Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas

Abstract

Glioblastoma is one of the most common primary tumor types of central nervous system (CNS) with high malignance and lethality. Although many treatment options are currently available, the therapy of brain cancers remains challenging because of blood-brain-barrier (BBB) which prevents most of the chemotherapeutics into the CNS. In this work, a poly(amidoamine) dendrimer-based carrier was fabricated and modified with angiopep-2 (Ang2) peptide that has been demonstrated to bind to low density lipoprotein receptor-relative protein-1 (LRP1) on the endothelial cells of BBB and could therefore induce BBB penetration of the carrier. To improve tumor-targeting effect towards the glioma sites, the dendrimer was simultaneously functionalized with an epidermal growth factor receptor (EGFR)-targeting peptide (EP-1) which was screened from a "one-bead one-compound" (OBOC) combinatorial library. EP-1 peptide was demonstrated to have high affinity and specificity to EGFR at both the molecular and cellular levels. The dual-targeting dendrimer exhibited outstanding BBB penetrability and glioma targeting efficiency both in vitro and in vivo, which strikingly enhanced the anti-gliomas effect of the drugs and prolonged the survival of gliomas-bearing mice. These results show the potential of the dual-targeting dendrimer-based carrier in the therapy of gliomas through enhancing BBB penetrability and tumor targeting.

Nanodelivery Systems Targeting Epidermal Growth Factor Receptors for Glioma Management

“…Furthermore, PAMAM was concurrently functionalized with an EGFR-targeting peptide (EP-1) to achieve specificity and improved affinity to target EGFR. The above results showed the potential of the dual drug-loaded PAMAM in the treatment of gliomas by improving BBB penetration and specific EGFR targeting efficiency, both in vitro and in vivo ( Figure 6 ) [ 148 ].…”

“… ( A ) Schematic representation of fabrication of the dual drug loaded polyamidoamine (PAMAM) dendrimers in the treatment of gliomas by improving BBB penetration; ( B ) Assessment of the affinity and specificity of peptide EP-1 toward EGFR; ( C ) In vitro evaluation of biocompatibility and anti-tumor efficacy of the dual drug-loaded PAMAM dendrimers; ( D ) Flow cytometry evaluation for intracellular uptake of different DOX-loaded dendrimers. Reprinted from [ 148 ] Ivyspring International Publisher, 2020. * p < 0.1, ** p < 0.01, *** p < 0.001, **** p < 0.0001 (Student’s t -test).…”

Dendrimers as Modulators of Brain Cells

“…DGL-PEG-T7/DNA NPs showed extraordinary gene silencing activity and dual-targetability to BBB as well as glioma cells expressing TfRs. Unlike such TfR-targeted nanoparticles, the PAMAM dendrimers synthesized by Liu et al simultaneously recruited two different ligands, angiopep-2 (Ang2) and epidermal growth factor receptor (EGFR)-targeting peptide (EP-1), to achieve the dual-targetability [ 104 ]. Ang-2 peptides are specific ligands binding with lipoprotein receptor-relative protein-1 (LRP1) on endothelial cells of BBB.…”

Nanomedicine Revisited: Next Generation Therapies for Brain Cancer

“…[ 80,85,93,99–101 ] Groups have shown that nanoparticles with targeting moieties binding to these ligands exhibit significant increase in specificity and uptake by GBM cells ≈13‐fold (Tf‐R), ≈1.4‐fold (EGFR), ≈3.5‐fold (Fn14), and ≈2.3‐fold (LRP‐1) when compared to controls without the moiety. [ 85,99–101 ] It is important to note that this variation between targeting ligands may be due to the preclinical model used and mode of nanoparticle delivery (systemic vs local), but regardless, improved targeting is evident and can be further optimized with combinations of moieties. Nanoparticle systems have also been designed that respond to environmental conditions such as pH and the presence of certain enzymes that are unique to the tumor microenvironment.…”