Transtumoral targeting enabled by a novel neuropilin-binding peptide

Abstract

We have recently described a class of peptides that improve drug delivery by increasing penetration of drugs into solid tumors. These peptides contain a C-terminal Cend Rule (CendR) sequence motif (R/K)XX(R/K), which is responsible for cell internalization and tissue-penetration activity. Tumor-specific CendR peptides contain both a tumor-homing motif and a cryptic CendR motif that is proteolytically unmasked in tumor tissue. A previously described cyclic tumor-homing peptide, LyP-1 (sequence: CGNKRTRGC), contains a CendR element and is capable of tissue penetration. We use here the truncated form of LyP-1, in which the CendR motif is exposed (CGNKRTR; tLyP-1), and show that both LyP-1 and tLyP-1 internalize into cells through the neuropilin-1-dependent CendR internalization pathway. Moreover, we show that neuropilin-2 also binds tLyP-1 and that this binding equally activates the CendR pathway. Fluorescein-labeled tLyP-1 peptide and tLyP-1-conjugated nanoparticles show robust and selective homing to tumors, penetrating from the blood vessels into the tumor parenchyma. The truncated peptide is more potent in this regard than the parent peptide LyP-1. tLyP-1 furthermore improves extravasation of a co-injected nanoparticle into the tumor tissue. These properties make tLyP-1 a promising tool for targeted delivery of therapeutic and diagnostic agents to breast cancers and perhaps other types of tumors.

Single peptide ligand-functionalized uniform hollow mesoporous silica nanoparticles achieving dual-targeting drug delivery to tumor cells and angiogenic blood vessel cells

“…expressed, were used as the models of tumor cells and tumor neovascular endothelial cells, respectively. 20,22,23,47,48 Low cytotoxicity of the carrier itself is a primary concern in the development of a drug delivery system. Figure 6A and B shows the viability of MDA-MB-231 cells and HUVECs incubated with HMSN, pHMSN, or tHMSN for 48 hours (as determined by CCK-8 assay).…”

“…On the basis of the results for cellular uptake and cytotoxicity of the drug-loaded nanoparticles, it can be concluded that tHMSN could enhance endocytosis of cargoes and thereby mediating more robust cytotoxicity compared with pHMSN. Meanwhile, given the overexpression of NRP in many tumor cells and angiogenic blood vessel cells, [18][19][20] such an ability should have a degree of selectivity and dualtargeting performance.…”

“…Thus, NRP is a potential therapeutic target for dual-targeted anti-mammary drug delivery. tLyp-1 (sequence CGNKRTR), 20,21 a newly reported heptapeptide which are screened by phage display library, is a ligand which is selectively targeted both to NRP1 and NRP2. Therefore, tLyp-1-decorated nanoparticles may be expected to have dual-targeting functions, and previous studies 22,23 have shown that such polymer nanoparticles have precise dual-targeting efficacy and penetrate extensively into tumor parenchyma.…”

Hybrid Nanotechnologies for Detection and Synergistic Therapies for Breast Cancer

“…We have identified a peptide in our panel of tumor-homing peptides that specifically recognizes the fibroblasts that reside in early premalignant breast lesions. This peptide, iRGD, is prototype compound among the tumor-penetrating peptides we have described recently Roth et al, 2012;Alberici et al, 2012). Systemically injected iRGD homes to individual cells around the premalignant PyMT glands (Fig.…”

Gold nanorods/mesoporous silica-based nanocomposite as theranostic agents for targeting near-infrared imaging and photothermal therapy induced with laser

“…In such nanostructure (Figure 1), tLyp-1, a newly reported tumor-homing heptapeptide, 44 acted as a ligand selectively targeted to neuropilin protein (a membranous receptor that was overexpressed in many types of tumor cells 45 ) on the cell surface and thus succeeded in achieving active targeting and ligand-mediated endocytosis. Second, mesoporous silica, a porous nanostructural biomaterial that allows for high drug loading capacity and attachment of different functional groups, was introduced to protect and shield the GNRs against their self-aggregation as well as be loaded with imaging agent and be decorated with functional peptide.…”