Neuroblastoma-targeted nanocarriers improve drug delivery and penetration, delay tumor growth and abrogate metastatic diffusion

Abstract

Selective tumor targeting is expected to enhance drug delivery and to decrease toxicity, resulting in an improved therapeutic index. We have recently identified the HSYWLRS peptide sequence as a specific ligand for aggressive neuroblastoma, a childhood tumor mostly refractory to current therapies. Here we validated the specific binding of HSYWLRS to neuroblastoma cell suspensions obtained either from cell lines, animal models, or Schwannian-stroma poor, stage IV neuroblastoma patients. Binding of the biotinylated peptide and of HSYWLRS-functionalized fluorescent quantum dots or liposomal nanoparticles was dose-dependent and inhibited by an excess of free peptide. In animal models obtained by the orthotopic implant of either MYCN-amplified or MYCN single copy human neuroblastoma cell lines, treatment with HSYWLRS-targeted, doxorubicin-loaded Stealth Liposomes increased tumor vascular permeability and perfusion, enhancing tumor penetration of the drug. This formulation proved to exert a potent antitumor efficacy, as evaluated by bioluminescence imaging and micro-PET, leading to (i) delay of tumor growth paralleled by decreased tumor glucose consumption, and (ii) abrogation of metastatic spreading, accompanied by absence of systemic toxicity and significant increase in the animal life span. Our findings are functional to the design of targeted nanocarriers with potentiated therapeutic efficacy towards the clinical translation.

Graphene Oxide Nanoribbons Induce Autophagic Vacuoles in Neuroblastoma Cell Lines

“…The two different cell lines reported in the present study show different tumorigenicity, the SK-N-BE(2) cell line is less differentiated and has MYC-N amplification. One possible therapeutic approach would be to enhance growth suppressor genes and to suppress growth of undifferentiated cells [7,8]. New immune therapies targeting infiltrating macrophages, which seem to promote tumor growth and resistance to therapy, are developed in neuroblastoma [9].…”

Enhancement of Tumor Homing by Chemotherapy‐Loaded Nanoparticles

“…The N‐terminus of the YSHSHSYWLRSGGGC, an NB‐targeting peptide previously identified (reported here as “pep”), was fused to C‐terminus of CRALK (CRALKYSHSHSYWLRSGGG, called TP), a peptide containing the Cend‐Rule motif expected to bind NRP‐1 after cleavage and promote cell and tissue penetration (TP). Thus, according to the Cend‐Rule mechanism, this novel peptide is expected to bind NRP‐1 only after cleavage at the lysine residue, but not in his intact form.…”

“…The receptor for this motif was demonstrated to be neuropilin‐1 (NRP‐1), an important co‐receptor for an isoform of vascular endothelial growth factor upregulated in pathological angiogenesis and solid tumors . Recently, by applying a multidisciplinary, high‐throughput proteomic approach, we reported the identification and characterization of novel tumor targeting/tumor homing peptides specific for cells present in high‐risk neuroblastoma (NB), the most common extracranial solid tumor in children . Moreover, one of the most promising ligands, reporting a peptide sequence similarity with a conserved portion of the pentraxin domain involved in the homo‐ and hetero‐oligomerization of neuronal pentraxin‐2 (NPTX2) and its receptor (NPTXR), was deeply validated for its capability to actively target tumor cells in animal models of human NB .…”

“…Recently, by applying a multidisciplinary, high‐throughput proteomic approach, we reported the identification and characterization of novel tumor targeting/tumor homing peptides specific for cells present in high‐risk neuroblastoma (NB), the most common extracranial solid tumor in children . Moreover, one of the most promising ligands, reporting a peptide sequence similarity with a conserved portion of the pentraxin domain involved in the homo‐ and hetero‐oligomerization of neuronal pentraxin‐2 (NPTX2) and its receptor (NPTXR), was deeply validated for its capability to actively target tumor cells in animal models of human NB . In the attempt to further increase drug delivery and penetration in tumor tissues, we have modified this peptide by adding a consensus motif capable of recognizing NRP‐1, taking advantage from the fact that this receptor is upregulated also in NB .…”

Ligand-targeted theranostic nanomedicines against cancer

“…Additionally, depending on receptor location, i.e., tumor vs. tumor endothelial cells, internalization of nanomedicines will minimize or maximize, respectively, their distribution within the tumor via the bystander effect [31]. Off-target effects are minimized by using targeted liposomes loaded with doxorubicin to treat neuroblastoma [32–35]. Targeting liposomal doxorubicin to cultured human breast cancer or pancreatic adenocarcinoma cells was improved by inserting different targeting peptides purified as fusion proteins of the bacteriophage pVIII major coat proteins [36].…”