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Design of nano-formulations to transport anti-cancer drugs

Cesare Gabriele Gaglio

Design of nano-formulations to transport anti-cancer drugs.

Rel. Gianluca Ciardelli, Jacek Adam Tuszynski, Clara Mattu. Politecnico di Torino, Corso di laurea magistrale in Ingegneria Biomedica, 2022

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Microtubules-targeting agents (MTAs) are an attractive class of compounds that has been broadly used in cancer treatment since the 1960s. Their main mechanism of action is based on their interaction with microtubules, one of the principal components of the cell cytoskeleton, blocking cell division at the mitotic phase. The main issues with the use of MTAs are their scarce selectivity, as microtubules are present in all cells, and the multi-drug resistance (MDR) of cancer cells. The ideal MTA should selectively attack cancer cells and elude multi-drug resistance mechanisms. Selectivity can be achieved by targeting tubulin isotypes that are overexpressed in tumor tissues, while MDR can be eluded by avoiding interaction between the drug and transmembrane efflux pumps such as P-gp. Colchicine is an alkaloid compound that received FDA approval for the treatment of the symptoms of gout and Familial Mediterranean Fever in 2009. However, other off-label uses have been reported and its use as anti-cancer compound has been investigated. Unlike taxanes and vinca alkaloids, Colchicine is capable of eluding one mechanism of resistance in cancer cells; indeed, its efficacy is not reduced by the overexpression of βIII-tubulin that is commonly found in cancer cells. Unfortunately, the use of colchicine is hindered by its high toxicity and poor bioavailability. When administered orally, colchicine has been associated with gastrointestinal side effects in most patients, while intravenous administration can cause more severe side effects, such as tissue necrosis, intravascular coagulation and even death. For this reason, the latter administration route has been banned in 2008 by FDA. To overcome the limitations imposed by the high toxicity and poor solubility of the compound, several colchicine-derivatives have been proposed. Among these, CCI-001, a novel colchicine derivative, developed, synthesized and patented by Professor Tuszynski et al. from the University of Alberta, Canada, has demonstrated promising results in cancer treatment. CCI-001 presents a greater affinity for β-III tubulin, which is overexpressed in many tumors and silenced in healthy cells. CCI-001 outperformed other state-of-the-art drugs in in vitro studies and showed promising results in in vivo studies. A clinical trial on CCI-001 is currently ongoing. Unfortunately, CCI-001 is highly hydrophobic, resulting in low absorption rate and difficult administration. Therefore, new delivery systems are needed to improve the biodistribution of this drug while maintaining its high efficacy against cancer cells. The aim of this work was to develop an effective nanoformulation for CCI-001 made of shell-core pegylated nanoparticles (NPs), with a polymeric core and a lipidic shell. The NPs were obtained by nanoprecipitation, using different polymers, PLGA and NHSC2000, a proprietary polyurethane. Yield, particle size, zeta potential, morphology and drug entrapment efficacy were first assessed, showing that nanoparticles possess a small size, narrow size distribution and stability in aqueous solution at 4°C for up to a week. NHSC2000 NPs showed a significantly higher EE% of 6% compared to that of PLGA (1%). In vitro studies on U87 cells demonstrated good cytotoxicity of drug-loaded NPs, while empty carriers did not significantly affect cell viability. Overall, our results showed that nanoformulations of CCI-001 can be obtained with high loading efficacy without altering the anti-cancer effect of the drug, warranting their further investigation.

Relators: Gianluca Ciardelli, Jacek Adam Tuszynski, Clara Mattu
Academic year: 2021/22
Publication type: Electronic
Number of Pages: 59
Corso di laurea: Corso di laurea magistrale in Ingegneria Biomedica
Classe di laurea: New organization > Master science > LM-21 - BIOMEDICAL ENGINEERING
Aziende collaboratrici: Politecnico di Torino
URI: http://webthesis.biblio.polito.it/id/eprint/23804
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