A Novel Blood-Brain Barrier-Penetrating and Vascular-Targeting Chimeric Peptide Inhibits Glioma Angiogenesis.

The high vascularization of glioma highlights the potential value of anti-angiogenic therapeutics for glioma treatment. Previously, we designed a novel vascular-targeting and blood-brain barrier (BBB)-penetrating peptide, TAT-AT7, by attaching the cell-penetrating peptide TAT to a vascular-targeting peptide AT7, and we demonstrated that TAT-AT7 could target binding to the vascular endothelial growth factor receptor 2 (VEGFR-2) and Neuropilin-1 (NRP-1), which are both highly expressed in endothelial cells. TAT-AT7 has been proven to be a good targeting peptide which could effectively deliver the secretory endostatin gene to treat glioma via the TAT-AT7-modified polyethyleneimine (PEI) nanocomplex. In the current study, we further explored the molecular binding mechanisms of TAT-AT7 to VEGFR-2 and NRP-1 and its anti-glioma effects. Accordingly, TAT-AT7 was proven to competitively bind to VEGFR-2 and NRP-1 and prevent VEGF-A165 binding to the receptors by the surface plasmon resonance (SPR) assay. TAT-AT7 inhibited endothelial cells' proliferation, migration, invasion, and tubule formation, as well as promoted endothelial cells' apoptosis in vitro. Further research revealed that TAT-AT7 inhibited the phosphorylation of VEGFR-2 and its downstream PLC-γ, ERK1/2, SRC, AKT, and FAK kinases. Additionally, TAT-AT7 significantly inhibited angiogenesis of zebrafish embryo. Moreover, TAT-AT7 had a better penetrating ability and could penetrate the BBB into glioma tissue and target glioma neovascularization in an orthotopic U87-glioma-bearing nude mice model, and exhibited the effect of inhibiting glioma growth and angiogenesis. Taken together, the binding and function mechanisms of TAT-AT7 were firstly revealed, and TAT-AT7 was proven to be an effective and promising peptide for the development of anti-angiogenic drugs for targeted treatment of glioma.

Transcytosable Peptide-Paclitaxel Prodrug Nanoparticle for Targeted Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.

Amphiphilic self-assembly peptides: Rational strategies to design and delivery for drugs in biomedical applications.

Amphiphilic self-assembling peptides are widely used in tissue and cell engineering, antimicrobials, drug-delivery systems and other biomedical fields due to their good biocompatibility, functionality, flexibility of design and synthesis, and tremendous potential as delivery carriers for drugs. Currently, the design and study of amphipathic peptides by a bottom-up method to develop new biomedical materials have become a hot topic. However, defined rules have not been established for the design and development of self-assembled peptides. Therefore, the focus of this review is to summarize and provide several rational strategies for the design and study of amphiphilic self-assembly peptides. In addition, this paper also describes the types and general self-assembling mechanism of amphipathic peptides, and outlines their applications in the delivery of hydrophobic drugs, nucleic acid drugs, peptide drugs and vaccines. Amphiphilic self-assembled peptides are expected to exploit new functional materials for drug delivery and other applications.

Design and screening of a novel neuropilin-1 targeted penetrating peptide for anti-angiogenic therapy in glioma.

AIMS: This study aimed to design and screen a dual functional fusion peptide that could penetrate the blood-brain barrier and target neuropilin 1 (NRP1) overexpressed in vascular endothelial cells for the anti-angiogenesis of glioma treatment. MAIN METHODS: At the cellular level, the in vitro anti-angiogenic activity of six NRP1 targeting peptides was screened by testing the ability to inhibit the proliferation and tube formation of HUVECs. Then, the in vitro anti-angiogenic activity of two fusion peptides containing different linkers was screened by testing the ability to inhibit HUVECs proliferation, tube formation and migration. The effect of fusion peptide on VEGFR2 related signal pathway was confirmed by Western-blotting. Surface plasmon resonance technology was used to detect the affinity of the fusion peptide to NRP1. The ability of FITC-labeled peptides to penetrate cells was confirmed by cell uptake assay. By establishing an orthotopic glioma model, we evaluated the ability of FITC-labeled peptides to penetrate the blood-brain barrier and their anti-glioma growth activity in vivo. KEY FINDINGS: We found that NRP1 targeting peptide RP7 and linker cysteine were the most suitable key components in the fusion peptide. We also found that the fusion peptide Tat-C-RP7 we constructed had the strongest ability to penetrate the blood-brain barrier and anti-angiogenic activity in vitro and in vivo. SIGNIFICANCE: At present, NRP1 targeting peptide as a drug delivery tool and molecular probe seems to have received more attention. We constructed a fusion peptide Tat-C-RP7 with strong anti-angiogenic activity for the treatment of glioma.