Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells

Laakkonen, Pirjo; Åkerman, Maria E.; Biliran, Hector; Yang, Meng; Ferrer, Fernando; Kärpänen, Terhi; Hoffman, Robert M.; Ruoslahti, Erkki

doi:10.1073/pnas.0403317101

Cited by 253 publications

(269 citation statements)

References 19 publications

(28 reference statements)

Supporting

Mentioning

258

Contrasting

Unclassified

Order By: Relevance

“…The increased cytotoxicity of LyP1LPs toward heattreated cells is ascribed to a combination of hyperthermal chemotherapy and targeting to (upregulated) receptor proteins. Although it was reported that LyP-1 peptide itself has a therapeutic effect (22), the peptide amount on the particles is much less than was needed for the antitumor activity. By contrast, the heatinduced cytotoxicity of LyP1LPs toward C8161 melanoma cells was significantly less pronounced; this is attributed to lower levels of expression of p32 on the C8161 cellular surface and higher resistance to DOX, relative to MDA-MB-435 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The LyP-1 peptide has been reported to selectively recognize lymphatics and tumor cells in certain tumor types and subsequently inhibit tumor growth (21,22). Recently, it was found that the p32 or gC1qR receptor, whose expression is elevated on the surface of tumor-associated cells undergoing stress, is the target molecule for the LyP-1pep-tide (23).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Cooperative nanomaterial system to sensitize, target, and treat tumors

Park

Maltzahn²,

Xu³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

287

232

View full text Add to dashboard Cite

A significant barrier to the clinical translation of systemically administered therapeutic nanoparticles is their tendency to be removed from circulation by the mononuclear phagocyte system. The addition of a targeting ligand that selectively interacts with cancer cells can improve the therapeutic efficacy of nanomaterials, although these systems have met with only limited success. Here, we present a cooperative nanosystem consisting of two discrete nanomaterials. The first component is gold nanorod (NR) "activators" that populate the porous tumor vessels and act as photothermal antennas to specify tumor heating via remote near-infrared laser irradiation. We find that local tumor heating accelerates the recruitment of the second component: a targeted nanoparticle consisting of either magnetic nanoworms (NW) or doxorubicinloaded liposomes (LP). The targeting species employed in this work is a cyclic nine-amino acid peptide LyP-1 (Cys-Gly-Asn-Lys-Arg-ThrArg-Gly-Cys) that binds to the stress-related protein, p32, which we find to be upregulated on the surface of tumor-associated cells upon thermal treatment. Mice containing xenografted MDA-MB-435 tumors that are treated with the combined NR/LyP-1LP therapeutic system display significant reductions in tumor volume compared with individual nanoparticles or untargeted cooperative system. cancer therapy | gold nanorods | liposomes | magnetic nanoworms | protein expression

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Cooperative nanomaterial system to sensitize, target, and treat tumors

Park

Maltzahn²,

Xu³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

287

232

View full text Add to dashboard Cite

show abstract

“…Imaging under a blue light and examination of the distribution of f luoresceinconjugated peptides after tail vein injection have been described (24,25).…”

Section: Methodsmentioning

confidence: 99%

Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds

Pilch

Brown

Komatsu

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

145

122

View full text Add to dashboard Cite

Screening of a phage library for peptides that bind to clotted plasma in the presence of liquid plasma yielded two cyclic decapeptides, CGLIIQKNEC (CLT1) and CNAGESSKNC (CLT2). When injected intravenously into mice bearing various types of tumors, fluorescein-conjugated CLT peptides accumulated in a fibrillar meshwork in the extracellular compartment of the tumors, but were not detectable in other tissues of the tumor-bearing mice. The tumor homing of both peptides was strongly reduced after coinjection with unlabeled CLT2, indicating that the two peptides recognize the same binding site. The CLT peptide fluorescence colocalized with staining for fibrin(ogen) present in the extravascular compartment of tumors, but not in other tissues. The CLT peptides did not home to tumors grown in fibrinogen-null mice or in mice that lack plasma fibronectin. The CLT peptides also accumulated at the sites of injury in arteries, skeletal muscle, and skin. We conclude that the CLT peptides recognize fibrin-fibronectin complexes formed by clotting of plasma proteins that have leaked into the extravascular space in tumors and other lesions. These peptides may be useful in targeting diagnostic and therapeutic materials into tumors and injured tissues.fibronectin ͉ imaging ͉ phage display ͉ tumor targeting ͉ fibrin

