Nanocarrier-Mediated Targeting of Tumor and Tumor Vascular Cells Improves Uptake and Penetration of Drugs into Neuroblastoma

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor in children, accounting for about 8% of childhood cancers. Despite aggressive treatment, patients suffering from high-risk NB have very poor 5-year overall survival rate, due to relapsed and/or treatment-resistant tumors. A further increase in therapeutic dose intensity is not feasible, because it will lead to prohibitive short-term and long-term toxicities. New approaches with targeted therapies may improve efficacy and decrease toxicity. The use of drug delivery systems allows site specific delivery of higher payload of active agents associated with lower systemic toxicity compared to the use of conventional (“free”) drugs. The possibility of imparting selectivity to the carriers to the cancer foci through the use of a targeting moiety (e.g., a peptide or an antibody) further enhances drug efficacy and safety. We have recently developed two strategies for increasing local concentration of anti-cancer agents, such as CpG-containing oligonucleotides, small interfering RNAs, and chemotherapeutics in NB. For doing that, we have used the monoclonal antibody anti-disialoganglioside (GD2), able to specifically recognize the NB tumor and the peptides containing NGR and CPRECES motifs, that selectively bind to the aminopeptidase N-expressing endothelial and the aminopeptidase A-expressing perivascular tumor cells, respectively. The review will focus on the use of tumor- and tumor vasculature-targeted nanocarriers to improve tumor targeting, uptake, and penetration of drugs in preclinical models of human NB.

Tumor vascular targeted liposomal-bortezomib minimizes side effects and increases therapeutic activity in human neuroblastoma

“…Indeed, the efficacy of the passive targeting was amplified when BTZ-containing SL were directed to CD13-positive tumor vasculature, in accordance with findings showing that (NGR)-containing peptides are ligands for enhancing drug delivery and to alter drug penetration barriers [19,39].…”

Anti-GD2 MABS and Next-Generation mAb-Based Agents for Cancer Therapy

“…Furthermore, anti-GD2 mAbs can be used to impart selectivity to nanoparticle-based carriers which have the potential to load and transport higher amounts of drugs, increase penetration to the tumor and metastatic sites and overcome the limiting pharmacokinetic properties that result in insufficient drug delivery associated with other agents [120]. Different nanoparticle formats that have been bioconjugated with anti-GD2 full size mAbs or Fab fragments include: liposomes, which have small diameter and are able to differentially accumulate and penetrate into solid tumors (with highly permeable capillaries) relative to normal tissue (with less permeable tight junctions) [121][122][123][124]; porous silica nanoparticles, which are inert, biodegradable, nontoxic and more stable due to uniform particle size [125]; gold nanorods and carbon nanotubes capable of absorbing near-infrared laser light leading to in vitro photothermal destruction of tumor cells [126,127].…”

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

“…with ketamine (Imalgene 1000, Merial Italia SpA., Milan, Italy) and xilezine (Xilor 2%, Bio98 Srl, Milan, Italy), subjected to laparotomy, and injected with 1 × 10 6 GI-LI-N or SH-SY5Y, in the capsule of the left adrenal gland, as previously described (9,11,14,15). Mice were monitored at least twice a week for evidence of tumor development and quantification of tumor size, and were sacrificed by cervical dislocation under xilezine, at the appearance of the first signs of poor health, such as abdominal dilation, dehydration, severe weight loss or paraplegia.…”