Community Research and Development Information Service - CORDIS

FP7

NANORESISTANCE Result In Brief

Project ID: 286125
Funded under: FP7-PEOPLE
Country: Cyprus

Theranostic nanoparticles to overcome drug resistance in cancer

Theranostics, a combination of diagnosis and therapy, can affect treatment or the disease state. European researchers used theranostic nanoparticles to deliver anti-cancer drugs directly into the cell and overcome resistance issues.
Theranostic nanoparticles to overcome drug resistance in cancer
Epidermal growth factor receptor (EGFR) is a member of the protein kinase superfamily and constitutes one of the mostly studied and validated cancer biomarkers. EGFR mutations occur in many cancers including lung adenocarcinomas and glioblastoma, and tyrosine kinase (TK) inhibitors have provided a successful intervention. However, EGFR-targeted therapies eventually develop acquired resistance documented by either aberrant expression or nuclear translocation of phosphorylated active EGFR, indicating the need for alternative approaches to circumvent this resistance.

To address this challenge, scientists on the EU-funded NANORESISTANCE (Management of resistance to tyrosine kinase inhibitors with advanced nanosystems) project used nanosystem-based delivery platforms for the intracellular delivery of fluorescent conjugates of TK inhibitors. As a first step, the consortium synthesised de novo a library of functionalised, target-specific, anilinoquinazoline based tyrosine kinase inhibitors for mutant, aberrantly expressed and activated EGFR. Aniliniquinazolines were selected for their capacity to interact with the active site of the kinase and effectively inhibit their activation. Anilinoquinazolines with superior inhibiting activity were conjugated to carbon nanotubes (CNT).

The approach exhibited high affinity, avidity and specificity for EGFR and delivery in the cytosol occurred independently of receptor-mediated uptake. The delivery was screened in vitro in TK inhibitor-resistant cells and in orthotopic mouse models with glioblastoma, the most aggressive form of brain tumor. Drug delivery by this approach induced apoptosis both in vitro and vivo followed by prolonged animal survival and improvement of neurological signs.

As an alternative approach to overcoming resistance, scientists tested nuclear delivery using new magnetic silica core-shell nanoparticles functionalised with the drug. To screen the functionality of nanoparticles in vitro, the consortium developed a chip biosensor analysis method using surface plasmon resonance (SPR) and cellular imaging. This enabled them to study the interaction of nanoparticles with proteins or other biological targets.

Innovative mathematical models and advanced image processing algorithms enabled scientists to predict the biodistribution and assess the release kinetics of nanoparticle-conjugated drugs. Notably, they found that the nanoparticles were preferentially delivered to the tumor peripheral zone, the tumor area which is responsible for disease progression and metastasis. This area is protected by the so-called blood-brain-barrier and free anilinoquinazoline drugs cannot, otherwise, be delivered.

Overall, the NANORESISTANCE theranostic approach promises to achieve effective targeted therapies by circumventing mechanisms of resistance, delivering the drugs to tumor sites inaccessible to free drugs and ultimately using lower amounts of the indicated therapeutic agents. This is expected to minimise possible side effects and improve disease course as well as cancer patient survival. Watch the project’s video here.

Related information

Keywords

Nanoparticles, drug resistance, cancer, EGFR, tyrosine kinase, inhibitor, aniliniquinazolines, carbon nanotubes
Record Number: 190530 / Last updated on: 2016-11-10
Domain: Biology, Medicine