show abstract

“…Directing therapeutic agents to tumor cells, tumor blood vessels or tumor lymphatic vasculature is likely to enhance the efficacy of anti-cancer drugs and decrease side effects (1). Different strategies have been pursued to achieve this goal, among which 'homing' peptides are promising alternatives because they bind to surface molecules specific to the tumor, and tumor endothelial and tumor lymphatic cells (2)(3)(4), but are smaller than other agents such as antibody fragments, which allow them to easily penetrate tumor tissues. A prominent example for homing peptides is an Arg-Gly-Asp (RGD) sequence that was selected by using phage-display peptides to target tumors, focusing on targeting ·(v) integrins in tumor blood vessels (5).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro

Yang

Li²,

Wang³

et al. 2006

Oncol Rep

View full text Add to dashboard Cite

Abstract. The Arg-Gly-Asp (RGD) sequence was selected by using phage-display peptides to target tumors, focusing on targeting ·(v) integrins in tumor blood vessels. Recent studies suggest that peptides containing the RGD sequence can bind to tumor cells, as well as tumor endothelial cells. To investigate whether the RGD peptide has other effects on tumor cells expressing ·(v) integrins, besides its tumor targeting capability, we designed and synthesized a 10-amino peptide that contained the RGD sequence in a cyclic conformation with a disulfide bond, which specifically bound to breast cancer cell lines MDA-MB-231 and MCF-7. We found that this RGD peptide, GCGGRGDGGC, inhibited tumor cell proliferation in a dosedependent manner, and also induced apoptosis and G1-phase cell cycle arrest in both of the cell lines that bound and internalized the peptide. Normal ovarian epithelial cells, which did not bind the RGD peptide, were unaffected. RGD peptide treatment also reduced cell invasiveness in both cell lines in vitro. This study suggests that the RGD peptide not only possesses tumor targeting capacity, but also has direct tumor cytotoxic and invasiveness inhibition effects dependent on the blockage of ·(v) integrin activity, which would make it more efficient in tumor targeting therapy. IntroductionTargeting agents specifically to tumors and their metastases is a central challenge in improving existing cancer detection and therapy. Directing therapeutic agents to tumor cells, tumor blood vessels or tumor lymphatic vasculature is likely to enhance the efficacy of anti-cancer drugs and decrease side effects (1). Different strategies have been pursued to achieve this goal, among which 'homing' peptides are promising alternatives because they bind to surface molecules specific to the tumor, and tumor endothelial and tumor lymphatic cells (2-4), but are smaller than other agents such as antibody fragments, which allow them to easily penetrate tumor tissues. A prominent example for homing peptides is an Arg-Gly-Asp (RGD) sequence that was selected by using phage-display peptides to target tumors, focusing on targeting ·(v) integrins in tumor blood vessels (5). The RGD motif is present in many extracellular matrix components, such as fibronectin and vitronectin, and binds to integrins. Peptides containing the RGD sequence are commonly employed in tumor imaging (6,7) and tumor targeting therapy while coupled with therapeutic agents such as radionucleotides (8,9) and chemotherapeutic drugs (10,11).The RGD-peptide receptor-·(v) integrins are also expressed on the surface of many kinds of tumor cells. Studies indicate that the RGD sequence can bind not only to tumor endothelial cells, but also to tumor cells in vivo (3,12). And in vitro, the RGD peptide can be internalized by tumor cells (13). It is known that ·(v) integrins can mediate adhesion and migration in some tumor cell lines (13) and regulate cell proliferation and survival (14). However, whether the RGD peptide has any direct anti-tumor effects on tumor cells expr...

show abstract

Antitumor activity of a homing peptide that targets tumor lymphatics and tumor cells

Cited by 253 publications

References 19 publications

Cooperative nanomaterial system to sensitize, target, and treat tumors

Cooperative nanomaterial system to sensitize, target, and treat tumors

Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds

Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro

Contact Info

Product

Resources

About