated in combination with ultrasound but this approach was only tested in vitro.300 Dye-labeled–peptide-abraxane inhibited tumor growth in mice.301 Imaging applications: Near-infrared fluorescence imaging and ex vivo imaging of lymphanogenesis were performed using Cy5.5-peptide injected via the middle phalanges of both upper extremities in 4T1 tumor bearing mice.302 Oligonucleotide Delivery: Baculovirus displaying peptide-VSVG protein fusions and carrying the luciferase gene specifically transduced cells in vitro.303,304 Functional Peptide Activity: The LyP-1 peptide itself induced apoptosis of cancer cell lines in culture and inhibited MDA-MB-435 tumor growth in mice.256 Note: LyP-1 has been shown to home to tumor lymphatics in vivo when used in a variety of formats.255,256,298,299,301,302,304–308 LyP-1 also accumulates in atherosclerotic plaques, primarily in the associated macrophage.309,310 |
|
| Breast (MDA-MB-231 and MCF-7 in mice treated with sunitinib and responding to therapy)h | EGEVGLG242 (T7 phage, V after sunitinib treatment) | Imaging applications: A peptide-AlexaFluor 750 conjugate was used for near-infrared imaging of sunitinib treated MDA-MB-435 and MCF7 tumors in mice. | |
| Medullary Thyroid Carcinoma (TT) | CHTFEPVGC311 (pIII, T) | Oligonucleotide Delivery: Peptide linked to adenovirus vector delivered the GFP gene to cells in vitro resulting in GFP expression but this peptide has not been tested in vivo.311 | |
| Basal cell squamous carcinoma from K14-HPV16 micei | CGKRK312 CDTRL312 (T7 phage, V) |
Therapeutic Applications: The CGKRK peptide was conjugated to a clot inducing nanoworm particle. This conjugate induces clotting in prostate tumors in mice, resulting in a reduction of tumor burden.313 A CGKRK peptide-D[KLAKLAK]2-iron oxide nanoworm decreased the number of blood vessels in bFGF-Matrigel plugs in mice. When systemically injected into mice bearing induced brain tumors, the peptide-conjugate cured most mice.276 CGKRK Peptide-D[KLAKLAK]2-iron oxide nanoworms co-injected with the iRGD peptide into mice with 005 tumors prolonged survival.276 Oligonucleotide Delivery: Baculovirus displaying CGKRK peptide-VSVG protein fusions and carrying the luciferase gene specifically transduced cells in vitro,303 and the CGKRK peptide has been used to transfect cancer cells with a spider silk derived gene carrier.314 Note: Both peptides home to the vasculature of several different tumor types but the CGKRK peptide binds to a broader number of tumor types. |
|
| Melanoma (C8161)i | CLSDGKRKC257 (LSD) (T7 phage, L) | Therapeutic Applications: LSD peptide-D(KLAKLAK)2 conjugate reduced C8161 orthotopic tumor lymphatic vessels in mice. | |
| Melanoma (murine B16-F10)g,i | TRTKLPRLHLQS159 (WDC-2) (pIII, T) | Therapeutic Applications: Phage inhibited B16-F10 tumor growth when injected adjacent to tumor, but the free peptide was not tested. The anti-tumor effect is likely due to infiltration of neutrophils induced by the phage particle. | |
| RIP1-Tag2 mice Pancreatic isletsi | CRGRRST315 (RGR) CRSRKG315 (RSR) CKAAKNK315 (KAA) CKGAKAR315 (KAR) FRVGVADV315 (VGVA) (T7 phage, V/T) |
PDGFRβ is a candidate receptor for RGR peptide |
Therapeutic Applications: Combination treatment with RGR peptide-anti-CD40 antibody and murine IL-2-peptide fusion protein increased survival in RIP1-Tag2 mice. 80% of mice treated with the combination treatment plus adoptive transfers of anti-Tag CD4+ and CD8+ T cells survived long-term.316 Note: KAA and KAR peptides bind to the RIP1-Tag2 tumor vasculature. RSR binds specifically to angiogenic islet vasculature but not to the tumor vasculature. VGVA and RGR bind to both angiogenic and tumor vasculature.315 |
| Dysplastic Colon Mucosa/colon adenomas from CPC;Apc mice | QPIHPNNM317 T7 phage, T) | Imaging applications: FITC-labeled peptide bound adenomas in CPC;Apc mice as viewed by endoscopy317 and microendoscopy.318 | |
| Colorectal (Bevacizumab-treated LS174T) | LLADTTHHRPWT241 (BRP) (h) (pIII, bevacizumab-treated V) | Imaging applications: BRP peptide-IRDye800 conjugate was used for near-infrared imaging of bevacizumab-treated LS174T tumors in mice. PET imaging using a 18F-BRP-peptide detected LS174T tumors in mice treated with bevacizumab.241 | |
| Colorectal (Colon 26 cells orthotopically implanted in BALB/c mice) | CTPSPFSHC319 (TCP-1) (pIII phage, V) |
Therapeutic Applications: The peptide homes to the vasculature of the colon 26 tumor in a mouse but not to normal vasculature. Conjugation of TCP-1 to the proapoptotic peptide D(KLAKLAK)2 conjugate induces apoptosis in the tumor vasculature. Note: The peptide binds to vasculature of resected human colorectal tumors. |
|
| Gliomas (irradiated murine GL261) | GIRLRG320 (h) (T7 phage, irradiated V) | GRP78 |
Therapeutic Applications: Peptide conjugated to a nanoparticle encapsulating paclitaxel inhibits MDA-MB-231 tumor growth in irradiated mice.320 Imaging applications: Peptide-AlexaFluor 750 has been used for near-infrared imaging in mice with irradiated G1261 tumors.320 |
| Hepatocarcinoma (BEL-7402) | AGKGTPSLETTP321 (A54) (pIII, T) | Therapeutic Applications: Peptide-doxorubicin conjugate inhibited tumor growth and increased survival in mice with BEL-7402 tumors.152 | |
| Human Renal Carcinoma Tumor Endothelial Cells | CVGNDNSSC250 (pIII, V) | Therapeutic Applications: Biotinylated peptide conjugated to saporin induced apoptosis in tumor endothelial cells in mice. | |
| Waldenström macro-globulinemia B cell malignancy (from pancreas of a human patient) | CGRRAGGSC77 (pIII, T) | IL-11Rα77,251 |
Therapeutic Applications: A peptide-proapoptotic peptide D(KLAKLAK)2 conjugate induced apoptosis in LNCaP and MDA-PCa-2b prostate cell lines in vitro.152 Imaging applications: 111In-DTPA-IR dye-peptide construct was used for both SPECT/CT and near-infrared imaging in a mouse bearing a MDA-MB-231 tumor.322 |
a
All tumors are human xenografts unless otherwise noted.
b
Cysteine residues that form disulfide bonds are indicated in bold.
c
Common peptide names that have been used in the literature are indicated in parenthesis next to the peptide sequence.
d
The phage display library type is also indicated in parentheses. All phage are filamentous unless noted as T7 phage.
e
T indicates tumor cell targeting, V indicates tumor vasculature targeting, L indicates tumor lymphatics homing, and M indicates tumor associated macrophage homing. ND means it is unclear whether the peptide binds the tumor cells or tumor vasculature.
f
Intravenous injections used for selection unless otherwise indicated.
g
Selection used intraperitoneal injections instead of intravenous injections.
h
Selection used intracardiac injections instead of intravenous injections.
i
Combination of ex vivo/in vivo panning employed.
j
This peptide has been used in numerous other studies not listed.