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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - NinZA (Theranostic molecular zipper based switchable nanomedicine for overcoming drug resistance)

Teaser

Summary

Why drug resistance is important?
Resistance to drugs is a major challenge that significantly reduces therapeutic efficacy, induces recurrence of disease and generates cross-resistance to a wide spectrum of drugs, resulting in multidrug resistance (MDR). The most recent threat is the extreme case known as extensive drug resistance (XDR). This is an even more ominous condition that can appear as a â€˜Diagnose for Deathâ€™, if the resistance remains unsolved.

What is the problem?
Among others, unintentional exposure to drugs to normal healthy cells and tissues at sub-threshold dose help them to become resistant to a broad range of drugs. The steady rise in the number and types of drug resistance has increased suffering, therapeutic expense, organ disability and death. Drug resistance phenomena is not restricted to the disease host cells only. In Europe, patients with HIV show even more alarming figure where one in ten HIV case is drug-resistant. From the molecular point of view, a single signalling pathway does not govern MDR. Rather, it is a complex phenomenon with various defence mechanisms that collectively defuse the drug actions including pumping out the drug from the cells. Huge efforts have been made to stop such drug efflux pump but their translation into clinics failed due to high toxicity, lack of specificity, limited efficacy and their ability to alter pharmacokinetic and bio-distribution profiles of the actual parent drugs. Thus a fresh therapeutic protocol is required, which can be custom-tuned to individual resistance type.

Overall objectives of the project
During this fellowship I aimed to develop a novel class of biomimetic remotely responding theranostic (combined diagnosis and therapeutic) molecular â€œzipperâ€ enabled nanoarchitectures that can respond to stop the drug resistance mechanisms.
I sought to develop nanosystems that are biocompatible, immunologically safe, and compatible to blood and will allow to design its surface with cargo drugs. I envisaged a zipper like molecular architecture using polymeric donor and respective acceptor branches to insulate the cargo drugs, nucleic acids while transported.
I intended to test the NinZA module with a three dimensional multi-cellular spheroid model for a comparative study on the cells resistance to drug response on a real time basis. Thus the nano-architecture platform will probe drug resistance through a controllable on/off switchable model. Furthermore, I sought a series of complementary career skills training that will enhance my research management, leadership, and presentation and teaching skills and make me an exciting EU candidate with translational research goals. This Fellowship helped to gain new scientific and career skills to position me to become a leading independent academic in the interface of chemistry and biology for translational Nanomedicine.

Work performed

We have developed integrated systems combining molecular targeting, diagnostics and therapeutics system that is emerging as a future theranostic (combined diagnosis and therapy) medicine to overcome drug resistance. These comprise of complement-safe and blood compatible gold and iron based nanosystems that are biocompatible. We have developed strategies to functionalise multi-armed polyethylene glycol to improve stealth effect with increased circulation time to prevent opsonisation and to enhance therapeutic index. During the Fellowship, I have developed small peptides that can form a zipper like molecular architecture to hide the drug molecules and stop unintentional exposure during transportation. A 3D drug resistance cancer spheroid model system has been developed and tested to overcome drug resistance using such a nanosystem. The developed nanosystems are visible to magnetic resonance imaging and terahertz spectroscopy and thus enabling them to be used for deep tissue imaging for successful non-invasive real time theranostics.

WP1: Synthesis of SPION based zipper-enabled nano-architectures:
We have synthesised ultra-small gold nanoparticle and super paramagnetic iron oxide nanoparticles (SPIONs) size below 10nm. These nanoparticles are biocompatible and complement-safe. The surface has been modified with a new type of multi-armed polymer linkers to achieve high capacity loading of drugs/protein and to give stealth properties.

WP2: Characterization and Optimization of zip-unzip mechanism:
We have developed polymer and peptide based biocompatible molecules that are useful for making a molecular architecture responsive to pH, ionic strength and temperature. We have also developed small peptide based molecules that can be anchored to nanoparticles and sensitive to enzymes those are usually over expressed during inflammation and cancer.

WP3: Targeting MDR and real time activity assessment:
The NinZA module is optimised to hold different drugs and targeting units simultaneously to target MDR. These NinZA particles have very high colloidal stability and a comparative flocculation test has been done to prove this. We have developed a tumour 2D and 3D spheroid model to target with NinZA specifically working for MDR. We have developed the platform for real time monitoring of the drug efflux pump.

WP4: Overcoming MDR: Resistance cell response and fate
We evaluated drug resistance profiles of multicellular spheroids treated with chemotherapeutic agents inside NinZA. Our strategy could be clinically applicable for the profiling of drug resistance in pre-treated post diagnosed cancer cells with unknown resistance profiles. We have further developed a nanoscale coacervate with a biocompatible amino acids grafted polymer that can form complexes with cationic polyelectrolytes. Doxorubicin sequestered with the coacervate via pi-pi interaction. The degree of ionization and zipper-like chain conformation of the polymers change with pH. The developed NinZA coacervate has shown to largely decrease the IC50 of against drug sensitive, moderately drug-resistant, and drug-resistant model described in WP3.

Final results

This is first time we have focused on nanosystems that are immune compatible. We are also building the concept and designing molecules which can conceal and hide the drugs during transportation to the disease site. A multicellular drug resistant spheroid model has been developed to study drug resistance along with real time monitoring of drug efflux and retention by drug resistant and drug sensitive cells. The present project will contribute strongly to capacity and capability building in EU to join the fight against drug resistance.
The collateral damages caused by stronger drugs to overcome MDR, immensely impact on the socio-economic structure on the family and the healthcare system. The proposed strategy and outcomes at the global platform will create broad awareness as-well-as will open up new therapeutic solutions to the problem. The initial impact of this project lead us to develop long-term strategies with a core group of scientists who can potentially focus on how to overcome drug resistance. The results of this project helped us to win two international grants: a Scheme for Promotion of Academic and Research Collaboration (SPARC) grant on nanotechnology based strategies to combat antimicrobial resistance with India, and a seed grant to develop nano-vaccines with Sweden and to establish a research fellowship between Cambridge and University of Zhejiang in China.